Innovative approaches to bipolar disorder and its treatment

Ann N Y Acad Sci. 2016 Feb; 1366(1): 76–89.

Section Editor: Daniel H. Geschwind
¹

,
^1
,
2
,
^1
,
2
,
^1
,
2
,
^1
,
2
,
3
,
^1
,
2
,
^1
,
2
and
^1
,
2

Paul J. Harrison

¹Department of Psychiatry, University of Oxford, Oxford, United Kingdom

²Oxford Health NHS Foundation Trust, Oxford, United Kingdom

Andrea Cipriani

¹Department of Psychiatry, University of Oxford, Oxford, United Kingdom

²Oxford Health NHS Foundation Trust, Oxford, United Kingdom

Catherine J. Harmer

¹Department of Psychiatry, University of Oxford, Oxford, United Kingdom

²Oxford Health NHS Foundation Trust, Oxford, United Kingdom

Anna C.

Nobre

¹Department of Psychiatry, University of Oxford, Oxford, United Kingdom

²Oxford Health NHS Foundation Trust, Oxford, United Kingdom

³Oxford Centre for Human Brain Activity, Warneford Hospital, Oxford, United Kingdom

Kate Saunders

¹Department of Psychiatry, University of Oxford, Oxford, United Kingdom

²Oxford Health NHS Foundation Trust, Oxford, United Kingdom

Guy M. Goodwin

¹Department of Psychiatry, University of Oxford, Oxford, United Kingdom

²Oxford Health NHS Foundation Trust, Oxford, United Kingdom

John R. Geddes

¹Department of Psychiatry, University of Oxford, Oxford, United Kingdom

²Oxford Health NHS Foundation Trust, Oxford, United Kingdom

¹David Geffen School of Medicine, University of California, Los Angeles

¹Department of Psychiatry, University of Oxford, Oxford, United Kingdom

²Oxford Health NHS Foundation Trust, Oxford, United Kingdom

³Oxford Centre for Human Brain Activity, Warneford Hospital, Oxford, United Kingdom

Corresponding author. ^*Address for correspondence: Paul J. Harrison, University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK. [email protected]

Received 2015 Dec 23; Revised 2016 Feb 25; Accepted 2016 Mar 1.

Copyright © 2016 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.This article has been cited by other articles in PMC.

Abstract

All psychiatric disorders have suffered from a dearth of truly novel pharmacological interventions. In bipolar disorder, lithium remains a mainstay of treatment, six decades since its effects were serendipitously discovered. The lack of progress reflects several factors, including ignorance of the disorder’s pathophysiology and the complexities of the clinical phenotype. After reviewing the current status, we discuss some ways forward. First, we highlight the need for a richer characterization of the clinical profile, facilitated by novel devices and new forms of data capture and analysis; such data are already promoting a reevaluation of the phenotype, with an emphasis on mood instability rather than on discrete clinical episodes. Second, experimental medicine can provide early indications of target engagement and therapeutic response, reducing the time, cost, and risk involved in evaluating potential mood stabilizers. Third, genomic data can inform target identification and validation, such as the increasing evidence for involvement of calcium channel genes in bipolar disorder. Finally, new methods and models relevant to bipolar disorder, including stem cells and genetically modified mice, are being used to study key pathways and drug effects. A combination of these approaches has real potential to break the impasse and deliver genuinely new treatments.

Keywords: bipolar disorder, clinical, genetics, mood, therapy

Introduction

Bipolar disorder is classically described as clinically significant episodes of depression and elevated mood (mania or hypomania) with intervening periods of normal mood (euthymia).1 A distinction is made between type I and type II bipolar disorders that depends on the duration and severity of the episodes of mood elevation. In reality, the profile of bipolar disorder is complex and heterogeneous, both longitudinally and cross‐sectionally, and includes mixed mood states, persistent mood instability, and cognitive dysfunction.2, 3, 4, 5, 6, 7 During mood swings there may be features of psychosis (delusions and hallucinations) that are mood congruent. Although psychotic symptoms are seen only in a minority of patients, they explain the early terminology of manic–depressive psychosis. Psychotic symptoms also contribute to the uncertain position of bipolar disorder within psychiatric classifications that place it between schizophrenia and other mood disorders. 8 The substantial morbidity of bipolar disorder arises primarily from the depressive episodes,9 and there is frequent comorbidity with anxiety disorders and substance misuse.10 Bipolar disorder affects 1–4% of the population, depending on the criteria used, with onset usually in adolescence or early adulthood.11 It is one of the leading causes of disability worldwide and is associated with significant direct and indirect costs.12 Suicide occurs in at least 5% of patients,13 and there is a marked increase in mortality rates from natural causes, especially cardiovascular disease.14 Consequently, life expectancy in bipolar disorder is reduced by 10 years or more.15, 16

The current treatment of bipolar disorder

The prevalence of, morbidity from, and mortality and costs associated with bipolar disorder make its effective treatment and, ideally, prevention important goals within psychiatry. The following summary provides a brief overview of the current evidence and recommendations for treatment of bipolar disorder. Our discussion focuses on the results of network meta‐analyses, which are advanced statistical approaches to evidence synthesis that allow different interventions to be ranked for their relative effectiveness, even if they have not been compared in an individual trial17, 18 (for further review of bipolar disorder therapies see Ref. 19, and for recent clinical guidelines see Refs. 20, 21, 22).

Evidence‐based treatment recommendations

The mainstay of therapy for all three phases of bipolar disorder (mania, depression, and prophylaxis) is pharmacological. The first‐line treatment for mania is an antipsychotic; inclusion of over 16,000 patients and 14 different treatments indicated that olanzapine and risperidone had the best profiles in terms of efficacy and tolerability.23 A subsequent update of the literature included several newer antimanic agents (notably cariprazine, a dopamine D₂/D₃ receptor partial agonist), but came to broadly similar conclusions. 24

Bipolar depression is often long lasting and difficult to treat, requiring a different approach from that used in unipolar depression.25 The evidence regarding effective interventions is limited, and network meta‐analysis has reached inconsistent conclusions depending on how studies were included.26, 27 The broad consensus is that quetiapine, olanzapine, antidepressants, lamotrigine, and lurasidone have some efficacy but show varying tolerability. Relative efficacy is not well established by these analyses. Several recent clinical trials not included in these meta‐analyses provide new avenues for treatment of bipolar depression. Durgam et al.28 report efficacy of cariprazine (at 1.5 mg/day, but not at lower or higher doses) in a relatively large 8‐week trial. In a 12‐month double‐blind, placebo‐controlled, randomized trial, Geddes et al.29 showed that the combination of lamotrigine and quetiapine is more effective than quetiapine alone in patients with bipolar depression; unexpectedly, the benefit of lamotrigine was not seen in patients also randomized to folic acid. There is some evidence that the atypical antipsychotic lurasidone may have particular efficacy in bipolar depression with mixed features,30 and preliminary data support use of armodafinil as an adjunctive therapy.31, 32 Intravenous ketamine as an add‐on therapy to mood stabilizers shows potential to have a rapid but often transient antidepressant effect.33 Finally, a recent study highlights that electroconvulsive therapy remains a useful option for treatment‐resistant bipolar depression.34

For prevention of relapse in bipolar disorder, lithium remains the most effective and best studied monotherapy.35, 36 Comparison of lithium with other treatments is limited by the design of most relapse‐prevention studies, which are enriched for patients who have responded to the investigational drug for treatment of an episode of mania or depression.37 A network meta‐analysis of maintenance treatment was published in 2014, based on 33 trials involving 17 treatments or combinations and 6846 participants. 38 This meta‐analysis included studies lasting at least 12 weeks with either a prophylaxis (where only euthymic participants were eligible) or a relapse‐prevention design (responders to the investigational drug during the acute phase were randomly assigned to either remain on the drug or be switched to placebo or comparator). The results support efficacy of a number of interventions, but only quetiapine and lithium prevented recurrence of both polarities of mood episode. Olanzapine, risperidone, and lithium in combination with valproate were significantly better than placebo in the prevention of manic episodes, and lamotrigine was better than placebo for depressive relapse. Valproate did not differ from placebo when depression and mania were considered separately. It is also noteworthy that, from a methodological viewpoint, the quality of the studies included in the meta‐analysis varied considerably, and these differences affected the final ranking of treatments. The efficacy of lithium was observed even when trial designs favored the active comparator. Hence, despite not being particularly well tolerated, lithium was supported as first‐line treatment; quetiapine, olanzapine, and lamotrigine were considered second line.38

Although the preceding discussion has focused on medication, because of their primary role in bipolar disorder and the number of new randomized clinical trials and meta‐analyses to highlight, psychological and psychosocial treatments, particularly lifestyle interventions, also play a role.19 In a recent systematic review,39 the authors concluded that the evidence is strongest for psychoeducation in the prevention of relapse in the early years after onset of bipolar disorder, with much more limited evidence for the use of cognitive behavioral and interpersonal therapies in the acute phases of the illness.

Limitations of existing therapies

The preceding summary of evidence‐based guidelines and meta‐analyses emphasize that effective treatments for bipolar disorder are available. However, their effectiveness is modest, and all the drugs have significant side effects and potential harms.

Lithium’s efficacy has to be balanced against its many side effects and potential toxicity. The risk of renal failure is a particular concern for both patients and clinicians. In fact, several recent studies show that this risk, though real, is considerably lower than often believed, especially if periods of acute lithium toxicity are avoided.40, 41, 42, 43, 44 There is an additional concern for women of childbearing age with bipolar disorder regarding pregnancy and breastfeeding. As well as a high risk of puerperal relapse,45 there are teratogenic and other risks to the fetus and baby associated with lithium and other mood stabilizers. Again, however, it is reassuring that the absolute pregnancy‐associated risks of lithium are not as great as previously thought,40, 46, 47 and some of the adverse pregnancy outcomes are related to bipolar disorder itself and not to its treatment.48 The risks of renal and other harms from lithium also have to be weighed against the strong evidence that it has an antisuicide effect49 and may also reduce risks of dementia,50 stroke,51 and overall mortality. 52 Thus, in total, lithium appears to be a safer drug, when used judiciously, than usually considered.53, 54 Nevertheless, it is clearly associated with many side effects and risks, as are other mood stabilizers,55, 56, 57 and these limitations emphasize the need to develop new treatments for bipolar disorder which are more effective, tolerable, and safe.

Given the compelling need, why have there been no new drug treatments for bipolar disorder (other than repurposing of antipsychotics and anticonvulsants) since the introduction of lithium salts over 60 years ago? There are many reasons for this dearth of innovation. Most importantly, we do not have a good enough understanding of the pathophysiology of bipolar disorder, and therefore of rational drug targets for its treatment. The mechanisms of action of drugs currently used for bipolar disorder are unclear (in contrast to the better established pharmacological targets of antipsychotic, antidepressant, and anxiolytic drugs) and remain under active investigation. It is a paradox that lithium has one of the most specific therapeutic actions in psychiatry, yet has multiple different pharmacological and cellular effects.58 Prominent (and overlapping) hypotheses focus on lithium’s inhibition of inositol monophosphatase and glycogen synthase kinase 3, and its effects on calcium signaling, mitochondrial function, and, more recently, neuroplasticity, neurogenesis, and G protein–activated potassium channels.58, 59, 60 The finding that two noncoding RNAs show genome‐wide association with lithium response may reveal additional targets and novel insight.61

A better understanding of the mechanism of action of lithium and other effective drugs should generate targets and aid new drug development. For example, the inhibition of inositol monophosphatase by lithium has led to evaluation of the putative lithium analogue ebselen, which shares this property. Ebselen has been found to have therapeutically relevant effects in animal models and in human subjects and is now proceeding into further development. 62, 63 Although the mechanism of action of sodium valproate is unknown, it includes some of the effects noted for lithium in addition to having epigenetic effects via histone deacetylase inhibition.64, 65 For lamotrigine, the mechanism of action (at least in epilepsy) is thought to be via inactivation of presynaptic voltage‐gated sodium channels, and hence inhibition of glutamate release;66 however, it has many other actions which may be relevant to its role in bipolar disorder.67

Other reasons for the lack of effective innovation in bipolar disorder therapy include uncertainty about how best to define and determine therapeutic response, the lack of validated animal models (see below), and neglect in research funding compared to that for schizophrenia.68 Study of bipolar disorder poses additional problems because of the episodic nature of the condition, which requires long‐term studies to demonstrate prophylactic efficacy, as well as treatment trials for manic and depressive episodes. This scientific failure is of course not unique to bipolar disorder; it has been a problem across psychiatry and has contributed significantly to the recent withdrawal of many pharmaceutical companies from the field.69 Fortunately, the field may have reached a turning point, first, by taking advantage of novel ways to measure the clinical phenotype and the impact of a therapeutic intervention; and second, by building upon the advances in understanding of the etiology and pathogenesis of bipolar disorder that are emerging from genomics and from novel experimental approaches, such as genetic mouse models and human‐induced pluripotent stem cells (iPSCs). The remainder of this review summarizes recent progress in these areas.

Refining the bipolar phenotype and how it is measured: a focus on mood instability

Psychiatric diagnoses are traditionally based on retrospective assessment of the history; follow‐up assessments are similarly based on the patient’s account of the intervening weeks or months since the last appointment. Diagnosis has focused on the identification of “episodes,” and clinical outcome is often dichotomized, so that if a patient is not judged as reaching criteria for an episode, he/she is considered to be “well.”

These approaches are particularly problematic in bipolar disorder, wherein mood may fluctuate considerably—in either direction—during any time period evaluated in this way. The failure to measure symptom levels between episodes is a limitation because subsyndromal symptoms predict poor outcome and relapse.70, 71 One way to address this is to have more frequent and contemporaneous assessments of mood. In the recently completed CEQUEL trial of lamotrigine augmentation of quetiapine in bipolar depression,29 the primary outcome variable was the self‐report Quick Inventory of Depressive Symptoms,72 which was completed by participants remotely after a weekly text or e‐mail prompt. This approach had several advantages. First, it allowed subjects to be followed up relatively frequently and without requiring clinic visits beyond those required for their usual care––a valuable feature as trials become larger and longer. Second, weekly rating allows for a much more fine‐grained analysis of the response to treatment than just the prespecified time points at 12, 22, and 52 weeks, and reveals effects of lamotrigine beyond simply its antidepressant action (unpublished observations). In a separate study, analysis of daily mood ratings collected via a smartphone app showed a clear distinction in mood variability (as well as mood symptoms) between subjects with bipolar disorder and those with borderline personality disorder.73

The use of novel technologies can not only help us to capture mood and other mental state data more efficiently and accurately, but can move bipolar disorder research beyond our reliance on psychopathology to capture physiological, behavioral, and environmental data in order to identify the biological correlates and ultimately the underlying processes. Such data capture is increasingly feasible through the capabilities of smartphones, smartwatches, and wearable devices, and can include actigraphy, posture, GPS position, heart rate, temperature, and other factors. Many of these data can be acquired automatically, without requiring any action on the part of the subject, while others require their input. For example, in ongoing studies, we and others are using smartphones, wrist‐worn devices, and skin patches to capture data on physical activity, heart rate, and sleep, as well as delivering bespoke tests of cognitive function and emotional processing via apps on smartphones or tablets.74 These uses of remote technologies to augment treatment trials in bipolar disorder complement their rapid––though still largely untested and unregulated––implementation into routine clinical monitoring and self‐monitoring.75, 76, 77 In these respects, bipolar disorder is at the forefront of the big data revolution in health care. However, considerable further work is required to demonstrate the validity,78, 79, 80 feasibility,81, 82 and acceptability83 of these devices and approaches.

The significance of mood instability in bipolar disorder

These issues can be well illustrated by reference to the investigation of mood instability, which, as we noted earlier, is a common feature of bipolar disorder, despite the textbook view that the disorder is one of discrete mood episodes interspersed with normal (and stable) mood. Although the presence of persistent mood instability is in fact well known to experienced clinicians and demonstrable using conventional methods,84, 85 remote monitoring and multidimensional data capture facilitate a more quantitative assessment and can be coupled to sophisticated mathematical techniques for data analysis.86, 87, 88 In addition to being a clinical feature of bipolar disorder, there is increasing evidence that mood instability is a symptom that is relatively common in the general population and a risk factor for a number of illness outcomes. Thus, it occurs in those at high risk for bipolar disorder89 and predicts its onset,90 it occurs during the prodrome of the disorder,7, 91 and it is independently associated with poor prognoses.92, 93, 94 Mood instability also contributes to borderline personality disorder and attention‐deficit disorder phenotypes.5

Given these considerations, research into mood instability will benefit from better definition95, 96 and improved understanding of its neural, molecular, and genetic bases. 97 Indeed, there is an iterative process whereby the need to characterize, quantify, and understand mood instability and its correlates drives the development of devices and methods to achieve this, while the capabilities provided by the developments enhance the focus on the phenomenon and its measurement. For example, advances in neuroimaging methods and analysis tools allow investigation of mood instability and its relationship to variation in cognition, brain activity, and neural dynamics. By looking at patterns of correlation among signals across different brain areas, it is possible to reveal the functional networks,98 with activity in these networks varying dynamically as individuals perform psychological tasks or are at rest.99 By measuring brain activity at high temporal resolution using techniques such as magnetoencephalography,100 it becomes possible to measure the fluctuating dynamics across brain networks as they unfold.101, 102 Other methods identify the functional networks that are most active at any given time point103 and make it possible to derive measures of neural instability, and thereby to investigate what instabilities in neural processing may underpin cognitive and mood instability at various time scales. These approaches afford a new dimension to investigations of the neural bases of psychological disorders linked to mood instability, potentially revealing differences in the dynamics in brain networks linked to mood or cognition or differences in their regulation by executive control or reward‐related functions.

A combination of these and other new methods may also allow identification of predictive markers for the effects of mood‐stabilizing therapies and development of experimental medicine models for testing potential new bipolar disorder therapies. For example, lithium may affect mood instability or its cognitive and neural correlates independent of, and earlier than, its established efficacy against clinical episodes of mania or depression. To test this hypothesis, we are exploring the effects of first exposure to lithium on the variability of mood, neural response and networks, and cognitive function (focused on reward‐based decision making, learning, and attention), in a double‐blind, placebo‐controlled study. 74 An effect of lithium on one or more metrics of variability will help identify biomarkers that can be used to test novel candidate mood stabilizers more rapidly than is the case using traditional randomized controlled trial designs. By reducing the time and thereby the costs and risks involved, an experimental medicine model of bipolar disorder would encourage reinvestment in the field. A precedent for such a model is provided by the conceptually equivalent discovery of cognitive and emotional biomarkers predictive of antidepressant efficacy in unipolar depression.104 The successful identification and validation of these markers is now used to inform and refine decision making about novel putative antidepressant medications.105

In summary, mood instability is of interest and potential importance in bipolar disorder in its own right. It also illustrates the novel conceptual and technical approaches that are being taken to characterize and understand the bipolar phenotype. In principle, the same rationale and multidisciplinary approaches can be applied to other features, such as reward sensitivity106 and sleep and circadian rhythm dysregulation (see below).

Better understanding of etiology and pathophysiology

Although improving the measurement and clinical characterization of the bipolar disorder phenotype can facilitate more powerful and rapid identification of the effects of potential new treatments, transformative advances in therapy will require a substantially better understanding of the biological basis of the disorder. This, in turn, requires additional knowledge and novel tools. Fortunately, progress has been made in several areas, including genetics, animal models, and cellular models.

Therapeutic potential of bipolar disorder genetics

Bipolar disorder has a high heritability (over 80%), with a complex non‐Mendelian genetic basis.107 The majority of genetic risk is associated with multiple polymorphisms, with a very small contribution from copy number variants and other rare variants.107, 108, 109, 110 The leading bipolar disorder loci and genes based on existing genome‐wide association studies (GWAS) are summarized in Table ; many more will emerge with a forthcoming much larger assembly of data from GWAS from the Psychiatric Genomics Consortium. 108 As with other diseases, genetic information has the potential to inform and improve bipolar disorder treatments, both by highlighting targets and pathways and by enabling personalized medicine.107 However, the magnitude and immediacy of such effects are limited because of the complexities of the genetic architecture and the many steps that lie between identification of a genetic locus and validation of a drug target.111, 112, 113, 114, 115, 116

Table 1

Genome‐wide significant bipolar disorder risk loci, implicated genes, and their therapeutic potential

Locus	Gene symbol(s)	Gene name(s)	Therapeutic potentiala
10q21.2	ANK3	Ankyrin 3 (encodes ankyrin‐G)	++
12p13. 3	CACNA1C	Voltage‐dependent calcium channel, L‐type, α1C (encodes Cav1.2)	++++
11q14.1	TENM4 b	Teneurin transmembrane protein 4	+
19p12	NCAN	Neurocan	++
5p15.31	ADCY2	Adenylate cyclase 2	+++
3p22. 2	TRANK1	Tetratricopeptide repeat and anykrin repeat containing 1	+
10q24.33	AS3MT	Arsenite methyltransferase	++
6q25.2	SYNE1	Spectrin repeat containing, nuclear envelope 1	+
6q16.1	MIR2113/POU3F2 c, d	MicroRNA 2113/POU class 3 homeobox 2	+
16p11. 2	MAPK3 e	Mitogen‐activated protein kinase 3	++
2q32.1	ZNF804A e	Zinc finger protein 804A	+
3p21.1	ITIh4/ITIh5 c, e	Inter‐α‐trypsin inhibitor heavy chains 3 and 4	+
3p21	PBRM1 f	Polybromo 1	+

An abnormality of calcium signaling has long been considered a potential pathophysiological mechanism in bipolar disorder, based mostly on biochemical data in peripheral blood cells. 117, 118, 119 It is therefore noteworthy that calcium channel genes are prominent in the genomic data.107, 113 The evidence is threefold. CACNA1C, which encodes the Ca_v1.2 subunit of L‐type voltage‐gated channel, is one of the genes most robustly identified by GWAS; second, the functional category of calcium signaling is enriched among bipolar disorder–associated genes; and third, rare variants in calcium channel subunits are also implicated.107, 118, 120 The involvement of calcium channel genes in bipolar disorder is not only significant in terms of prior pathophysiological findings but because some data suggest that calcium channel antagonists (used to treat hypertension and angina) may have a role in bipolar disorder treatment.121 However, the findings are inconclusive, with randomized clinical trial data limited to small trials of verapamil for mania.24, 122 Nevertheless, the recent genetic data provide impetus to further investigate the role of L‐type calcium channel antagonists in bipolar disorder treatment; trials using these agents in bipolar disorder can now select or stratify participants based on CACNA1C risk genotype. 123 Compared to verapamil, other drugs in this class have properties that may be advantageous in bipolar disorder, such as improved brain penetration, longer half‐life, and greater L‐type calcium channel subunit selectivity. Looking ahead, the ideal L‐type calcium channel antagonist for bipolar disorder would have specificity for isoforms that are preferentially expressed in the brain, compared to those expressed in the heart and blood vessels, in order to maximize efficacy and minimize cardiovascular side effects.122, 124

Several of the other genes listed in Table also have potential as drug targets, although it may prove difficult to exploit these leads.125 For example, ankyrin G (encoded by ANK3) is involved in coupling voltage‐gated sodium channels to the axonal cytoskeleton.126 At first sight, this suggests a potential therapeutic role in regulation of neuronal excitability; but recent studies emphasize the complexity and diversity of ankyrin G distribution and function, and it is not clear which aspects are most relevant to bipolar disorder. 127, 128 It is also not known what impact the ANK3 risk variants have upon gene regulation or function, and therefore whether a drug targeting this gene product should enhance, inhibit, or stabilize ankyrin G activity.129

Genome‐wide association studies also confirm that bipolar disorder is not a discrete entity, genetically speaking. That is, much of the genetic risk for bipolar disorder is shared with schizophrenia, and a lesser but still significant amount with major depression, complementing the phenotypic overlaps and comorbidities known to every clinician.8, 130 There is also evidence, albeit less robust, for genetically distinct subgroups within bipolar disorder, for example in terms of the nature of psychotic or manic symptoms.131, 132, 133 Genetics is thereby contributing to the current interest in reconceptualizing psychiatric disorders, such as bipolar disorder, both transdiagnostically and in terms of their underlying biology, most prominently by the National Institute of Mental Health Research Domain Criteria initiative. 134 This reformulation has therapeutic implications, encouraging a search for treatment targets and mechanisms that similarly cross conventional diagnostic boundaries. For bipolar disorder, these might include attentional or cognitive impairments2, 7, 135, 136 and, as noted earlier, mood instability independent of depressive or manic episodes. It might also include treatments to normalize sleep and circadian rhythms, with increasing evidence that such abnormalities are not just part of its symptomatology but may contribute to its onset and maintenance.137, 138, 139, 140, 141 Given these considerations, it is interesting that CACNA1C and other calcium channel genes also show genome‐wide association with sleep quality142, 143 and aspects of memory,144, 145 in addition to their role in risk for bipolar disorder and other psychiatric disorders.

Better experimental methods to model bipolar disorder and its treatment

Along with genomics, cellular and animal models are crucial components of the target identification and drug discovery processes for many diseases. Both have been used in a number of studies in bipolar disorder, with interesting, though modest, findings.

Cellular models

Existing data from bipolar disorder cellular models have recently been systematically reviewed.146 Most data come from studies using peripheral cells, and hence have inherent limitations (because they are non‐neuronal; and in the specifc case of lymphoblasts because they have undergone viral transformation). Moreover, many positive findings have not been replicated and their interpretation is unclear. Nevertheless, as mentioned earlier, these in vitro approaches have provided considerable evidence in bipolar disorder for abnormalities affecting calcium signaling, as well as alterations in mitochondrial function, apoptosis, and the circadian system. Abnormalities are generally greater in the presence of cellular stressors than at baseline, and are often normalized by lithium treatment. Reassuringly, some of the in vitro findings are complemented by similar findings in postmortem brain, and together provide some clues for novel therapeutic targets. 147

Most ongoing in vitro medical research now uses iPSCs and cell reprogramming technologies to produce (directly or indirectly) neural precursors, neurons of various types, and even brain organoids. Bipolar disorder is no exception to these significant research advances, although data thus far remain limited and results modest.148, 149, 150, 151, 152 With regard to therapy, three recent papers are pertinent. Yoshimizu et al.152 studied neurons induced from subjects genotyped for the main bipolar disorder risk polymorphism in CACNA1C to examine the expression and function of calcium channels. Neurons derived from subjects homozygous for the risk variant expressed more CACNA1C mRNA and showed enhanced current density, compared to heterozygotes and nonrisk homozygous subjects. These results suggest that the risk variants of CACNA1C involve a gain of function (see also Ref. 153), and thus strengthen the case, discussed earlier, that L‐type calcium channel antagonists might be potential therapeutic agents in bipolar disorder. An alternative experimental design is to compare cells derived from drug‐responsive versus nonresponsive patients and to help identify the key molecular pathways and processes that may underlie therapeutic responsiveness in vivo. Using this approach, neurons induced from fibroblasts taken from lithium responders were found to have greater adhesiveness than those from nonresponders.148 Mertens et al.151 also showed a different molecular and functional profile of induced neurons from bipolar disorder patients according to their lithium responsiveness in vivo; notably, their data implicated mitochondrial and calcium signaling abnormalities, in line with the earlier data of this kind. The indications from iPSC studies that lithium responsiveness may reflect a pathophysiologically meaningful subtype of bipolar disorder complement the increasing evidence that it also delineates a clinically identifiable subtype of the disorder,154 for example, in terms of symptom profile and family history, and hence the potential value of biomarkers predictive of lithium response. 155

Although these and other findings using reprogrammed cells are very preliminary, the rapid technical developments in the field promise significant advances and increases of scale in the near future, and the methods are likely to play a central role in target validation and drug discovery for bipolar disorder, as well as in the understanding of its etiology and pathophysiology.156

Mouse models

The value of rodents for modeling psychiatric disorders and advancing treatment has been increasingly questioned.157 This applies both to genetic modifications and to phenotypes produced by pharmacological or behavioral interventions (e.g., amphetamine sensitization, isolation rearing). The problem is even greater for bipolar phenotype than, for example, for schizophrenia, since the animal model ideally needs to recapitulate spontaneous fluctuation between states––its definitive characteristic––as well as exhibit depressive‐like, manic‐like, and psychotic‐like phenotypes.158 However, progress is being made, partly due to a shift in views about the bipolar phenotype and what is being modeled,159 and partly due to technical advances in genetic and neural circuit manipulation of rodents (for recent examples, see Refs. 160, 161, 162, 163).

Perhaps the best known genetic mouse model relevant to bipolar disorder is the ClockΔ19 mouse. This mouse strain has a mutation in the gene encoding CLOCK, a key regulator of the circadian system,164 and exhibits a characteristic diurnal behavioral profile of manic‐like (i.e., hyperactive) activity, with more reward‐related and less anxious or depressive features during the light phase, but normal behavior in the dark. The manic‐like behavior coincides with, and is at least partly caused by, increased firing of midbrain dopaminergic neurons, as shown using an optogenetic approach.162 Another circadian protein (the nuclear receptor REV‐ERBα) is involved in similar mood‐related behaviors and also regulates dopamine.163 Such findings argue for a renewed focus on dopamine, and on circadian rhythms, in the phenotype of bipolar disorder and potentially as targets for treatment.

These examples show how genetically modified mice are being used to investigate cellular and molecular mechanisms contributing to bipolar disorder–relevant phenotypes, even though the genes concerned, Clock and Nr1d1 (encoding REV‐ERBa), do not currently show strong genetic association with bipolar disorder itself. A complementary approach is to study mice in which a manipulated gene locus does show genome‐wide association with bipolar disorder. For example, Leussis et al.161 investigated ANK3 (Table ) by examining heterozygous Ank3^+/– mice and by knocking down Ank3 selectively in the dentate gyrus using RNA interference. Both manipulations led to reduced anxiety and increased reward motivation compared to wild‐type mice. The Ank3^+/– mice also showed greater stress reactivity, developing more depression‐like behaviors and enhanced corticosterone levels after chronic stress. Furthermore, the phenotypes were normalized by chronic administration of lithium.

Conclusions

Bipolar disorder exemplifies the challenges and the opportunities faced by psychiatry as it attempts, belatedly, to move forward from descriptive psychopathology and serendipitously discovered therapies of limited efficacy and tolerability to a more valid nosology and treatments that are based on rational understanding of pathophysiology, the latter requiring advances in molecular genetics and neuroscience. Althoug history cautions us to be prudent and not expect fundamental breakthroughs to be imminent, recent developments across a range of disciplines have permitted real optimism. Our discussion above has highlighted several developments: novel approaches to how the bipolar phenotype is conceptualized and measured and the prospects of linking this phenotype mechanistically to underlying genetic, molecular, and neural circuits. A range of new technologies (from remote biosensors to reprogrammed cells and optogenetics) and approaches (from big data to mathematical modeling and experimental medicine) are driving these developments. In addition to invigorating psychiatric research and bringing cutting‐edge neuroscientists and other disciplines to bear on these complex problems, these innovative approaches should encourage the pharmaceutical industry, other commercial partners (including device and software manufacturers), and funding bodies to invest in the field. The personal burden and substantial costs of bipolar disorder––to patients, families, and society––together with the unsatisfactory state of current interventions and outcomes, provide additional motivation to finally break the impasse regarding how the disorder is understood and treated. Input is also required from patients themselves: research needs their full involvement and engagement, both through participation and in advocacy. They know only too well the limitations of current treatments.

Conflicts of interest

In the past 2 years, P.J.H. has served as an expert witness on patent litigation involving drugs used to treat bipolar disorder. A.C. has served as an expert witness for a patent litigation case involving quetiapine. C.J.H. has received consultancy fees from Lundbeck and P1vital, is a shareholder and company director of Oxford Psychologists Ltd., and has received research funding from UCB, J&J, Lundbeck, and Sunovion. G.M.G. holds shares in P1vital and has served as consultant, advisor, or speaker for AstraZeneca, Abbvie, Cephalon/Teva, Convergence, Eli Lilly, GSK, Lundbeck, Medscape, Merck, Otsuka, P1vital, Servier, Sunovion, and Takeda. The other authors report no conflicts of interest.

Acknowledgments

The authors’ bipolar disorder research is supported by a Wellcome Trust Strategic Award (CONBRIO: Collaborative Network for Bipolar Research to Improve Outcomes). Additional support came from the Wellcome Trust “Sleep and Circadian Neuroscience Institute” Strategic Award (G.M.G. and P.J.H.), grants from the UK Medical Research Council (P.J.H. and C.J.H.), European Union FP7 Marie Curie Integrative Training Network (A.C.N.), and the European Union Innovative Medicines Initiative Stembancc program (P.J.H., J.R.G., A.C. and G.M.G.). J.R.G. and G.M.G. are National Institute for Health Research (NIHR) senior investigators. A.C.N. is a Wellcome Trust senior investigator. K.S. was a Brain and Behavior Research Foundation young investigator. A.C. is supported by the NIHR Oxford Cognitive Health Clinical Research Facility. The views expressed here are those of the authors and not necessarily those of the funders, the National Health Service, the NIHR, or the Department of Health.

References

2.

Bourne, C.
, Aydemir O., Balanza‐Martinez V., et al
2013.
Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta‐analysis. Acta Psychiatr. Scand.
128: 149–162. [PubMed] [Google Scholar]3.

Ostergaard, S.D.
, Bertelsen A., Nielsen J., et al
2013.
The association between psychotic mania, psychotic depression and mixed affective episodes among 14,529 patients with bipolar disorder. J. Affect. Disord.
147: 44–50. [PubMed] [Google Scholar]4.

Vieta, E.
& Valentí M.. 2013.
Mixed states in DSM‐5: implications for clinical care, education, and research. J. Affect. Disord.
148: 28–36. [PubMed] [Google Scholar]6.

Faedda, G.L.
, Marangoni C., Serra G., et al
2015.
Precursors of bipolar disorders: a systematic literature review of prospective studies. J. Clin. Psychiatry
76: 614–624. [PubMed] [Google Scholar]7.

Tsitsipa, E.
& Fountoulakis K.. 2015.
The neurocognitive functioning in bipolar disorder: a systematic review of data. Ann. Gen. Psychiatry
14: 42. [PMC free article] [PubMed] [Google Scholar]9.

Miller, S.
, Dell’Osso B. & Ketter T.A.. 2014.
The prevalence and burden of bipolar depression. J. Affect. Disord.
169(Suppl. 1): S3–S11. [PubMed] [Google Scholar]10.

Di Florio, A.
, Craddock N. & van den Bree M.. 2014.
Alcohol misuse in bipolar disorder. A systematic review and meta‐analysis of comorbidity rates. Eur. Psychiatry
29: 117–124. [PubMed] [Google Scholar]11.

Merikangas, K.R.
, Akiskal H.S., Angst J., et al
2007.
Lifetime and 12‐month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch. Gen. Psychiatry
64: 543–552. [PMC free article] [PubMed] [Google Scholar]12.

Parker, G.
, McCraw S., Hadzi‐Pavlovic D. & Fletcher K.. 2013.
Costs of the principal mood disorders: a study of comparative direct and indirect costs incurred by those with bipolar I, bipolar II and unipolar disorders. J. Affect. Disord.
149: 46–55. [PubMed] [Google Scholar]13.

Pompili, M.
, Gonda X., Serafini G., et al
2013.
Epidemiology of suicide in bipolar disorders: a systematic review of the literature. Bipolar Disord. 15: 457–490. [PubMed] [Google Scholar]14.

Hayes, J.F.
, Miles J., Walters K., et al
2015.
A systematic review and meta‐analysis of premature mortality in bipolar affective disorder. Acta Psychiatr. Scand.
131: 417–425. [PMC free article] [PubMed] [Google Scholar]15.

Chesney, E.
, Goodwin G.M. & Fazel S.. 2014.
Risks of all‐cause and suicide mortality in mental disorders: a meta‐review. World Psychiatry
13: 153–160. [PMC free article] [PubMed] [Google Scholar]16.

Kessing, L.V.
, Vradi E. & Andersen P.K.. 2015.
Life expectancy in bipolar disorder. Bipolar Disord. 17: 543–548. [PubMed] [Google Scholar]17.

Cipriani, A.
, Geddes J.R., Higgins J. & Salanti G.. 2013.
Conceptual and technical challenges in network meta‐analysis. Ann. Intern. Med.
159: 130–137. [PubMed] [Google Scholar]18.

Mavridis, D.
, Giannatsi M., Cipriani A. & Salanti G.. 2015.
A primer on network meta‐analysis with emphasis on mental health. Evid. Based Ment. Health
18: 40–46. [PubMed] [Google Scholar]20.
National Institute for Health and Clinical Excellence
. 2014.
Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care. NICE clinical guideline 185. http://guidance.nice.org.uk/CG185. Accessed March 23, 2016.21.

Malhi, G.S.
, Bassett D., Boyce P., et al
2015.
Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust. N.Z. J. Psychiatry
49: 1087–1206. [PubMed] [Google Scholar]22.

Goodwin, G.M.
& Consensus Group of the British Association for Psychopharmacology
. 2009.
Evidence‐based guidelines for treating bipolar disorder: revised third edition—recommendations from the British Association for Psychopharmacology. J. Psychopharmacol.
23: 346–388. [PubMed] [Google Scholar]23.

Cipriani, A.
, Barbui C., Salanti G., et al
2011.
Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple‐treatments meta‐analysis. Lancet
378: 1306–1315. [PubMed] [Google Scholar]24.

Yildiz, A.
, Nikodem M., Vieta E., et al
2015.
A network meta‐analysis on comparative efficacy and all‐cause discontinuation of antimanic treatments in acute bipolar mania. Psychol. Med.
45: 299–317. [PubMed] [Google Scholar]25.

Frye, M.A.
, Prieto M.L., Bobo W.V., et al
2014.
Current landscape, unmet needs, and future directions for treatment of bipolar depression. J. Affect. Disord.
169(Suppl 1): S17–S23. [PubMed] [Google Scholar]26.

Kendall, T.
, Morriss R., Mayo‐Wilson E., Marcus E.; Guideline Development Group of the National Institute for Health and Care Excellence
. 2014.
Assessment and management of bipolar disorder: summary of updated NICE guidance. Br. Med. J. 349: g5673. [PubMed] [Google Scholar]27.

Taylor, D.M.
, Cornelius V., Smith L. & Young A.H.. 2014.
Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple‐treatments meta‐analysis. Acta Psychiatr. Scand.
130: 452–469. [PubMed] [Google Scholar]28.

Durgam, S.
, Earley W., Lipschitz A., et al
2016.
An 8‐week randomized, double‐blind, placebo‐controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression. Am. J. Psychiatry
173: 271–281. [PubMed] [Google Scholar]29.

Geddes, J.R.
, Gardiner A., Rendell J., et al
2016.
Comparative evaluation of quetiapine plus lamotrigine versus quetiapine monotherapy (and folic acid versus placebo) in people with bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial. Lancet Psychiatry
3: 31–39. [PubMed] [Google Scholar]30.

McIntyre, R.S.
, Cucchiaro J., Pikalov A., et al
2015.
Lurasidone in the treatment of bipolar depression with mixed (subsyndromal hypomanic) features: post hoc analysis of a randomized placebo‐controlled trial. J. Clin. Psychiatry
76: 398–405. [PubMed] [Google Scholar]31.

Calabrese, J.R.
, Frye M.A., Yang R., Ketter T.A.; Armodafinil Treatment Trial Study Network
. 2014.
Efficacy and safety of adjunctive armodafinil in adults with major depressive episodes associated with bipolar I disorder: a randomized, double‐blind, placebo‐controlled, multicenter trial. J. Clin. Psychiatry
75: 1054–1061. [PubMed] [Google Scholar]32.

Ketter, T.A.
, Yang R. & Frye M.A.. 2015.
Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder. J. Affect. Disord.
181: 87–91. [PubMed] [Google Scholar]33.

McCloud, T.L.
, Caddy C., Jochim J., et al
2015.
Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults. Cochrane Database Syst. Rev.
9: CD011611. [PubMed] [Google Scholar]34.

Schoeyen, H.K.
, Kessler U., Andreassen O.A., et al
2015.
Treatment‐resistant bipolar depression: a randomized controlled trial of electroconvulsive therapy versus algorithm‐based pharmacological treatment. Am. J. Psychiatry
172: 41–51. [PubMed] [Google Scholar]35.

Geddes, J.R.
, Burgess S., Hawton K., et al
2004.
Long‐term lithium therapy for bipolar disorder: systematic review and meta‐analysis of randomized controlled trials. Am. J. Psychiatry
161: 217–222. [PubMed] [Google Scholar]36.

Geddes, J.R.
, Goodwin G.M., Rendell J.; BALANCE Investigators
. 2010.
Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open‐label trial. Lancet
375: 385–395. [PubMed] [Google Scholar]37.

Cipriani, A.
, Barbui C., Rendell J. & Geddes J.R.. 2014.
Clinical and regulatory implications of active run‐in phases in long‐term studies for bipolar disorder. Acta Psychiatr. Scand.
129: 328–342. [PubMed] [Google Scholar]38.

Miura, T.
, Noma H., Furukawa T.A., et al
2014.
Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta‐analysis. Lancet Psychiatry
1: 351–359. [PubMed] [Google Scholar]39.

Miziou, S.
, Tsitsipa E., Moysidou S., et al
2015.
Psychosocial treatment and interventions for bipolar disorder: a systematic review. Ann. Gen. Psychiatry
14: 19. [PMC free article] [PubMed] [Google Scholar]40.

McKnight, R.F.
, Adida M., Budge K., et al
2012.
Lithium toxicity profile: a systematic review and meta‐analysis. Lancet
379: 721–728. [PubMed] [Google Scholar]41.

Close, H.
, Reilly J., Mason J.M., et al
2014.
Renal failure in lithium‐treated bipolar disorder: a retrospective cohort study. PLoS One
26: e90169. [PMC free article] [PubMed] [Google Scholar]42.

Clos, S.
, Rauchhaus P., Severn A., et al
2015.
Long‐term effect of lithium maintenance therapy on estimated glomerular filtration rate in patients with affective disorders: a population‐based cohort study. Lancet Psychiatry
2: 1075–1083. [PubMed] [Google Scholar]43.

Kessing, L.V.
, Gerds T.A., Feldt‐Rasmussen B., et al
2015.
Use of lithium and anticonvulsants and the rate of chronic kidney disease: a nationwide population‐based study. JAMA Psychiatry
72: 1182–1191. [PubMed] [Google Scholar]44.

Shine, B.
, McKnight R.F., Leaver L. & Geddes J.R.. 2015.
Long‐term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet
386: 461–468. [PubMed] [Google Scholar]45.

Wesseloo, R.
, Kamperman A.M., Munk‐Olsen T., et al
2016.
Risk of postpartum relapse in bipolar disorder and postpartum psychosis: a systematic review and meta‐analysis. Am. J. Psychiatry
173: 117–127. [PubMed] [Google Scholar]46.

Diav‐Citrin, O.
, Schechtman S., Tahover E., et al
2014.
Pregnancy outcome following in utero exposure to lithium: a prospective, comparative, observational study. Am. J. Psychiatry
171: 785–794. [PubMed] [Google Scholar]47.

Bergink, V.
& Kushner S.A.. 2014.
Lithium during pregnancy. Am. J. Psychiatry
171: 712–715. [PubMed] [Google Scholar]48.

Bodén, R.
, Lundgren M., Brandt L., et al
2012.
Risks of adverse pregnancy and birth outcomes in women treated or not treated with mood stabilisers for bipolar disorder: population based cohort study. Br. Med. J. 345: e7085. [PMC free article] [PubMed] [Google Scholar]49.

Cipriani, A.
, Hawton K., Stockton S. & Geddes J.R.. 2013.
Lithium in the prevention of suicide in mood disorders: updated systematic review and meta‐analysis. BMJ
346: f3646. [PubMed] [Google Scholar]50.

Gerhard, T.
, Devenand D.P., Huang C., et al
2015.
Lithium treatment and risk for dementia in adults with bipolar disorder: population‐based cohort study. Br. J. Psychiatry
207: 46–51. [PubMed] [Google Scholar]51.

Lan, C.C.
, Liu C.C., Lin C.J., et al
2015.
A reduced risk of stroke with lithium exposure in bipolar disorder: a population‐based retrospective cohort study. Bipolar Disord. 17: 705–714. [PubMed] [Google Scholar]52.

Smith, E.G.
, Austin K.L., Kim H.M., et al
2015.
Mortality associated with lithium and valproate treatment of US Veterans Administration patients with mental disorders. Br. J. Psychiatry
207: 55–63. [PubMed] [Google Scholar]53.

Davis, J.M.
, Rosenbaum A., Shahinian V. & Brosius F.C.. 2015.
Prevention of lithium‐associated renal failure: recent evidence. Lancet Psychiatry
2: 1045–1047. [PubMed] [Google Scholar]54.

Goodwin, G.M.

2015.
The safety of lithium. JAMA Psychiatry
72: 1167–1169. [PubMed] [Google Scholar]55.

Moore, J.L.
& Aggarwal P.. 2012.
Lamotrigine use in pregnancy. Exp. Opin. Pharmacother.
13: 1213–1216. [PubMed] [Google Scholar]56.

Correll, C.
, Detraux J., De Lepeliere J. & De Hert M.. 2015.
Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder. World Psychiatry
14: 119–136. [PMC free article] [PubMed] [Google Scholar]57.

Tanoshima, M.
, Kobayashi T., Tanoshima R., et al
2015.
Risks of congenital malformations in offspring exposed to valproic acid in utero: a systematic review and cumulative meta‐analysis. Clin. Pharmacol. Ther.
98: 417–441. [PubMed] [Google Scholar]59.

Berridge, M.J.

2014.
Calcium signalling and psychiatric disease: bipolar disorder and schizophrenia. Cell Tissue Res. 357: 477–492. [PubMed] [Google Scholar]60.

Tselnicker, I.F.
, Tsemakhovich V., Rishal I., et al
2014.
Dual regulation of G proteins and the G‐protein–activated K⁺ channels by lithium. Proc. Natl. Acad. Sci. U.S.A.
111: 5018–5023. [PMC free article] [PubMed] [Google Scholar]61.

Hou, L.
, Heilbronner U., Degenhardt F., et al
2016.
Genetic variants associated with response to lithium treatment in bipolar disorder: a genome‐wide association study. Lancet. doi: 10.1016/S0140-6736(16)00143-4. [PMC free article] [PubMed] [Google Scholar]63.

Singh, N.
, Sharpley A.L., Emir U.E., et al
2016.
Effect of the putative lithium mimetic ebselen on brain myo‐inositol, sleep, and emotional processing in humans. Neuropsychopharmacology. doi: 10.1038/npp.2015.343. [PMC free article] [PubMed] [Google Scholar]64.

Schloesser, R.J.
, Martinowich K. & Manji H.K.. 2012.
Mood‐stabilizing drugs: mechanisms of action. Trends Neurosci. 35: 36–46. [PubMed] [Google Scholar]65.

Chiu, C.T.
, Wang Z., Hunsberger J.G. & Chuang D.M.. 2013.
Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharmacol. Rev.
65: 105–142. [PMC free article] [PubMed] [Google Scholar]67.

Ketter, T.A.
, Manji H.K. & Post R.M.. 2003.
Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders. J. Clin. Psychopharmacol.
23: 484–495. [PubMed] [Google Scholar]68.

Goodwin, G.M.
& Geddes J.R.. 2007.
What is the heartland of psychiatry? Br. J. Psychiatry
191: 189–191. [PubMed] [Google Scholar]69.

Nutt, D.
& Goodwin G.. 2011.
ECNP summit on the future of CNS drug research in Europe 2011. Eur. Neuropsychopharmacol.
21: 495–499. [PubMed] [Google Scholar]70.

Paykel, E.S.
, Abbott R., Morriss R., et al
2006.
Sub‐syndromal and syndromal symptoms in the longitudinal course of bipolar disorder. Br. J. Psychiatry
189: 118–123. [PubMed] [Google Scholar]71.

Bauer, M.
, Glenn T., Grof P., et al
2010.
Subsyndromal mood symptoms: a useful concept for maintenance studies of bipolar disorder. Psychopathology
43: 1–7. [PubMed] [Google Scholar]72.

Rush, A.J.
, Trivedi M.H., Ibrahim H.M., et al
2003.
The 16‐item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS‐C), and self‐report (QIDS‐SR): a psychometric evaluation in patients with chronic major depression. Biol. Psychiatry
54: 573–583. [PubMed] [Google Scholar]73.

Bilderbeck, A.C.
, Saunders K.E.A., Clifford G.D., et al
2015.
Daily and weekly mood ratings: relative contributions to the differentiation of bipolar disorder and borderline personality disorder. Bipolar Disord. 17(Suppl. 1): 129–130. [Google Scholar]74.

Saunders, K.E.A.
, Cipriani A., Rendell J., et al
2016.
Oxford lithium trial (OxLith) of the early affective, cognitive, neural, biochemical effects of lithium carbonate in bipolar disorder: study protocol for a randomised controlled trial. Trials
17: 116. [PMC free article] [PubMed] [Google Scholar]75.

Glenn, T.
& Monteith S.. 2014.
New measures of mental state and behavior based on data collected from sensors, smartphones, and the Internet. Curr. Psychiatry Rep.
16: 523. [PubMed] [Google Scholar]76.

Faurholt‐Jepsen, M.
, Frost M., Ritz C., et al
2015.
Daily electronic self‐monitoring in bipolar disorder using smartphones—the MONARCA I trial: a randomized, placebo‐controlled, single‐blind, parallel group trial. Psychol. Med.
45: 2691–2704. [PubMed] [Google Scholar]77.

Hidalgo‐Mazzei, D.
, Mateu A., Reinares M., et al
2015.
Self‐monitoring and psychoeducation in bipolar patients with a smart‐phone application (SIMPLe) project: design, development and studies protocols. BMC Psychiatry
15: 52. [PMC free article] [PubMed] [Google Scholar]78.

Nicholas, J.
, Larsen M.E., Proudfoot J. & Christensen H.. 2015.
Mobile apps for bipolar disorder: a systematic review of features and content quality. J. Med. Internet Res. 17: e198. [PMC free article] [PubMed] [Google Scholar]79.

Tourus, J.
& Powell A.C.. 2015.
Current research and trends in the use of smartphone applications for mood disorders. Internet Interv.
2: 169–173. [Google Scholar]80.

Faurholt‐Jepsen, M.
, Munkholm K., Frost M., et al
2016.
Electronic self‐monitoring of mood using IT platforms in adult patients with bipolar disorder: a systematic review of the validity and evidence. BMC Psychiatry
16: 7. [PMC free article] [PubMed] [Google Scholar]81.

Onnela, J.‐P.
& Rauch S.L.. 2016.
Harnessing smartphone‐based digital phenotyping to enhance behavioral and mental health. Neuropsychopharmacology. doi: 10.1038/npp.2016.7. [PMC free article] [PubMed] [Google Scholar]82.

Schwartz, S.
, Schultz S., Reider A. & Saunders E.F.H.. 2016.
Daily mood monitoring of symptoms using smartphones in bipolar disorder: a pilot study assessing the feasibility of ecological momentary assessment. J. Affect. Disord.
191: 88–93. [PMC free article] [PubMed] [Google Scholar]83.

Saunders, K.E.A.
, Bilderbeck A.C., Panchal P., et al
2015.
Acceptability and tolerability of ambulatory monitoring in bipolar disorder: a patient perspective. Bipolar Disord. 17(Suppl. 1): 86. [Google Scholar]84.

Henry, C.
, Van den Bulke D., Bellivier F., et al
2008.
Affective lability and affect intensity as core dimensions of bipolar disorders during euthymic period. Psychiatry Res. 159: 1–6. [PubMed] [Google Scholar]85.

Ortiz, A.
, Bradler K., Garnham J., et al
2015.
Nonlinear dynamics of mood regulation in bipolar disorder. Bipolar Disord. 17: 139–149. [PubMed] [Google Scholar]86.

Bonsall, M.B.
, Wallace‐Hadrill S.M., Geddes J.R., et al
2012.
Nonlinear time‐series approaches in characterizing mood stability and mood instability in bipolar disorder. Proc. Biol. Sci.
279: 916–924. [PMC free article] [PubMed] [Google Scholar]88.

Bonsall, M.B.
, Geddes J.R., Holmes E.A. & Goodwin G.M.. 2015.
Bipolar disorder dynamics: affective instabilities, relaxation oscillations and noise. J. R. Soc. Interface
12: 20150670. [PMC free article] [PubMed] [Google Scholar]89.

Birmaher, B.
, Goldstein B.I., Axelson D.A., et al
2013.
Mood lability among offspring of parents with bipolar disorder and community controls. Bipolar Disord. 15: 253–263. [PMC free article] [PubMed] [Google Scholar]90.

Hafeman, D.M.
, Merranko J., Axelson D., et al
2016.
Toward the definition of a bipolar prodrome: dimensional predictors of bipolar spectrum disorders in at‐risk youths. Am. J. Psychiatry. doi: 10.1176/appi.ajp.2015.15040414. [PMC free article] [PubMed] [Google Scholar]91.

Howes, O.D.
, Lim S., Theologos G., et al
2011.
A comprehensive review and model of putative prodromal features of bipolar affective disorder. Psychol. Med.
41: 1567–1577. [PMC free article] [PubMed] [Google Scholar]92.

Patel, R.
, Lloyd T., Jackson R., et al
2015.
Mood instability is a common feature of mental health disorders and is associated with poor clinical outcomes. BMJ Open
5: e007504. [PMC free article] [PubMed] [Google Scholar]93.

Strejilevich, S.A.
, Martino D.J., Murru A., et al
2013.
Mood instability and functional recovery in bipolar disorders. Acta Psychiatr. Scand.
128: 194–202. [PubMed] [Google Scholar]94.

Gershon, A.
& Eidelman P.. 2015.
Inter‐episode affective intensity and instability: predictors of depression and functional impairment in bipolar disorder. J. Behav. Ther. Exp. Psychiatry
46: 14–18. [PMC free article] [PubMed] [Google Scholar]95.

Solhan, M.B.
, Trull T.J., Jahng S. & Wood P.K.. 2009.
Clinical assessment of affective instability: comparing EMA indices, questionnaire reports, and retrospective recall. Psychol. Assess.
21: 425–436. [PMC free article] [PubMed] [Google Scholar]96.

Marwaha, S.
, He Z., Broome M., et al
2014.
How is affective instability defined and measured? A systematic review. Psychol. Med.
44: 1793–1808. [PubMed] [Google Scholar]97.

Broome, M.R.
, He Z., Iftikhar M., et al
2015.
Neurobiological and behavioural studies of affective instability in clinical populations: a systematic review. Neurosci. Biobehav. Rev.
51: 243–254. [PubMed] [Google Scholar]98.

Beckmann, C.F.
, DeLuca M., Devlin J.T. & Smith S.M.. 2005.
Investigations into resting‐state connectivity using independent component analysis. Phil. Trans. R. Soc. Lond. B Biol. Sci.
360: 1001–1013. [PMC free article] [PubMed] [Google Scholar]99.

Smith, S.M.
, Miller K.L., Moeller S., et al
2012.
Temporally‐independent functional modes of spontaneous brain activity. Proc. Natl. Acad. Sci. U.S.A.
109: 3131–3136. [PMC free article] [PubMed] [Google Scholar]101.

Brookes, M.J.
, Woolrich M., Luckhoo H., et al
2011.
Investigating the electrophysiological basis of resting state networks using magnetoencephalography. Proc. Natl. Acad. Sci. U.S.A.
108: 16783–16788. [PMC free article] [PubMed] [Google Scholar]102.

Luckhoo, H.
, Hale J.R., Stokes M.G., et al
2012.
Inferring task‐related networks using independent component analysis in magnetoencephalography. Neuroimage
62: 530–541. [PMC free article] [PubMed] [Google Scholar]103.

Baker, A.P.
, Brookes M.J., Rezek I.A., et al
2014.
Fast transient networks in spontaneous human brain activity. eLife
3: e01867. [PMC free article] [PubMed] [Google Scholar]104.

Harmer, C.J.
, Cowen P.J. & Goodwin G.M.. 2011.
Efficacy markers in depression. J. Psychopharmacol.
25: 1148–1158. [PubMed] [Google Scholar]105.

Warren, M.B.
, Pringle A. & Harmer C.J.. 2015.
A neurocognitive model for understanding treatment action in depression. Philos. Trans. R. Soc. Lond. B Biol. Sci.
370: 20140213. [PMC free article] [PubMed] [Google Scholar]106.

Phillips, M.L.
& Swartz H.A.. 2014.
A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research. Am. J. Psychiatry
171: 829–843. [PMC free article] [PubMed] [Google Scholar]107.

Craddock, N.
& Sklar P.. 2013.
Genetics of bipolar disorder. Lancet
381: 1654–1662. [PubMed] [Google Scholar]108.

Shinozaki, G.
& Potash J.B.. 2014.
New developments in the genetics of bipolar disorder. Curr. Psychiatry Rep.
16: 493. [PubMed] [Google Scholar]109.

Mühleisen, T.W.
, Leber M., Schulze T.G., et al
2014.
Genome‐wide association study reveals two new risk loci for bipolar disorder. Nat. Commun.
11: 3339. [PubMed] [Google Scholar]111.

Hasler, G.
& Wolf A.. 2015.
Toward stratified treatments for bipolar disorders. Eur. Neuropsychopharmacol.
25: 283–294. [PubMed] [Google Scholar]112.

Plenge, R.M.
, Scolnick E.M. & Altshuler D.. 2013.
Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov.
12: 581–594. [PubMed] [Google Scholar]114.

Nelson, M.R.
, Tipney H., Painter J.L., et al
2015.
The support of human genetic evidence for approved drug indications. Nat. Genet.
47: 856–860. [PubMed] [Google Scholar]115.

Papassotiropoulos, A.
& de Quervain D.J.. 2015.
Failed drug discovery in psychiatry: time for human genome‐guided solutions. Trends Cogn. Sci.
19: 183–187. [PubMed] [Google Scholar]117.

Warsh, J.J.
, Andreopoulos S. & Li P.P.. 2004.
Role of intracellular calcium signaling in the pathophysiology and pharmacotherapy of bipolar disorder: current status. Clin. Neurosci. Res.
4: 201–213. [Google Scholar]118.

Bhat, S.
, Dao D.T., Terrillion C.E., et al
2012.
CACNA1C (Ca_v1.2) in the pathophysiology of psychiatric disease. Prog. Neurobiol.
99: 1–14. [PMC free article] [PubMed] [Google Scholar]119.

McCarthy, M.J.
, Le Roux M.J., Wei H., et al
2016.
Calcium channel genes associated with bipolar disorder modulate lithium’s amplification of circadian rhythms. Neuropharmacology
101: 439–448. [PMC free article] [PubMed] [Google Scholar]120.

Ament, S.A.
, Szelinger S., Glusman G., et al
2015.
Rare variants in neuronal excitability genes influence risk for bipolar disorder. Proc. Natl. Acad. Sci. U.S.A.
112: 3576–3581. [PMC free article] [PubMed] [Google Scholar]121.

Levy, N.A.
& Janicak P.G.. 2000.
Calcium channel antagonists for the treatment of bipolar disorder. Bipolar Disord. 2: 108–119. [PubMed] [Google Scholar]122.

Cipriani, A.
, Saunders K., Attenburrow M.‐J., et al
2016.
Calcium channel antagonists in bipolar disorder. A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development. Mol. Psychiatry. In press. [PMC free article] [PubMed] [Google Scholar]123.

Ostacher, M.J.
, Iosifescu D.V., Hay A., et al
2014.
Pilot investigation of isradipine in the treatment of bipolar depression motivated by genome‐wide association. Bipolar Disord. 2: 199–203. [PubMed] [Google Scholar]124.

Striessnig, J.
, Pinggera A., Kaur G., et al
2014.
L‐type Ca²⁺ channels in heart and brain. Wiley Interdiscip. Rev. Membr. Transp. Signal.
3: 15–38. [PMC free article] [PubMed] [Google Scholar]125.

Hopkins, A.L.
& Groom C.R.. 2002.
The druggable genome. Nat. Rev. Drug Discov.
1: 727–730. [PubMed] [Google Scholar]126.

Rasband, M.N.

2010.
The axon initial segment and the maintenance of neuronal polarity. Nat. Rev. Neurosci.
11: 552–562. [PubMed] [Google Scholar]127.

Smith, K.R.
, Kopeikina K.J., Fawcett‐Patel J.M., et al
2014.
Psychiatric risk factor ANK3/ankyrin‐G nanodomains regulate the structure and function of glutamatergic synapses. Neuron
84: 399–415. [PMC free article] [PubMed] [Google Scholar]128.

Durak, O.
, de Anda F.C., Singh K.K., et al
2015.
Ankyrin‐G regulates neurogenesis and Wnt signaling by altering the subcellular localization of β‐catenin. Mol. Psychiatry
20: 388–397. [PMC free article] [PubMed] [Google Scholar]129.

Rueckert, E.H.
, Barker D., Ruderfer D., et al
2013.

Cis‐acting regulation of brain‐specific ANK3 gene expression by a genetic variant associated with bipolar disorder. Mol. Psychiatry
18: 922–929. [PMC free article] [PubMed] [Google Scholar]130.
Cross‐Disorder Group of the Psychiatric Genomics Consortium
. 2013.
Identification of risk loci with shared effects on five major psychiatric disorders: a genome‐wide analysis. Lancet
381: 1371–1379. [PMC free article] [PubMed] [Google Scholar]131.

Craddock, N.
, Jones L., Jones I.R., et al; Wellcome Trust Case Control Consortium (WTCCC).
2010.
Strong genetic evidence for a selective influence of GABA_A receptors on a component of the bipolar disorder phenotype. Mol. Psychiatry
15: 146–153. [PMC free article] [PubMed] [Google Scholar]132.

Goes, F.S.
, Hamshere M.L., Seifuddin F., et al; Bipolar Genome Study (BIGS).
2012.
Genome‐wide association of mood‐incongruent psychotic bipolar disorder. Transl. Psychiatry
2: e180. [PMC free article] [PubMed] [Google Scholar]133.

Greenwood, T.A.
, Bipolar Genome Study (BiGS) Consortium
& Kelsoe J.R.. 2013.
Genome‐wide association study of irritable vs. elated mania suggests genetic differences between clinical subtypes of bipolar disorder. PLoS One
8: e53804. [PMC free article] [PubMed] [Google Scholar]134.

Insel, T.
, Cuthbert B., Garvey M., et al
2010.
Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am. J. Psychiatry
167: 748–751. [PubMed] [Google Scholar]135.

Lee, R.S.
, Hermens D.F., Scott J., et al
2014.
A meta‐analysis of neuropsychological functioning in first‐episode bipolar disorders. J. Psychiatr. Res.
57: 1–11. [PubMed] [Google Scholar]136.

Martinez‐Aran, A.
& Vieta E.. 2015.
Cognition as a target in schizophrenia, bipolar disorder and depression. Eur. Neuropsychopharmacol.
25: 151–157. [PubMed] [Google Scholar]137.

Harvey, A.G.

2008.
Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony, and regulation. Am. J. Psychiatry
165: 820–829. [PubMed] [Google Scholar]138.

Levenson, J.C.
, Axelson D.A., Merranko J., et al
2015.
Differences in sleep disturbances among offspring of parents with and without bipolar disorder: association with conversion to bipolar disorder. Bipolar Disord. 17: 836–848. [PMC free article] [PubMed] [Google Scholar]139.

Ritter, P.S.
, Höfler M., Wittchen H.U., et al
2015.
Disturbed sleep as risk factor for the subsequent onset of bipolar disorder—data from a 10‐year prospective‐longitudinal study among adolescents and young adults. J. Psychiatr. Res.
68: 76–82. [PubMed] [Google Scholar]140.

Cretu, J.B.
, Culver J.L., Goffin K.C., et al
2016.
Sleep, residual symptoms, and time to relapse in recovered patients with bipolar disorder. J. Affect. Disord.
190: 162–166. [PubMed] [Google Scholar]141.

Pinho, M.
, Sehmbi M., Cudney L., et al
2016.
The association between biological rhythms, depression, and functioning in bipolar disorder: a large multi‐center study. Acta Psychiatr. Scand. 133: 102–108. [PubMed] [Google Scholar]142.

Byrne, E.M.
, Gehrman P.R., Medland S.E., et al; Chronogen Consortium
. 2013.
A genome‐wide association study of sleep habits and insomnia. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162B: 439–451. [PMC free article] [PubMed] [Google Scholar]143.

Parsons, M.J.
, Lester K.J., Barclay N.L., et al
2013.
Replication of genome‐wide association studies (GWAS) loci for sleep in the British G1219 cohort. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162B: 431–438. [PubMed] [Google Scholar]144.

Heck, A.
, Fastenrath M., Ackermann S., et al
2014.
Converging genetic and functional brain imaging evidence links neuronal excitability to working memory, psychiatric disease, and brain activity. Neuron
81: 1203–1213. [PMC free article] [PubMed] [Google Scholar]145.

Heck, A.
, Fastenrath M., Coynel D., et al
2015.
Genetic analysis of association between calcium signaling and hippocampal activation, memory performance in the young and old, and risk for sporadic Alzheimer disease. JAMA Psychiatry
72: 1029–1036. [PMC free article] [PubMed] [Google Scholar]146.

Viswanath, B.
, Jose S.P., Squassina A., et al
2015.
Cellular models to study bipolar disorder: a systematic review. J. Affect. Disord.
15: 36–50. [PubMed] [Google Scholar]147.

Andreazza, A.C.
& Young L.T.. 2015.
The neurobiology of bipolar disorder: identifying targets for specific agents and synergies for combination treatment. Int. J. Neuropsychopharmacol. 17: 1039–1052. [PubMed] [Google Scholar]148.

Chen, H.M.
, DeLong C.J., Bame M., et al
2014.
Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients. Transl. Psychiatry
4: e375. [PMC free article] [PubMed] [Google Scholar]149.

Wang, J.L.
, Shamah S.M., Sun A.X., et al
2014.
Label‐free, live optical imaging of reprogrammed bipolar disorder patient‐derived cells reveals a functional correlate of lithium responsiveness. Transl. Psychiatry
4: e428. [PMC free article] [PubMed] [Google Scholar]150.

Madison, J.M.
, Zhou F., Nigam A., et al
2015.
Characterization of bipolar disorder patient‐specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol. Psychiatry
20: 703–717. [PMC free article] [PubMed] [Google Scholar]151.

Mertens, J.
, Wang Q.‐W., Kim Y., et al; Pharmacogenomics of Bipolar Disorder Study
. 2015.
Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature
527: 95–99. [PMC free article] [PubMed] [Google Scholar]152.

Yoshimizu, T.
, Pan J.Q., Mungenast A.E., et al
2015.
Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons. Mol. Psychiatry
20: 162–169. [PMC free article] [PubMed] [Google Scholar]153.

Bigos, K.L.
, Mattay V.S., Callicott J.H., et al
2010.
Genetic variation in CACNA1C affects brain circuitries related to mental illness. Arch. Gen. Psychiatry
67: 939–945. [PMC free article] [PubMed] [Google Scholar]154.

Malhi, G.S.
& Geddes J.R.. 2014.
Carving bipolarity using a lithium sword. Br. J. Psychiatry
205: 337–339. [PubMed] [Google Scholar]155.

Tighe, S.K.
, Mahon P.B. & Potash J.B.. 2011.
Predictors of lithium response in bipolar disorder. Ther. Adv. Chronic Dis.
2: 209–226. [PMC free article] [PubMed] [Google Scholar]156.

Harrison, P.J.
, Cader M.Z. & Geddes J.R.. 2016.
Reprogramming psychiatry: stem cells and bipolar disorder. Lancet
387: 823–825. [PubMed] [Google Scholar]158.

Einat, H.

2007.
Different behaviors and different strains: potential new ways to model bipolar disorder. Neurosci. Biobehav. Rev.
31: 850–857. [PubMed] [Google Scholar]159.

Cosgrove, V.E.
, Kelsoe J.R. & Suppes T.. 2016.
Toward a valid animal model of bipolar disorder: how the research domain criteria help bridge the clinical–basic science divide. Biol. Psychiatry
79: 62–70. [PubMed] [Google Scholar]160.

Han, K.
, Holder J.L., Schaaf C.P., et al
2013.
SHANK3 overexpression causes manic‐like behaviour with unique pharmacogenetic properties. Nature
503: 72–77. [PMC free article] [PubMed] [Google Scholar]161.

Leussis, M.P.
, Berry‐Scott E.M., Saito M., et al
2013.
The ANK3 bipolar disorder gene regulates psychiatric‐related behaviors that are modulated by lithium and stress. Biol. Psychiatry
73: 683–690. [PubMed] [Google Scholar]162.

Sidor, M.M.
, Spencer S.M., Dzirasa K., et al
2015.
Daytime spikes in dopaminergic activity drive rapid mood‐cycling in mice. Mol. Psychiatry
20: 1406–1419. [PMC free article] [PubMed] [Google Scholar]163.

Chung, S.
, Lee E.J., Yun S., et al
2014.
Impact of circadian nuclear receptor REV‐ERBα on midbrain dopamine production and mood regulation. Cell
157: 858–868. [PubMed] [Google Scholar]164.

McClung, C.A.

2011.
Circadian rhythms and mood regulation: insights from pre‐clinical models. Eur. Neuropsychopharmacol.
21(Suppl. 4): S683–S693. [PMC free article] [PubMed] [Google Scholar]

Bipolar disorder – Diagnosis and treatment

Diagnosis

To determine if you have bipolar disorder, your evaluation may include:

• Physical exam. Your doctor may do a physical exam and lab tests to identify any medical problems that could be causing your symptoms.
• Psychiatric assessment. Your doctor may refer you to a psychiatrist, who will talk to you about your thoughts, feelings and behavior patterns. You may also fill out a psychological self-assessment or questionnaire. With your permission, family members or close friends may be asked to provide information about your symptoms.
• Mood charting. You may be asked to keep a daily record of your moods, sleep patterns or other factors that could help with diagnosis and finding the right treatment.
• Criteria for bipolar disorder. Your psychiatrist may compare your symptoms with the criteria for bipolar and related disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published by the American Psychiatric Association.

Diagnosis in children

Although diagnosis of children and teenagers with bipolar disorder includes the same criteria that are used for adults, symptoms in children and teens often have different patterns and may not fit neatly into the diagnostic categories.

Also, children who have bipolar disorder are frequently also diagnosed with other mental health conditions such as attention-deficit/hyperactivity disorder (ADHD) or behavior problems, which can make diagnosis more complicated. Referral to a child psychiatrist with experience in bipolar disorder is recommended.

Treatment

Treatment is best guided by a medical doctor who specializes in diagnosing and treating mental health conditions (psychiatrist) who is skilled in treating bipolar and related disorders. You may have a treatment team that also includes a psychologist, social worker and psychiatric nurse.

Bipolar disorder is a lifelong condition. Treatment is directed at managing symptoms. Depending on your needs, treatment may include:

• Medications. Often, you’ll need to start taking medications to balance your moods right away.
• Continued treatment. Bipolar disorder requires lifelong treatment with medications, even during periods when you feel better. People who skip maintenance treatment are at high risk of a relapse of symptoms or having minor mood changes turn into full-blown mania or depression.
• Day treatment programs. Your doctor may recommend a day treatment program. These programs provide the support and counseling you need while you get symptoms under control.
• Substance abuse treatment. If you have problems with alcohol or drugs, you’ll also need substance abuse treatment. Otherwise, it can be very difficult to manage bipolar disorder.
• Hospitalization. Your doctor may recommend hospitalization if you’re behaving dangerously, you feel suicidal or you become detached from reality (psychotic). Getting psychiatric treatment at a hospital can help keep you calm and safe and stabilize your mood, whether you’re having a manic or major depressive episode.

The primary treatments for bipolar disorder include medications and psychological counseling (psychotherapy) to control symptoms, and also may include education and support groups.

Medications

A number of medications are used to treat bipolar disorder. The types and doses of medications prescribed are based on your particular symptoms.

Medications may include:

• Mood stabilizers. You’ll typically need mood-stabilizing medication to control manic or hypomanic episodes. Examples of mood stabilizers include lithium (Lithobid), valproic acid (Depakene), divalproex sodium (Depakote), carbamazepine (Tegretol, Equetro, others) and lamotrigine (Lamictal).
• Antipsychotics. If symptoms of depression or mania persist in spite of treatment with other medications, adding an antipsychotic drug such as olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), aripiprazole (Abilify), ziprasidone (Geodon), lurasidone (Latuda) or asenapine (Saphris) may help. Your doctor may prescribe some of these medications alone or along with a mood stabilizer.
• Antidepressants. Your doctor may add an antidepressant to help manage depression. Because an antidepressant can sometimes trigger a manic episode, it’s usually prescribed along with a mood stabilizer or antipsychotic.
• Antidepressant-antipsychotic. The medication Symbyax combines the antidepressant fluoxetine and the antipsychotic olanzapine. It works as a depression treatment and a mood stabilizer.
• Anti-anxiety medications. Benzodiazepines may help with anxiety and improve sleep, but are usually used on a short-term basis.

Finding the right medication

Finding the right medication or medications for you will likely take some trial and error. If one doesn’t work well for you, there are several others to try.

This process requires patience, as some medications need weeks to months to take full effect. Generally only one medication is changed at a time so that your doctor can identify which medications work to relieve your symptoms with the least bothersome side effects. Medications also may need to be adjusted as your symptoms change.

Side effects

Mild side effects often improve as you find the right medications and doses that work for you, and your body adjusts to the medications. Talk to your doctor or mental health professional if you have bothersome side effects.

Don’t make changes or stop taking your medications. If you stop your medication, you may experience withdrawal effects or your symptoms may worsen or return. You may become very depressed, feel suicidal, or go into a manic or hypomanic episode. If you think you need to make a change, call your doctor.

Medications and pregnancy

A number of medications for bipolar disorder can be associated with birth defects and can pass through breast milk to your baby. Certain medications, such as valproic acid and divalproex sodium, should not be used during pregnancy. Also, birth control medications may lose effectiveness when taken along with certain bipolar disorder medications.

Discuss treatment options with your doctor before you become pregnant, if possible. If you’re taking medication to treat your bipolar disorder and think you may be pregnant, talk to your doctor right away.

Psychotherapy

Psychotherapy is a vital part of bipolar disorder treatment and can be provided in individual, family or group settings. Several types of therapy may be helpful. These include:

• Interpersonal and social rhythm therapy (IPSRT). IPSRT focuses on the stabilization of daily rhythms, such as sleeping, waking and mealtimes. A consistent routine allows for better mood management. People with bipolar disorder may benefit from establishing a daily routine for sleep, diet and exercise.
• Cognitive behavioral therapy (CBT). The focus is identifying unhealthy, negative beliefs and behaviors and replacing them with healthy, positive ones. CBT can help identify what triggers your bipolar episodes. You also learn effective strategies to manage stress and to cope with upsetting situations.
• Psychoeducation. Learning about bipolar disorder (psychoeducation) can help you and your loved ones understand the condition. Knowing what’s going on can help you get the best support, identify issues, make a plan to prevent relapse and stick with treatment.
• Family-focused therapy. Family support and communication can help you stick with your treatment plan and help you and your loved ones recognize and manage warning signs of mood swings.

Other treatment options

Depending on your needs, other treatments may be added to your depression therapy.

During electroconvulsive therapy (ECT), electrical currents are passed through the brain, intentionally triggering a brief seizure. ECT seems to cause changes in brain chemistry that can reverse symptoms of certain mental illnesses. ECT may be an option for bipolar treatment if you don’t get better with medications, can’t take antidepressants for health reasons such as pregnancy or are at high risk of suicide.

Transcranial magnetic stimulation (TMS) is being investigated as an option for those who haven’t responded to antidepressants.

Treatment in children and teenagers

Treatments for children and teenagers are generally decided on a case-by-case basis, depending on symptoms, medication side effects and other factors. Generally, treatment includes:

• Medications. Children and teens with bipolar disorder are often prescribed the same types of medications as those used in adults. There’s less research on the safety and effectiveness of bipolar medications in children than in adults, so treatment decisions are often based on adult research.
• Psychotherapy. Initial and long-term therapy can help keep symptoms from returning. Psychotherapy can help children and teens manage their routines, develop coping skills, address learning difficulties, resolve social problems, and help strengthen family bonds and communication. And, if needed, it can help treat substance abuse problems common in older children and teens with bipolar disorder.
• Psychoeducation. Psychoeducation can include learning the symptoms of bipolar disorder and how they differ from behavior related to your child’s developmental age, the situation and appropriate cultural behavior. Understanding about bipolar disorder can also help you support your child.
• Support. Working with teachers and school counselors and encouraging support from family and friends can help identify services and encourage success.

More Information

Show more related information

Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

You’ll probably need to make lifestyle changes to stop cycles of behavior that worsen your bipolar disorder. Here are some steps to take:

• Quit drinking or using recreational drugs. One of the biggest concerns with bipolar disorder is the negative consequences of risk-taking behavior and drug or alcohol abuse. Get help if you have trouble quitting on your own.
• Form healthy relationships. Surround yourself with people who are a positive influence. Friends and family members can provide support and help you watch for warning signs of mood shifts.
• Create a healthy routine. Having a regular routine for sleeping, eating and physical activity can help balance your moods. Check with your doctor before starting any exercise program. Eat a healthy diet. If you take lithium, talk with your doctor about appropriate fluid and salt intake. If you have trouble sleeping, talk to your doctor or mental health professional about what you can do.
• Check first before taking other medications. Call the doctor who’s treating you for bipolar disorder before you take medications prescribed by another doctor or any over-the-counter supplements or medications. Sometimes other medications trigger episodes of depression or mania or may interfere with medications you’re taking for bipolar disorder.
• Consider keeping a mood chart. Keeping a record of your daily moods, treatments, sleep, activities and feelings may help identify triggers, effective treatment options and when treatment needs to be adjusted.

Alternative medicine

There isn’t much research on alternative or complementary medicine — sometimes called integrative medicine — and bipolar disorder. Most of the studies are on major depression, so it isn’t clear how these nontraditional approaches work for bipolar disorder.

If you choose to use alternative or complementary medicine in addition to your physician-recommended treatment, take some precautions first:

• Don’t stop taking your prescribed medications or skip therapy sessions. Alternative or complementary medicine is not a substitute for regular medical care when it comes to treating bipolar disorder.
• Be honest with your doctors and mental health professionals. Tell them exactly which alternative or complementary treatments you use or would like to try.
• Be aware of potential dangers. Alternative and complementary products aren’t regulated the way prescription drugs are. Just because it’s natural doesn’t mean it’s safe. Before using alternative or complementary medicine, talk to your doctor about the risks, including possible serious interactions with medications.

Coping and support

Coping with bipolar disorder can be challenging. Here are some strategies that can help:

• Learn about bipolar disorder. Education about your condition can empower you and motivate you to stick to your treatment plan and recognize mood changes. Help educate your family and friends about what you’re going through.
• Stay focused on your goals. Learning to manage bipolar disorder can take time. Stay motivated by keeping your goals in mind and reminding yourself that you can work to repair damaged relationships and other problems caused by your mood swings.
• Join a support group. Support groups for people with bipolar disorder can help you connect to others facing similar challenges and share experiences.
• Find healthy outlets. Explore healthy ways to channel your energy, such as hobbies, exercise and recreational activities.
• Learn ways to relax and manage stress. Yoga, tai chi, massage, meditation or other relaxation techniques can be helpful.

Preparing for your appointment

You may start by seeing your primary care doctor or a psychiatrist. You may want to take a family member or friend along to your appointment, if possible, for support and to help remember information.

What you can do

Before your appointment, make a list of:

• Any symptoms you’ve had, including any that may seem unrelated to the reason for the appointment
• Key personal information, including any major stresses or recent life changes
• All medications, vitamins, herbs or other supplements you’re taking, and the dosages
• Questions to ask your doctor

Some questions to ask your doctor may include:

• Do I have bipolar disorder?
• Are there any other possible causes for my symptoms?
• What kinds of tests will I need?
• What treatments are available? Which do you recommend for me?
• What side effects are possible with that treatment?
• What are the alternatives to the primary approach that you’re suggesting?
• I have these other health conditions. How can I best manage these conditions together?
• Should I see a psychiatrist or other mental health professional?
• Is there a generic alternative to the medicine you’re prescribing?
• Are there any brochures or other printed material that I can have?
• What websites do you recommend?

Don’t hesitate to ask other questions during your appointment.

What to expect from your doctor

Your doctor will likely ask you a number of questions. Be ready to answer them to reserve time to go over any points you want to focus on. Your doctor may ask:

• When did you or your loved ones first begin noticing your symptoms?
• How frequently do your moods change?
• Do you ever have suicidal thoughts when you’re feeling down?
• Do your symptoms interfere with your daily life or relationships?
• Do you have any blood relatives with bipolar disorder or depression?
• What other mental or physical health conditions do you have?
• Do you drink alcohol, smoke cigarettes or use recreational drugs?
• How much do you sleep at night? Does it change over time?
• Do you go through periods when you take risks that you wouldn’t normally take, such as unsafe sex or unwise, spontaneous financial decisions?
• What, if anything, seems to improve your symptoms?
• What, if anything, appears to worsen your symptoms?

Feb. 16, 2021

What are alternative treatments to medication for depression?

I am not currently on medication, but my doctor is suggesting it. What are alternative treatments to medication?

Good question! Before delving into a list of alternatives, let’s first think about how to think about this decision.

It’s not about following a set of rules, or really even about following what the scientific evidence says—although scientific evidence can be helpful in assisting you to make an informed decision. It’s really about costs and benefits—costs and benefits to you. In making a decision, it helps to enumerate the costs, or risks, on the one hand and the potential benefits on the other. And this depends on your personal situation.

Let’s say the condition you’re working on is bipolar disorder, type I. Persons with this condition have had one, and typically several, manic episodes. These episodes cause extensive havoc, sometimes irreparable, in an individual’s life. Often, they entail hospitalization and sometimes even psychotic symptoms. And if you’ve had one manic episode, odds are you’ll have another one at some time in the future. Clearly there’s a lot of risk here, and the potential costs to you are enormous. And the evidence base is pretty clear that medications can help to treat and prevent manic episodes, as well as the episodes of depression that almost invariably accompany bipolar type I. So, there’s a lot of risk involved in going without medications.

Now at the other end of the spectrum, let’s say the condition you’re working on is a single, first episode of depression, without hospitalization, psychosis, or suicidality. Maybe there is even a clear and identifiable stress that brought it on, and maybe you’re able to “play with pain” and keep going in your roles at work and home. Here the risks are feeling miserable, and perhaps making yourself more prone to future episodes by not having medication treatment for this first episode (the evidence is not so clear about this last point). The benefits of treatment are, simply, feeling less miserable faster with some type of treatment, either with medications or with other alternatives.

These two scenarios are purposely oversimplified—real, individual situations are not often this clear. But the point is this: Treatment choice depends on potential costs to you and what the evidence says are the potential benefits of various treatment options.

Let’s say you’re hesitant to take medications. Are there evidence-based alternatives? Well, it depends on the condition. For bipolar disorder—either type I or type II, which has milder forms of mania called “hypomania”—the risks are typically high enough and the evidence of treatment benefit is strong enough that clinicians recommend medication in almost all cases. If you do your own cost-benefit analysis, you’ll likely see why. Also, if you battle severe or chronic or recurrent depressions, or depression with suicidal urges or psychosis, the cost-benefit typically favors medication. In both these cases, however, medication plus psychotherapy are optimal treatments.

In single episodes of depression, or recurrent depressions that are not extremely severe, there can be benefits from non-medication treatments. Cognitive-behavioral therapy and interpersonal therapy probably have the strongest evidence base as alternatives to medication for depression. There is also some evidence supporting family therapies, therapies oriented toward strengthening circadian (daily) rhythms, problem-solving therapy, and a group of approaches sometimes called “psychoeducation” that focuses on developing a better understanding of one’s symptom pattern and improving coping responses to symptoms. There is also some evidence that certain types of psychodynamic therapies derived from classic psychoanalysis may help. There are various self-guided books and apps and web programs based on these evidence-based psychotherapies, but rarely have they been tested in clinical trials. Shop carefully.

In terms of non-medication devices, electroconvulsive therapy (ECT), also called “shock therapy,” is probably the most effective form of treatment for severe or psychotic depressive episodes. Recently, a procedure called reverse transcranial magnetic stimulation (rTMS) has accrued some evidence for effectiveness in depression.

What of so-called “complementary,” “alternative,” or “integrative medicine” techniques? These include both dietary supplements or restrictions, and life-enhancing practices that are typically derived from eastern medicine or philosophy. This latter group includes such practices as yoga, tai-chi, qi-gong, acupuncture, acupressure, and certain types of meditation. None of these has a particularly strong evidence base for mood disorders, though some practices, such as yoga and related techniques, can be quite helpful physically and mentally in general. In terms of supplements or dietary restrictions, the question is more one of costs (including financially) and risks (in terms of toxicity and interactions with medications you may be taking). If you go this route, be sure to let your prescribers know exactly what you are taking and let them do a risk analysis.

It takes a partnership to make a good decision: You are the expert in your own situation and your own risk tolerance, and your clinician is the expert in the evidence. Put your heads together, jointly choose a path forward, monitor the results, and change plans if necessary.

Managing bipolar disorder without medication

Bipolar disorder is a diagnosis given to people who experience periods of intense low mood but also periods of elation and increased energy which can lead to impaired judgement and risky behaviour. The Royal College of Psychiatrists estimates that around 1% of the adult population experience bipolar symptoms at some point in their life.

UK guidance for the treatment of bipolar disorder has an emphasis on medication. However, more than 60% of people with the diagnosis stop taking their medication at some point. This is often because of the common and severe and unpleasant side effects that drugs such as lithium and olanzapine can produce. These include dizziness, diarrhoea, slowed movement and substantial weight gain.

Lithium – not for everyone.
Lithium by Shutterstock

A recent review also suggested that medication only helps a small proportion of those it is prescribed to. The review looked at 12 different medication regimes used under several different circumstances and found the highest success rate was just 33%. And lithium, a drug that NICE recommends as the “first-line, long-term pharmacological treatment for bipolar disorder” was found to benefit only about one in seven patients. It is also a very toxic drug. Recent research has found that around one in three of those taking lithium over many years will go on to suffer from chronic renal failure.

Despite this, patient decisions to stop taking medication are typically regarded by mental health professionals as being due to “lack of insight” or “inaccurate concerns” about a drug’s safety or efficacy. Many are also concerned about what might happen to people not taking medication if they fail to recognise when their mood is causing them difficulties. As some researchers have suggested that as many as half of patients with a bipolar diagnosis can suffer from a lack of awareness of their mental health difficulties, a common fear is that someone who is off their medication will lose the ability to identify when they aren’t well.

Personal strategies

To find out how people who stop taking medication manage, we conducted in-depth interviews with ten people with a bipolar diagnosis who had chosen to stop taking their medication for a period.

They told us that the first step they took was to conduct a cost/benefit analysis of the pros and cons of taking medication, and they described keeping this decision under regular review. They then asked themselves if their mood was actually causing them problems or concerns (some people do see positive aspects to experiencing their bipolar moods). Next they used their past experience to identify practical things they could do to help keep their mood at the level they wanted, or to adjust it if they felt it wasn’t “right”.

People use a wide range of strategies to manage their mood; the people we interviewed talked about more than 50 different approaches ranging from simple things like doing exercise, pampering themselves, talking to (or avoiding) specific friends or family members, to taking time off work, using techniques they had learned from psychological therapy, or even going on holiday or (in one case) moving temporarily abroad.

Running.
Jogging by Shutterstock

The important thing for the people we talked to, however, was that the strategies they used had to fit their understanding of themselves, their identity and their goals in life. This was different for each person and each individual needed to identify what worked for them. For some people financial constraints also stopped them using all the strategies they would have liked to.

An alternative for some people experiencing a “high” mood was to take the extra energy it gave them and consciously channel it into something positive, such as their work or a hobby or project. However, some people we talked to suggested that just “going with” a high mood could make things worse. They worked to manage high moods by identifying people close to them who could provide them with an objective view of how they were behaving – someone around to “check in with”. These people could also help those with bipolar work out whether the strategies they were using were working.

These frequent evaluations were another important factor for those managing without medication. If the strategies they had been using were not working, people initially tried to find better ways to adjust their mood. However, if things were getting bad, then they might instead stop trying to change their mood and just withdraw from their normal daily activities (and perhaps take time off work) until their mood settled. Some also turned to friends or family for practical support and advice, and some would also consider a temporary return to using medication.

The conversations with our participants highlighted two key things. The first was that far from showing a “lack of insight”, the people who talked to us described careful, well-reasoned and considered decision making around stopping their medication. The approach to managing moods they all described was also in stark contrast to the usual approach taken by mental health services to people with a bipolar diagnosis.

Services tend to focus heavily on medication prescription, and while some psychological therapies are available to help people manage low mood, it has been suggested that talking therapies should target improving people’s compliance with taking medication.

Research, such as the recent review, seems to be pointing to the ineffectiveness of medication for most people with a bipolar diagnosis, we would argue that services could better use their resources by working with patients in a collaborative way, helping them identify and supporting them in implementing whichever strategies (which might include or exclude medication) work best for them personally in managing their moods and helping them live fulfilling lives.

Bipolar Disorder Introduction – Alternative Mental Health Medicine

image by Colin Dunn (lic)Bipolar disorder (formerly called manic depression) is a mood disorder that causes drastic changes in mood from high manic phases to depressive low phases. The manic phase is characterized by feelings of elated mood and exaggerated self-importance, talkativeness, little need for sleep, increased sociability, racing thoughts, risky or inappropriate behavior, and increased sexual appetite. This period of mania is often followed by a period of depression, with the symptoms mentioned previously (loss of interest or pleasure in previously enjoyable activities; major changes in appetite; sleep problems; fatigue, a feeling of worthlessness or hopelessness; problems with concentration and making decisions; and thoughts of suicide). The change from the manic phase to the depressive phase is called “cycling”. Some people with Bipolar Disorder cycle quickly, while others cycle more slowly. The cycling can be “deep” with very severe manic and very severe depressive phases, or the cycling can be less severe with mild depression and manic phases.

The term “Bipolar Disorder” actually describes four different disorders which range in phase severity and how quickly someone’s mood cycles between phases.

Complementary and Alternative Therapies for Bipolar Disorder

There are no CAM therapies that can take the place of conventional medical therapies for the treatment of bipolar disorder based on current research understandings. Many of the supplements that have been studied for the treatment of bipolar disorder were selected on the basis of how well they treat unipolar or general depression. This is unfortunate, because depression and bipolar disorder are very different diseases which typically require separate interventions.

Even though there are no stand-alone CAM remedies for bipolar disorder, some preliminary studies suggest that many of the supplements suggested below will provide some benefit as adjunctive (complementary) treatments. The most convincing evidence suggests that Omega-3 fatty acids are helpful, but again, this supplement is not recommended as a solo treatment.

The following chart summarizes the common natural treatments for bipolar disorder and the degree of scientific study to support their use:

(A) Well Supported Integrative Therapies for Bipolar Disorder

Clinical use of lithium salts: guide for users and prescribers | International Journal of Bipolar Disorders

Mental illness and complementary / alternative treatments

Useful contacts

Complementary and Natural Healthcare Council
This is an independent regulatory body set up by the government. They set professional standards and a code of ethics that complementary therapists have to follow. They keep an independent register of qualified therapists, and can investigate complaints.

Telephone: 020 3668 0406
Address: 46-48 East Smithfield, London, E1W 1AW
Email: [email protected]
Website: www.cnhc.org.uk

The Aromatherapy Council
A UK professional body that sets and maintain education standards for aromatherapy professionals.

Website: www.aromatherapycouncil.org.uk

The Association of Natural Medicine (ANM)
The ANM is a membership body for complementary therapists. Registered therapists must show the ANM that they have the right qualifications and experience to be a therapist. They also run training for therapists.

Telephone: 07596 427084
Address: 27 Braintree Road, Witham, Essex, CM8 2DD
Email:[email protected]
Website: www.associationnaturalmedicine.co.uk

Association of Reflexologists (AoR)
This is a membership body for reflexologists. To be a member, therapists must show they have the right qualifications and experience to practice.

Telephone: 01823 351010
Address: Victoria House, Victoria Street, Taunton, Somerset, TA1 3FA
Email: [email protected]
Website: www.aor.org.uk

The British Acupuncture Council (BAcC)
A self-regulatory body of therapists who practice traditional acupuncture in the UK.

Telephone: 0208 735 0400
Address: 63 Jeddo Road, London, W12 9HQ
Email: [email protected]
Website: www.acupuncture.org.uk

British Complementary Medicine Association
An international umbrella organisation for therapists and their clients.

Telephone: 0845 345 5977
Address: BCMA, P.O. Box 5122, Bournemouth, BH8 0WG
Email: [email protected]
Website: www.bcma.co.uk

Complementary and Natural Healthcare Council
This is an independent regulatory body set up by the government. They set professional standards and a code of ethics that complementary therapists have to follow. They keep an independent register of qualified therapists, and can investigate complaints.

Telephone: 020 3668 0406
Address: 46-48 East Smithfield, London, E1W 1AW
Email: [email protected]
Website: www.cnhc.org.uk

Complementary Medical Association
This is an international association for complementary therapists. They promote ethical, responsible and professional complementary medicine.

Telephone: 0845 129 8434
Email: via form on website: www.the-cma.org.uk/contact-us
Website: www.the-cma.org.uk

The Complementary Therapies Association
An association that represents sports, spa and complementary therapists in the UK and Ireland.

Telephone: 0207 518 0323
Address: Room 2T.07, 17 Hanover Square, Mayfair, London, W1S 1BN
Email: [email protected]
Website: www.ctha.com

Federation of Holistic Therapists
A professional membership association for therapists in the UK and Ireland. Therapies include sports and remedial therapies, complementary healthcare, and holistic beauty treatments. Therapists must hold recognised qualifications to register.

Telephone: 023 8062 4350
Address: 18 Shakespeare Business Centre, Hathaway Close, Eastleigh, Hampshire, SO50 4SR
Email: [email protected]
Website: www.fht.org.uk

The National Institute of Medical Herbalists
A UK professional body representing herbal practitioners. You can search for qualified herbalists on their website. They also have an information service for professionals and the public about herbal medicine.

Telephone: 01392 426022
Address: Clover House, James Court, South Street, Exeter, EX1 1EE
Email: [email protected]
Website: www.nimh.org.uk

The Shiatsu Society UK
A non-profit organisation that represents practitioners and promotes professionalism.

Telephone: 01788 547900
Address: 20-22 Wenlock Road, London, N1 7GU
Email via website: www.shiatsusociety.org/contact
Website: www.shiatsusociety.org

UK Reiki Federation
They are a UK professional body representing Reiki practitioners. You can search for a practitioner in your area.

Telephone: 0203 432 6287
Address: Suite 437, 4th Floor, Davis House, Robert Street, Croydon, CR10 1QQ
Email: [email protected]
Website: www.reikifed.co.uk

The Alliance of Registered Homeopaths (ARH)
An organisation of qualified homeopaths which has a Code of Ethics and Practice

Telephone: 01825 714506
Address: Millbrook, Millbrook Hill, Nutley, Uckfield, TN22 3PJ
Email: [email protected]
Website: www.a-r-h.org

modern methods of treating the disease / “Russian Radio University” / Radio station “Radio Russia”

In the last issue we talked about what bipolar disorder is. Now let’s talk about the most modern methods of treating this ailment. Is it curable?

Andrey Arkadievich Shmilovich : This diagnosis was not very popular in our country, before it sounded like “manic-depressive psychosis”. The United States and some European countries are leaders in the study of this disease.From there, innovation comes to us. But now I can boast of the successes of our national psychiatry. The Moscow Research Institute of Psychiatry of the Ministry of Health of the Russian Federation has a department of affective disorders. Of course, when the phrase “the disease is incurable” sounds, it sounds scary. It sounds like a verdict in court. This is a wound that also makes the treatment worse. It all depends on what we mean by “cure”. If this is a confident and reliable control over symptoms, when the symptoms do not manifest themselves in any way, if at the same time a person is critical of this disease and can function absolutely normally, then we may well call this condition mental health and healing.

Unfortunately, there is a passion for drug therapy, and not only in Russia. It is not right. In psychiatry, psychotherapy and social methods of treatment must play a huge role. It is no coincidence that in bipolar affective disorder, the disease is accompanied by drug addiction. This is due to the fact that patients understand their illness, but try to “go to the people”, looking for folk remedies. And the main folk remedy all over the world is the alcohol market. A person immediately receives the tranquilizing effect of ethanol, which relieves the condition.But then the depression returns and the patient is in an even worse condition than he was before alcohol.

The main drug in the 21st century for the treatment of bipolar disorder is the so-called normotimic agent. It tones the structures that hold our emotions back. A person – this is very important – does not turn into a “vegetable”, he gains control over his emotions and can function normally.

90,000 8 treatments for bipolar disorder

Bipolar disorder (bipolar disorder, obsolete.MDP, manic-depressive psychosis) is a mental illness that manifests itself in an alternation of depressive and manic (euphoric) states, which change suddenly and at different intervals. BAR is long-term, often lifelong, and in the absence of treatment leads to the loss of the patient’s ability to work.

Contents:

10 symptoms of bipolar disorder in the diagnosis of pathology

The disease is combined with other mental disorders.Often, the patient’s attempts to cope with the disease on his own lead to drug, drug or alcohol dependence. Rehabilitation of drug addicts in this case is complicated by the course of the underlying disease and should be carried out taking it into account.

The disease is incurable, but this does not mean at all that the treatment of bipolar disorder is useless, on the contrary. Appropriate therapy can help keep the disease under control, avoid severe relapses, and maintain an acceptable lifestyle.In the absence of treatment, the symptoms increase, the alternation of hypomania and depression becomes more frequent, and these conditions themselves become more pronounced. Failure to take action will ruin the patient’s life over time.

This is one of the most common mental illnesses, according to various sources, the frequency of its occurrence ranges from 1 to 2.6%.

Each person more than once in his life has experienced a change of mood, including a sharp one – under the influence of certain factors, and some people have an extremely labile psyche and mood swings are practically normal for them.Does this mean bipolar disorder is involved? Of course no. However, it can be difficult even for a specialist to make a correct diagnosis, since bipolar disorder can be disguised as other mental pathologies, for example, depression or schizophrenia. This is a very serious problem, because an incorrect diagnosis means the wrong treatment tactics, which will not bring results, while the disease progresses. The disease manifests itself at a young age, more often in the interval of 15-21 years, however, it is diagnosed, as a rule, later, since patients and their relatives do not consider their condition painful for a long time, referring alarming symptoms to the peculiarities of transitional age.

What symptoms might indicate bipolar disorder? Manic and depressive states in such patients seem to be at different poles, manifested by extremes (hence the name: bi-polar, that is, at two different poles). Episodes of mania and depression can alternate directly with one another, or have light gaps, the so-called intermissions. Attacks of depression are longer than euphoria, and although mental disorders usually do not occur, they are very difficult to tolerate, including suicide.There is a certain gender dependence. So, in men with bipolar disorder, episodes of hypomania are more frequent, and in women – depression.

Hypomania:

• The person is in euphoria. This state differs from the usual good mood in its intensity – a person considers himself invulnerable, endowed with special, superhuman strength and good luck.
• It is difficult for a person to control his thoughts, they easily jump from one topic to another, sometimes incoherent. The speech is the same – very fast, nervous, lacking in sequence.
• No need for long night rest. Night sleep in such people is short, and sometimes even absent. Characteristically, after a sleepless night, the patient does not feel tired.
• Reckless behavior that can be described as erratic. The patient does not care, the sea is knee-deep. He can spend unreasonably large sums of money, risk his own and someone else’s life, commit other rash acts.
• Intolerance to other opinions, irritability up to aggression.

Less commonly, hypomania is accompanied by hallucinations, visions, delusions, which complicates the diagnosis and often leads to misdiagnosed schizophrenia.

Depression:

• Inability to experience positive emotions. Nothing brings joy, the world is black. The patient plunges into complete hopelessness, despair, he can be haunted by a feeling of guilt, his own uselessness.
• Sleepiness, excessive sleep, and in spite of this, tiredness.
• Increased appetite, which often causes weight gain.
• Suicidal thoughts, and sometimes attempts.
• No benefit from medications for clinical depression.

The listed signs are not strictly specific for bipolar disorder, that is, they can be detected in other diseases, so only a specialist can determine their etiology. Diagnostics is complex, it may require, in addition to the developed psychological tests for bipolar disorder, and instrumental examination in order to exclude organic brain damage.

The causes of bipolar disorder are not fully understood, but it is known that the direct etiological factor is a violation of the metabolism of neurotransmitters, which triggers a chain of pathological reactions. Presumably, this condition is genetically determined, and a strong single stress or the constant presence of stress factors that deplete the nervous system can serve as a direct impetus.

Innovative Treatments for Bipolar Disorder

The goals of treatment for bipolar disorder are:

• Elimination of symptoms of an affective attack (i.e.i.e. depression or euphoria).
• Entering the patient into remission and maintaining it for as long as possible (ideally, continuously).
• Socialization of the patient, his return to normal life.

This is the approach that is currently adopted in the treatment of bipolar disorder abroad, in contrast to what is often practiced in the countries of the former USSR, when they are limited to only the first stage.

All methods of therapy for bipolar disorder are divided into two types – medication and non-medication.The second group includes psychotherapy, rehabilitation and socialization activities.

Based on many years of clinical observations and research, protocols for BAD therapy have been developed and periodically updated, which regulate drug and non-drug treatment depending on the patient’s age, length of illness, the presence of previous therapy and a number of other parameters.

Drug therapy is selected individually, it can be one or a combination of the following groups of drugs:

• Normotimics – drugs that stabilize mood, which keep it in an acceptable range, preventing acute episodes of hypomania and depression.These are valproic acid, lithium preparations, carbamazepine, etc.
• Neuroleptics, or antipsychotics – help to eliminate psychosis, such its manifestations as hallucinations and illusions. This group includes Haloperidol, Fluanksol.
• Antidepressants – primarily Fluoxetine, as well as Citalopram, Paroxetine, Sertraline.

Psychosocial therapies that have proven effective in treating bipolar disorder include the following therapies:

• Cognitive-behavioral;
• Family;
• Interpersonal;
• Socio-rhythmic.

In addition, electroconvulsive therapy (ECT) can be used, which is indicated for acute episodes, especially in cases where the ability to take medications is limited.

Can bipolar disorder be cured in Israel

Experienced doctors are very careful about a complete cure for bipolar disorder, because due to the peculiarities of metabolism (namely, neurotransmitters), the risk of recurrence of the disease always remains.However, correctly selected therapy allows achieving a stable remission, which means for the patient the elimination of painful symptoms and a return to normal life, especially since the intellectual function does not suffer with this disease and the personality is not destroyed.

In Israel, patients with bipolar disorder live normal lives, they are socialized, work and differ from other people only by the need to constantly take medications and periodically visit a doctor. However, many other people, for example, those suffering from diabetes mellitus, have the same need.

It should be said that Israeli doctors have made significant progress in the treatment of mental disorders. An individual approach to the patient is practiced here and the most progressive methods of therapy are adopted. Psychosocial rehabilitation is widely used, the involvement of the patient’s family in the treatment process, training is provided to help the patient’s relatives better understand him, and his loved ones. The drugs of the latest generation are used, the latest protocols are applied, which provides fewer side effects and greater effectiveness.

Advanced treatment for bipolar disorder in Israel can be obtained by contacting the Renaissance Clinic. In addition to mental illness, she specializes in the treatment of addiction, which is very useful, since often patients with bipolar disorder suffer from it in one form or another.

Peculiarities of treatment of bipolar disorder without drugs in Moscow

Drug treatment of bipolar disorder abroad and in Russia is similar, the differences are mainly in psychosocial rehabilitation.Reviews about the treatment of bipolar disorder in Russia are not too optimistic and positive, they often talk about the failure of therapy, or about its temporary effect, despite the patient’s strict adherence to the doctor’s prescriptions and prescriptions.

However, patients with bipolar disorder in Moscow can receive the same treatment as abroad by contacting the Moscow branch of the Renaissance Clinic. It employs specialists trained abroad, applies the latest protocols and methods of rehabilitation, which are currently used in the therapy of bipolar disorder.In addition, the clinic offers modern treatment for alcoholism (as well as drug addiction treatment), which is relevant for patients with bipolar disorder.

In which clinics can bipolar disorder be treated in St. Petersburg

Both public and private psychiatric clinics are involved in the treatment of bipolar disorder in St. Petersburg.

Patients receive therapy here, which, however, is somewhat different from the latest methods adopted abroad.The drugs also differ – not all Russian analogues of imported drugs that they prefer to use in Russia have the same efficacy and the same safety profile as the originals.

Wanting to receive the most effective treatment for their disease, patients with bipolar disorder from St. Petersburg and other cities of Russia can contact either the Moscow branch of the Renaissance clinic, or consider the possibility of treatment in Israel.

Consider Bipolar Disorder Treatment Prices

When comparing prices for treatment of bipolar disorder in Moscow, St. Petersburg and other cities with those in Israel, a number of factors should be taken into account, the main of which is effectiveness.Citizens of Russia in Russian state clinics can receive free or partially free treatment, but the question arises about its effectiveness, whether the patient retains or restores his ability to work – can such treatment provide this? Treatment abroad will certainly be more expensive, but more likely to help the patient return to normal life.

Considering the possibility of treatment at the Renaissance clinic in Moscow or, for example, drug addiction treatment in Israel, you can calculate its approximate cost in advance.To do this, you need to contact us by filling out the contact form. Further steps will be prompted by the consultant – you may need to send the available honey by e-mail. documents and / or conduct an online consultation with a specialist, during which he will be able to more accurately determine the required amount of therapy. After that, you will receive an estimate in your hands, compiled taking into account individual indications and therefore quite accurate (subsequently, the cost may change, but insignificantly). Consulting services are free of charge.

Read Reviews of Bipolar Disorder Treatment

“For a long time I did not suspect that I was sick, I believed that life was not good for other, external reasons. Once, quite by accident, I came across an article on bipolar disorder, and I regained my sight. It was about me. I felt relief, since the disease means it can be treated I went to the doctor. I will not describe for a long time, I will say that the treatment helped me in some way, but life was far from normal. I was tired. But I decided not to give up and turned to the Renaissance in Israel.It turns out that there is an effective therapy – in two weeks I was a different person. A man, not a psycho. “

Ilya P., Rostov-on-Don, Russia

“The way mental illness is treated in our country and abroad is a huge difference! In Israel, a person with bipolar disorder is not considered to be abnormal, and you cannot tell it about him. Therefore, when such a diagnosis was found with his brother, we immediately went to Israel As far as possible, they helped him, in any case at his work they did not even guess that he was sick, they thought he was a man in depression, went to unwind and recovered.He lives as he lived, only takes pills. Thanks for your help! “

Elena Noyt, Kazan, Russia.

Methods for the treatment of hemorrhoids

Hemorrhoid treatment methods

• Device for suture ligation “BIOS”.
• Suture ligation of blood vessels supplying hemorrhoids under the control of ultrasound dopplerometry.

Currently, in connection with the development and improvement of technologies, the development of medications, new modern minimally invasive methods of hemorrhoid treatment appear, allowing effective therapy even in patients with advanced stages of the disease.So today, a technique is used that combines sclerotherapy with ultrasonic cavitation, which allows effective treatment of hemorrhoids not only in young patients, but also in elderly patients, patients with severe concomitant diseases and severe anemia, for whom the operation is contraindicated. Depending on the stage of enlargement of hemorrhoids, an approach to each patient is individually selected. The department uses various methods of dearterisation (dearterisation, deartesia with mucopexy).
Sclerotherapy of the internal hemorrhoid using the Proxon apparatus.

Vacuum alloying with Karl Storz reinforced latex rings.

Ultrasonic (harmonic) scalpel Harmonic Focus allows to perform dissection and coagulation of tissues without severe burns, which significantly reduces pain and contributes to the fastest recovery of working capacity.
The use of bipolar electrocautery with special clips allows the operation to be performed almost bloodlessly and significantly reduces the duration of the intervention even in patients with advanced hemorrhoids and significantly enlarged hemorrhoids.90,000 Modern methods of treatment of adenomyosis – GUZ TO Tula Regional Clinical Hospital

Adenomyosis is one of the common diseases that cause uterine bleeding, algomenorrhea, infertility, and is an indication for long-term hormone therapy and hysterectomy. The use of sparing and organ-preserving methods of surgical treatment for adenomyosis remains a topical issue in modern gynecology. According to both domestic and foreign authors, adenomyosis is a common cause of dysmenorrhea, menometrorrhagia, infertility, chronic pelvic pain of varying intensity, often leading to psychosomatic and autonomic disorders.

Among all the causes of female infertility, adenomyosis accounts for about 20%. Many authors point to a steady increase in the incidence of adenomyosis in all age groups, including a tendency towards an increase in the incidence of adenomyosis in young women who have not realized reproductive function. The frequency of its detection in the population, according to various authors, varies from 10 to 61%. In the removed uterus, the detection rate of adenomyosis reaches 46–70%.

The problem of treating patients with adenomyosis covers a wide range of conservative and surgical methods.The lack of effect of conservative treatment methods leads to an increase in the number of radical surgical interventions in young women. Radical surgical treatment (hysterectomy), widely used for the treatment of adenomyosis in the last century, cannot be considered the method of choice at the present stage of medical development. According to the literature, after hysterectomy, more than half of the operated patients develop vegetative-vascular, neuropsychiatric and sexual disorders.

It is especially important to study alternative methods of organ-saving treatment in young women with adenomyosis who want to preserve menstrual and reproductive function, as well as in the presence of contraindications to performing a radical volume of surgical intervention.Hormone therapy affects only one link in pathogenesis and temporarily stops the further progression of adenomyosis, brings it into remission. According to some reports, a gradual return of symptoms is observed almost immediately after the end of treatment, and the state of the myometrium after 4-6 months becomes identical to the myometrium of untreated patients.

One of the new directions of pharmacological correction in adenomyosis is the search for drugs that block the process of proliferation, neoangiogenesis, invasion and induce apoptosis.This is due to the fact that studies of the molecular biological characteristics of adenomyosis revealed a decrease in the level of apoptosis, an increase in proliferative, neoangiogenic and invasive activity in endometrioid heterotopies and the tissue of the surrounding myometrium. In the literature, there are numerous descriptions of two chemical compounds that have a corrective effect on molecular biological processes. In patients with adenomyosis or when it is combined with uterine myoma, it is advisable to take drugs containing I3C, EGCG, at the initial stage, when there are no indications for surgical treatment.With the development of molecular biology of the cell, studies of the endometrium and heterotopies in endometriosis become relevant.

The accumulated world experience in the surgical treatment of adenomyosis indicates that at a young age and with an unrealized reproductive function, women should, if possible, perform organ-saving operations and resort to radical surgical treatment in cases where all other possibilities of both surgical and drug treatment have been exhausted. There is experience in using various techniques for conducting organ-preserving operations in adenomyosis: resection of the endo- and myometrium, endometrial ablation, endosurgical electro-destruction and selective coagulation of foci of adenomyosis, interstitial laser-induced thermotherapy, occlusion of the ascending branches of the uterine arteries, ligation of the internal iliac arteries, ligation of internal arteries, internal ligation of the internal arteries.Some of the most commonly used organ-saving techniques are: bipolar resection of the endometrium and partially myometrium, as well as various techniques for endometrial ablation. A number of authors note that the effectiveness of endometrial resection and ablation depends on the depth of the glandular invasion and on the type of ablation. It should be noted that the limit for performing endometrial ablation in adenomyosis is the depth of invasion not exceeding 2.5 mm, that is, with an indicator bordering on physiological intussusception. With a deeper invasion, attempts to use endometrial thermal ablation are unsuccessful.A possible mechanism of recurrence of uterine bleeding after endometrial ablation is explained by the fact that the source of bleeding is not only a large mass of glandular tissue, but also a hyperplastic myometrium, which reduces the contractility of the uterus. Endometrial resection can be performed not only with diffuse, but also with submucous location of the adenomyosis node. According to the authors, it is possible to simultaneously carry out hysteroscopic removal of the adenomyotic node or lesion with a loop electrode, which increases the efficiency of the operation.

Both in our country and abroad, work was carried out on organ-preserving operations for adenomyosis using electromyolysis – electro-destruction and for the nodular form of adenomyosis and with a combination of adenomyosis and uterine fibroids by laparoscopic or laparotomic access. At the same time, there are indications of a number of researchers that the absence of a capsule and clear boundaries of the adenomyosis node with the adjacent myometrium makes the diagnosis difficult, and healthy organ tissue is very vulnerable when excising the nodular formation and, in fact, brings it closer to the wedge-shaped resection of the myometrium in the bottom of the uterus, but more sparing and effective.

Dear ladies! Do not forget to undergo a gynecological examination by a specialist doctor in a timely manner. For an outpatient consultation of a gynecologist, gynecologist-endocrinologist, you can contact the Clinical Diagnostic Center of the State Healthcare Institution “Tula Regional Clinical Hospital”.

The staff of the gynecological department of the State Institution of Healthcare “Tula Regional Clinical Hospital” from the bottom of our hearts wish you good health!

Rehabilitation Center – Profi-Detox

“Profi-Detox” is the leading rehabilitation center for drug and alcohol addicts in Kiev.This is a modern, specialized clinic that has been successfully returning patients to normal life for more than 20 years. The center employs a team of top-level specialists in the field of narcology, psychiatry, psychology, rehabilitation, physiotherapy and general medicine.

The rehabilitation process is taken seriously here, for this they use complex multi-step programs, the latest methods of therapy. Competent doctors help restore the body in the shortest possible time and get rid of destructive addiction forever.

Center for rehabilitation of alcohol and drug addicts

In our center we help to get rid of drug and alcohol addiction. The center’s competencies are multifaceted and unique. During treatment, the following program tasks are performed:

In our center we help to get rid of drug and alcohol addiction. The center’s competencies are multifaceted and unique. During treatment, the following program tasks are performed:

• change of thinking, emotions, replacement of destructive patterns of behavior;
• creating a positive therapeutic community;
• development of skills for adaptation in society;
• Accustoming to responsible behavior and healthy lifestyles.

In each specific case, the services are provided to the fullest extent possible. The process of recovery from addiction takes place according to an individual plan, which the specialist draws up after examination based on the diagnosis, the severity of the disorders.

We are one of the first rehabilitation centers that combined the best rehabilitation programs for addicts and brought them to life.

Treatment stages:

• consultation of the patient and family members;
• intervention and detoxification;
• inpatient rehabilitation;
• adaptation in society;
• Lifetime Support.

Before therapy, the patient is helped to determine motivations and personal values, to form goals and plans. This approach helps to establish contact with each patient, regardless of his age, gender and severity of alcoholism or drug addiction. The step-by-step course and the creation of healthy family relationships help increase the motivation for unconditional recovery.

How is rehabilitation going?

All services are provided strictly confidentially, no one will ever know that you were undergoing addiction treatment.Our main task is to help patients get rid of a heavy addiction, to return to society as a full-fledged person. The clinic’s specialists are doing everything possible to carry out this recovery. Programmed rehabilitation units:

• Psychological. Searching for goals and motivations, giving meaning to life.
• Labor. Learning new skills and abilities, new hobbies.
• Creative. Acceptance of yourself as real, harmonization of moods.
• Sports. Getting used to the benefits of physical exercise – exercise, active games.
• Pedagogical. Learns to be responsible, understand and correct mistakes.
• Educational. Awareness of real freedom to strive for.
• Codependency. Support groups for former drug and alcohol addicts, family, phase.

On the basis of research, the psychotherapist carries out psychocorrection, individual training, assigns classes in a group. In addition, psychologists work with addicts and their relatives to help restore normal family and interpersonal relationships.

At the end of the stay, the results achieved are analyzed. Patients are provided with post-rehabilitation support, further step-by-step steps are drawn up for full adaptation in society. Social counseling helps to return to the profession and school.

Profi-Detox Addiction Rehabilitation Center

In order to provide high-class treatment and rehabilitation, the doctors of the clinic work at a certified scientific level, confirm their qualifications. Our specialists are distinguished by thorough knowledge and many years of clinical experience in working with alcohol and drug addicts.The rehabilitation program at the Profi-Detox Center is rich and provides lasting relief from addiction with minimal risk of relapse.

We use the following methods:

• pharmacotherapy;
• psychotherapy;
• complex psychodiagnostics;
• family therapy;
• physiotherapy;
• complex of medical and recreational measures;
• alternative methods.

The program provides not only getting rid of physiological and psychological dependence, but also social adaptation.The conditions are created as comfortable as possible, patients are under the careful supervision of the medical staff and receive round-the-clock assistance.

Remember! Rehabilitation is an important follow-up to treatment, give it due consideration. And our doctors will help you choose the best methods.

90,000 Minimally invasive treatment for kidney doubling in young children

Doubling of the kidneys and ureters is one of the most common congenital anomalies of the urinary tract, the share of which among all malformations is 0.8% [1].Most doubled (duplex) renal systems do not require surgery. Nevertheless, in the case of the addition of symptoms such as obstruction of the ureter and the development of hydronephrosis, most often of the upper pole, which is associated with megaureter and ureterocele, as well as vesicorenal reflux (VRR), most often in the lower pole, or urinary incontinence due to ectopia of the upper polar ureter, surgical intervention becomes necessary. Children with double kidney disease are prone to significant morbidity, including recurrent urinary infection, which leads to loss of kidney function.Historically malformed and non-functioning renal fragments carry the risk of developing arterial hypertension and malignant neoplasms [2, 3]. Some studies have described histopathological changes in distant segments, such as the formation of metaplastic islets or areas of nephroblastomatosis [4]. At the end of the 20th century, a conservative approach in the treatment of kidney doubling was widespread, consisting in monitoring the abnormally developed kidney until pain or urinary infection appears [5, 6].Another mini-aggressive strategy, consisting in restoring normal urodynamics by dissecting the ureterocele or injecting a gel, led to a decrease in the dilatation of the non-functional fragment [7]. Some authors have provided data on the maturation of dysfunctional fragments after dissection of the ureterocele, confirmed by them by scanning the kidneys [8, 9]. However, these studies were based on approximate and inaccurate calculations of the areas of accumulation of the radiopharmaceutical during radionuclide scanning of the kidneys, and not on more accurate methods, such as functional magnetic resonance imaging.Until now, there is no reliable evidence of maturation of the dysplastic part of the duplex kidney, since the function of the affected segment may remain stable or deteriorate, while the general function of the kidney may improve due to the maturation of the intact part [10].

Surgical treatment for kidney doubling is recommended in case of clinical course of the disease. Currently, indications for partial nephrectomy are a nonfunctioning fragment of the kidney with recurrent urinary tract infections (UTI), urinary incontinence due to ectopia of the ureter or VRP with the development of hydronephrosis of the lower pole [11].After the long dominance of the open approach for performing partial (partial) nephrectomy [12, 13], minimally invasive approaches have become more widespread and are considered by some participants in this movement as the “gold standard” of treatment for this disease.

Alternative therapies, such as laparoscopic ligation of the ureter of the upper pole of the kidney [14], pyeloureteral anastomosis and distal ureteroureterostomy [15, 16], have been well described previously, but require special conditions for their implementation, such as the absence of reflux in the lower segment of the kidney.

Varieties of minimally invasive surgery. Heminephrectomy (GE) is the gold standard treatment for clinically manifest renal duplication. Other surgical interventions, such as ureteropyelostomy, ureteroureterostomy, necessitate an elective approach and are unsafe for the healthy segment of the kidney.

Laparoscopic technique has recently become very widely used in urology and pediatric surgery. The first laparoscopic nephrectomy in an adult patient was performed in 1991.R. Clayman [17]. In children, nephrectomy and nephroureterectomy were performed for the first time in 1993 [18]. In the same year, G. Jordan and B. Winslow [19] successfully performed the world’s first laparoscopic GNE in a child. Laparoscopic GNE has made its way into the world of surgical techniques with great potential to improve postoperative patient recovery and improve cosmetic performance, validating the progress of pediatric endosurgery. Since the first reports of laparoscopic GNE, the minimally invasive approach has become widespread, and in some large modern surgical centers has replaced open surgery for the surgical treatment of patients with urinary tract anomalies [20].The advantages and disadvantages of this method regularly become the subject of much discussion. Undoubtedly, high costs, as well as a more complex technique compared to the classical open technique are cited as disadvantages of laparoscopic GNE. Among the advantages of the method are a reduction in the period of hospital stay, a decrease in the duration of postoperative pain, a better cosmetic effect and a quick return to full physical activity of the child.

Another type of minimally invasive interventions designed to remove a segment of the kidney is represented by retroperitoneoscopy.The retroperitoneal approach has the advantages of avoiding colon mobilization, the risk of trauma to internal organs and the formation of adhesions [21]. Problems with this approach include difficulties in reverse orientation of the kidneys (location of the vascular pedicle of the organ) compared to the transperitoneal approach and limited working space. The surgeon must also be prepared for possible anatomical variations. In some cases the polar vessels will be clearly visible, while in others they will be represented by short loose vessels extending from the main renal vessel [22].M. Leclair et al. [23] published data on conversion to open surgery in 10 (21%) of 48 patients undergoing retroperitoneoscopic GNE. The authors reported the difficulties of parenchymal dissection when using bipolar diathermy at the start of the study, while these problems were resolved with the purchase of a harmonic scalpel.

More modern minimally invasive methods of treatment for kidney doubling are presented by robotic-assisted and single-port surgery [24, 25].Robotic GNE has shown advantages such as increased mobility and dexterity with instruments within the human body, less need for blood transfusions, shorter hospital stays, and reduced postoperative pain [26, 27]. Single-port surgery has also recently been implemented in pediatric practice [28, 29]. This technique made it possible to perform a complex kidney fragment removal operation using a single cutaneous and fascial incision hidden in the navel, providing the potential for superior cosmetic results.However, technical innovations related to the creation of technologically complex devices, as a rule, stimulate to a greater extent the “surgical euphoria” from possessing such innovations and does not allow to focus on researching the advantages of these newest methods.

In 2008 G. Lowe et al. [30] reported the use of new laparoscopic procedures designed to treat duplex renal anomalies. The procedures performed included pyeloureterostomy for incomplete doubling and inferior ureteroureterostomy along with distal total ureterectomy for obstructive ureterocele of the upper segment of the kidney.These procedures must be considered as complex in terms of technical execution, as well as in terms of the absolute success of the operation, in order to keep both segments of the duplex kidney system functioning. Only a few studies [30, 31] have provided evidence that laparoscopic upper urinary tract surgery can be successfully applied to a wide range of procedures. There is still a relative lack of evidence in the literature on the safety and effectiveness of these procedures in children.

Technical features of minimally invasive operations. Experience in minimally invasive surgery has always been considered one of the most important factors in achieving successful results in laparoscopy. Laparoscopic GNE is a difficult operation that is characterized by a steep learning curve [23, 32, 33]. This operation is considered difficult from a technical point of view and requires the use of special devices designed to ligate the vessels of the kidney and dissect its parenchyma; therefore, it is relatively uncommon among pediatric surgeons and urologists [34].

Nevertheless, the use of modern means of hemostasis (endoscopic clip applicators) and electrolysis devices intended for resection of parenchymal tissues made it possible to control bleeding and, therefore, laparoscopic resection became more widely used among surgeons [34].

Vascular control was previously achieved by applying conventional sutures to the vascular pedicle of the kidney. Modern methods of vascular ligation include the application of clips, the use of electrolysis or a harmonic scalpel, or the use of electrolysis devices with a diameter of 3 mm available today, which provide the ability to seal renal vessels in children with one hand without changing instruments [35].

The key point of the operation is a clear identification of the renal blood supply to the upper and lower pole of the kidney. This identification must be performed before the remaining normal part of the kidney can be safely removed. Vascular control is required before the separation of the parenchyma of the diseased and healthy parts of the kidney begins. After the vessels are clipped, the tissue of the fragment intended for resection is clearly demarcated. It becomes recognizable due to the change in the color of the avascular tissues, which facilitates the determination of the correct dissection plane of the renal parenchyma.Bloodless separation can be performed using bipolar electrocautery, electrolysis, or a harmonic scalpel using ultrasound energy.

An alternative to electrolysis devices is the end loop method. It consists in the fact that a loop made of Vicryl Endoloop material is drawn and tightly tightened around the kidney at the level of vascular demarcation that has arisen after clipping or ligation of the feeding vessels [21]. After this, the renal parenchyma is divided with scissors.Any residual bleeding can be controlled using conventional mono- or bipolar coagulation.

Another important issue in minimally invasive treatment of renal duplication concerns the way of treating the ureteral stump of the renal segment to be removed. In a study by M. Polok et al. [36] the ureteral stump was left open in 25 (75%) patients with obstructive ureteral involvement. In the remaining patients with BPP, the ureteral stump was sealed. Two (6%) patients required reoperation due to recurrent UTI as a result of reflux into the residual ureteral stump.R. Sydorak and D. Shaul [37] also reported this complication in 1 of 9 patients undergoing transperitoneal GNE. The authors emphasized that this complication could have been avoided if the entire ureter had been removed and tied at the entrance to the bladder. The authors confirmed that removal of the entire ureter is necessary in every case where vesicoureteral reflux exists.

Comparison of minimally invasive treatments for renal doubling. Several studies have compared different surgical approaches to the treatment of non-functioning segments in a duplicated kidney system.Currently, scientific works compare at least mainly two approaches to the treatment of kidney doubling; for example, laparoscopy and open surgery, or laparoscopy and retroperitoneoscopy. A. Golebiewski et al. [38] described their experience of laparoscopic treatment of 15 patients who underwent laparoscopic GNE and compared it with the results of treatment of 12 patients who underwent open GNE. This study did not reveal statistically significant differences in the duration of surgery (mean time 148 min for laparoscopy, range 100-220 min versus 124 min for open surgery, range 100-150 min).However, when using the open approach, the average length of hospital stay was shorter and the need for analgesia was greater than in patients from the laparoscopic intervention group [38].

In another retrospective multicenter study, Q. Ballouhey et al. [39] compared the results of treatment of 15 patients who underwent robotic GNE and 13 patients who underwent open GNE. On average, the hospital stay in the open intervention group was significantly longer than in the robotic intervention group (6.3 days, range 5-8 days versus 3.4 days, range 1-7 days; p <0.001).When comparing postoperative pain, the total consumption of morphine was significantly higher in the open group (0.52 mg / kg / day versus 1.08 mg / kg / day; p <0.001). There were no significant differences in the duration of surgery, the incidence of complications, or decreased renal function.

C. Esposito et al. [40] published data from an international multicenter European study analyzing the results of treatment of 102 children undergoing partial nephrectomy for 5 years using two different laparoscopic approaches – transperitoneal laparoscopic GNE (52 patients) and retroperitoneoscopic GNE (50).The overall incidence of complications was significantly higher after using the retroperitoneal approach (15 out of 50, or 30%) than laparoscopic (10 out of 52, or 19%; p = 0.05). The average duration of surgery (laparoscopy 166.2 min versus retroperitoneoscopy 255 min; p <0.001), as well as the average length of hospital stay (laparoscopy 3.5 days versus retroperitoneoscopy 4.1 days; p <0.001) was significantly shorter in the laparoscopic group. Postoperative loss of renal function was not recorded.The authors concluded that, compared to retroperitoneoscopic GNE, laparoscopic partial nephrectomy is a faster and safer procedure and is technically easier to perform in children, mainly due to the larger working space of the abdominal cavity. In addition, the ability to perform a total or subtotal ureterectomy in the case of reflux is also considered an advantage of laparoscopy and a disadvantage of retroperitoneoscopy.

M. Escolino et al. [41] also published the results of a comparison of the transperitoneal and retroperitoneal approaches in the treatment of renal doubling.The authors revealed an increase in the duration of the operation when using the retroperitoneal approach (80 min versus 50 min). The remaining ureteral stump after standard laparoscopy (range 3-7 mm) was significantly shorter than after retroperitoneoscopy (range 2-5 cm). Despite these findings, there is still no other evidence as to which approach – laparoscopic or retroperitoneoscopic – is advantageous for the patient. Nevertheless, the literature data reflect a higher rate of conversions and the development of complications of the retroperitoneal approach during the production of retroperitoneoscopic partial GNE than during the laparoscopic procedure.

A. Neheman et al. [42] presented several advantages in favor of minimally invasive approaches (laparoscopy, retroperitoneoscopy, and single-port surgery). Compared to the open approach, the use of all three endosurgical methods was accompanied by less blood loss during surgery and a shorter hospital stay. At the same time, the duration of surgery in the open intervention group was shorter than in the group of laparoscopy and retroperitoneoscopy, but longer than in the group of single-port surgery.For all other parameters, the advantages of one approach over the other were not revealed.

Single-port surgery assumes that all manipulations on the organs of the retroperitoneal space can be performed through one access located in the depth of the navel. This technique challenges classical multiport laparoscopy, but creates significant ergonomic difficulties such as collision of instruments from the outside, crowding (many instruments within one port) and, most importantly, crossing of instruments [43, 44].The latter means that all movements become unnatural, such as crossing your arms when playing the piano.

Despite the predominant cosmetic effect of the single-port approach, there is a lively debate about the place of this method in the treatment of kidney doubling. Y. Tam et al. [43] from Hong Kong found that single-port nephrectomy took longer than standard laparoscopy (156 versus 99 minutes on average). However, S. Islam et al. [45] reported that when considering the cost of their production, single-port nephrectomy and GNE were cheaper than standard laparoscopy (£ 942 vs. £ 1,127).

The safety and efficacy of robotic surgery (RH) for the production of various urological procedures in children, including when performing pyeloplasty, orchidopexy, and nephrectomy, has been proven [46]. The robotic system allows subtle and precise movements, which are ideal for reconstructive surgery in children [46]. The disadvantages of this method in children are the large size of the instruments, the loss of reverse tactile sensation from working with tissues, and high operating costs [47, 48].Most of the studies reporting robotic GNE compare their findings with the results of open surgery [49]. However, this comparison seems to be inappropriate because other minimally invasive methods such as conventional laparoscopy or single-port laparoscopy are the surgical “competitor” in terms of access, tissue trauma and cosmetic effect. Such comparisons are certainly limited. R. Malik et al. [49] compared the results of open surgery, standard laparoscopy, and RH and found that the robot provided comparable results in terms of postoperative complications and preservation of renal remnant function.Two other studies compared standard laparoscopy, single-port surgery, and RH for nephrectomy in children. Both studies confirmed a longer operative time when using RH, while other differences in postoperative analgesia and length of hospital stay were not found [29, 48].

H. Till et al. [50] presented a meta-analysis of studies on all three current minimally invasive methods of GNE – standard laparoscopy, single-port laparoscopy, and R.X. Although a single laparoscopic approach and a robot seem to offer clear advantages at first glance, it has been found that technologies should be selected according to the patient’s age. This study presents a comprehensive analysis of literature data to answer an important question for parents of patients: which procedure for removing a fragment of a kidney is best for the child?

There are serious concerns about the use of minimally invasive treatment technologies for kidney doubling in newborns and infants.S. Dingemann et al. [51] compared two age groups of patients younger (group 1) or older (group 2) 12 months of age who underwent laparoscopic GNE. The authors established an increase in the duration of surgery in group 2 (mean time 197 min versus 152 min) and found urinoma formation in 1 patient from group 1. The authors concluded that laparoscopic transperitoneal GNE is safe and feasible even in young children. The long-term results of these operations were also excellent regardless of the patient’s age at the time of the operation.

Laparoscopic GNE is a technically complex procedure, for mastering which requires personnel training [23, 32, 33]. Both the incidence of postoperative complications and the duration of the operation depend on the quality of training. It was found that the results of laparoscopic GNE are associated with the learning curve [36]. All complications in the series of cases presented by the authors (33 operations) occurred during the first 16 operations. With the increase in experience, the duration of the operation also decreased.Another study confirmed that the time it takes to complete the operation also depends on the experience of the surgeon. According to M. Polok et al. [36], the average duration of the operation was 137 minutes. With an increase in experience, this figure decreased significantly – from 140 to 125 minutes.

In the existing reports, the duration of GNE from the transperitoneal approach ranges from 167 to 190 minutes [33, 52-54]. At the same time, the duration of robotic-assisted GNE using the da Vinci robot increased in comparison with the duration of laparoscopic surgery [22].The average duration of the operation was much longer than in the mentioned laparoscopic series, reaching an average of 275 minutes.

Analysis of postoperative analgesia has demonstrated clear advantages of all minimally invasive technologies over open surgery, which are used to treat kidney anomalies. An open approach has been shown to be associated with an increased demand for narcotic and non-steroidal anti-inflammatory drugs. A non-narcotic regimen for postoperative analgesia in patients undergoing minimally invasive urological surgery has been previously described by Z.Lee et al. [55]. Their retrospective analysis presents 96 patients who underwent robotic pyeloplasty. Of these, 49 patients received intravenous doses of acetaminophen and ketorolac every 3 hours (group 1), 47 patients received non-steroidal anti-inflammatory drugs in combination with narcotic drugs (group 2). At the same time, the stay in the hospital of the patients of the 1st group was shorter than that of the patients of the 2nd group (on average 1.0 days versus 2.0 days; p <0.001). Thus, it has been suggested that the management of postoperative pain with nonsteroidal anti-inflammatory drugs is an effective regimen and may help to shorten the length of hospital stay in patients with renal duplication.

The next important question of surgical treatment in kidney doubling is the “fate” of the remaining segment of the kidney. In a multicenter review, G. Jayram et al. [56] examined the evolution of the renal remnant after laparoscopic GNE and found that 4.9% of patients in the younger age group experienced a significant decrease in function in the remainder of the kidney. The authors concluded that laparoscopy is associated with satisfactory results in children, but caution should be exercised when using laparoscopy in young children requiring HPE.

In another study, M. Leclair et al. [23] described, based on the results of a radionuclide study, a loss of function of more than 5% in 7 (24.13%) patients. The authors concluded that loss of function can occur as a result of unintentional stretching and subsequent stenosis of the vascular pedicle of the remainder of the kidney. However, several studies have demonstrated that the function of the remaining part of the kidney was preserved in the long term [30, 31, 57].

Treatment for concomitant anomalies. GNE of non-functioning parts in duplex kidney systems in children requires a longer experience in order to correctly assess the blood supply to the kidney segments, the anatomy and type of ureters (obstructive or refluxing), as well as the pathology of the vesicoureteral junction (ureterocele or ectopia of the ureteral orifice) during surgery. About 30% of all types of kidney doubling are associated with ureteral obstruction and ectopia, ureterocele and BPP. During the operation, the pediatric urologist must be able to solve all these problems.Consequently, his experience and technical equipment must correspond to the solution of these tasks.

Discussion about the ideal treatment approach for these cases is ongoing. Depending on the underlying malformations of this pathology, some authors suggest performing operations on the upper urinary tract [58-60], others on the lower urinary tract [7], others choose operations on the upper and lower sections, using both staged and one-step approaches [61]. Currently, most authors prefer to postpone the final reconstruction of combined malformations with kidney doubling for the 2nd or 3rd year of the patient’s life [61].However, performing surgery at a later age carries the risk of recurrent UTI, kidney damage, and bladder dysfunction [62–64]. Therefore, surgical interventions for renal doubling are recommended to be performed at an early age, including in newborns [57]. Early surgery prevents the development of UTIs and therefore effectively prevents renal scarring and subsequent loss of kidney function.

There is no consensus on the optimal treatment for ureterocele.Based on the theory that the ureterocele may not be dissected and that an enlarged ureteral stump will not cause problems after the kidney segment is removed, some authors recommend GNE without lower urinary tract intervention [7]. There are other views based on the experience of treating patients, showing that after HPE, repeated surgical interventions are often required in cases of ureteral ectopia, ureterocele, obstructive megaureter or high degree of VRP [3, 62].

Few authors recommend endoscopic techniques as the definitive procedure for correcting these conditions [65].However, most surgeons regard endoscopic intervention as the first line of treatment for UTI to prevent urosepsis until final surgery is performed [65]. To restore the lower urinary tract in VRP, endoscopic methods have gradually begun to be replaced by open surgical approaches. The effectiveness of the Deflux gel injection varies from 70 to 90% after 1-3 endoscopic injections. With regard to double ureters, there are reports of a small number of patients who underwent endoplasty of the ureteral orifice.Some authors report comparable results of using the gel in duplex systems compared to single systems [66, 67], others demonstrate significantly lower rates of the effectiveness of such therapy – 15.3–63% when used in duplex systems [65].

A negative prognosis for the use of the gel in doubling the kidneys and ureters is associated with a number of features inherent in these systems – grossly dilated massive orifices of the ureters, their lateralization, perpendicular passage of the ureteral tunnels in the bladder wall, or a connection with other anomalies such as ureterocele, neurocele bubble [68].

Based on these findings, the current preferred surgical approach is a combination of laparoscopic GNE and a full open bladder procedure, given the unfavorable anatomical features of the bladder that accompany duplex systems [57]. In support of this V. Ellerkamp et al. [57] reported on 13 patients with renal duplication who underwent simultaneous neoimplantation of the ureter using the open Politano-Leadbetter technique.If lower urinary tract reconstruction is needed, one-stage surgery is an excellent option to permanently correct a complex anomaly.

The minimally invasive approach for the treatment of kidney doubling is represented by transperitoneal laparoscopy, retroperitoneoscopy, single-port and robot-assisted surgery. These innovative techniques help reduce the need for postoperative analgesia, shorten hospital stay, reduce blood loss, while demonstrating safety.The choice of technology should be determined according to the patient’s age, technical capabilities and personal experience of the surgeon.

The authors declare no conflicts of interest.

The authors declare no conflicts of interest.

Information about the authors

Kozlov Yu.A. – https://orcid.org/0000-0003-2313-897X

Ochirov Ch.B. – https://orcid.org/0000-0002-6045-1087

Capuller V.M. – https://orcid.org/0000-0003-0076-5778

Yu.A. Kozlov, Ch.B. Ochirov, V.M. Kapuller Minimally invasive treatment for kidney doubling in young children. Endoscopic surgery. 2019; 25 (6): 49-57. https://doi.org/10.17116/endoskop20192506149

Corresponding author: Kozlov Yuri Andreevich –
e-mail: [email protected]

90,000 Modern approaches to the diagnosis and pharmacotherapy of bipolar affective disorder :: DIFFICULT PATIENT

S.N. Mosolov, E.G. Kostyukova
Moscow Research Institute of Psychiatry, Ministry of Health of Russia, Moscow

Issues of diagnosis and treatment of bipolar disorder (BAD) in recent years have been one of the most widely discussed medical problems, both in connection with the significant prevalence of this disease and in connection with the difficulties of its diagnosis and therapy. The prevalence of bipolar disorder, according to various epidemiological studies, ranges from 0.5 to 2% (on average, about 1%) [34, 35, 61], the risk of developing during life, according to some data, reaches 5% [37], and taking into account subsyndromal forms – 12% [12].At the same time, no significant differences in morbidity rates associated with geographical or ethnic reasons have been established [59].
According to Lish JD et al. [42], 73% of patients with bipolar disorder are initially misdiagnosed, and subsequently the correct diagnosis is not established until an average of eight years after being examined by three different doctors; 59% of patients experience their first episode in childhood or adolescence, with more than half of them not receiving treatment for the next five years or more.15% of patients with bipolar disorder commit suicide [32]. Women who fall ill at the age of 25, in the absence of adequate treatment, can, on average, lose five years of life, 12 years of normal health, and 14 years of normal social functioning [40]. Most often, at the first stage of the disease, bipolar disorder is misdiagnosed as schizophrenia and / or alcohol or drug dependence, but most often as recurrent depression. In 5-20% of patients, the initial diagnosis of recurrent depression is subsequently changed to a diagnosis of bipolar disorder [17].It is known that 17% of patients who are seen by a general practitioner and receive long-term maintenance antidepressant therapy as prescribed by him, actually suffer from bipolar disorder.
BAR undoubtedly requires much more attention than that which has been given to it until now and is still being given. The consequence of this is the controversy in the field of bipolar disorder therapy that has developed to date. On the one hand, it is generally accepted that the therapeutic capabilities of bipolar disorder can and should be improved, and modern therapy standards allow this to be done.On the other hand, the small number of studies conducted in accordance with the requirements of evidence-based medicine limit the ability to defend the reliability of the therapeutic efficacy of a particular method.
Over the past decade, there have been major changes in conceptual approaches to the diagnosis and treatment of bipolar disorder. Making a diagnosis based on operational criteria is undoubtedly an important, albeit controversial, advancement in psychiatry over the past century. The most structured criteria are offered by DSM-IV.Obviously, for practice, strict adherence to research diagnostic criteria may be too strict a standard. However, this is exactly the standard to strive for, as the validity of the diagnostic criteria, especially for mania, is very high. In daily clinical practice, the use of self-questionnaires and standardized interviews seems to be very useful to improve the quality of diagnosis [33].
Bipolar disorder is currently the most commonly used term to describe recurrent mood elevations, usually alternating with episodes of depression.Descriptions similar to bipolar disorder have existed since antiquity, but the term manic-depressive psychosis was first introduced by E. Kraepelin and included all variants of affective psychoses. Patients with unipolar, including psychotic, depression fell into this diagnostic category, regardless of whether they had episodes of manic states or not. The emphasis on diagnosing mania and thus on bipolarity has been relatively recent. BAR-I is currently defined by the presence of extensive manic and, as a rule, depressive episodes.The prevalence of BAR-I is estimated in the range from 2 to 21 cases per 100 thousand population per year. This variation in prevalence estimates is primarily due to diagnostic difficulties. Indicators based on the first visit to the hospital, which is an obvious indication of the severity of the condition, have a smaller scatter and are defined as approximately three to four people per 100 thousand of the population per year. The lifetime risk of developing BAR-I is approximately 0.5% [11, 43]. In psychiatric practice, BAR-I has a significant proportion among other diagnoses, both due to its significant prevalence and due to frequent exacerbations.It is characterized by a chronic course with a frequency of episodes defined on average as 9 per 10 years following the diagnosis. The recurrence rate in bipolar I disorder is higher than in unipolar depression, which is similar in severity [9, 60].
BAR-II is characterized by episodes of hypomania and extensive depression (Fig. 1). Using modern definitions (DSM-IV), the prevalence of BAR-II is higher compared to BAR-I [10].
The concept of bipolar spectrum disorders is often used to describe options for the course of the disease that differ from the criteria found in current diagnostic manuals.These include borderline BAD-II, affective temperament (hyperthymic, dysthymic, cyclothymic, irritable), BAR-III (cyclothymia), BAR-IV, BAR-V, and BAR-VI (including patients with a hereditary history of bipolar disorder, the so-called unipolar mania, mania caused by antidepressants, hyperthymic depression, etc.).
Many of the symptoms of bipolar spectrum disorders can occur with other medical conditions, including anxiety disorders, psychotic disorders, personality disorders, etc.A few features from the spectrum of “mild bipolar disorders” alone may not constitute a diagnosis, but collectively they indicate a greater likelihood of belonging to the bipolar spectrum than to unipolar depression or other disease.
Since the time of E. Kraepelin, it has been known that the disease often has a phase-return character and tends to progress, that is, an increase in the frequency of exacerbations. The modern pathomorphosis of mental illness has led to a significant increase in the number of such cases.In recent years, more and more patients with a fast-cycling course have begun to be observed, that is, who have undergone more than four episodes per year [29], and cases even with a 48-hour cycle are described in the literature [36]. The unjustifiably widespread use of antidepressants is believed to have played a role in this [55, 58]. Rapid cycling occurs in approximately one in four patients with bipolar disorder [26, 39] and is characterized by a poor prognosis and resistance to therapy [16, 56].
Concepts about the etiology of bipolar disorder are based primarily on genetic theory [49].First-line relatives show an accumulation of cases of unipolar depression and bipolar disorder. In comparison with schizophrenia, the influence on the development of bipolar disorder of environmental factors, such as pathology of pregnancy and childbirth or living in large cities, is much less reliable [14, 23, 43]. Factors such as early onset and delayed diagnosis increase the risk of comorbid mental disorders and aggravate the course of bipolar disorder [41].
Significant prevalence of the disease, chronic course and significant maladaptive effect determine the need to search for new effective and safe therapy, and modern ideas about its pathogenesis dictate the need for a radical revision of the traditionally used therapy tactics.
The pharmacogenic factor has a powerful influence on the course of the disease. It was found that mortality rates in patients receiving pharmacotherapy are statistically lower than in patients not receiving treatment. At the same time, mortality from suicides is reduced in the process of pharmacotherapy by more than four times. Also impressive is the reduction in suicidal attempts during lithium therapy and their sharp increase when therapy is discontinued (see table).
Given the chronic nature of bipolar disorder with the formation of various psychopathological formations at different periods of the disease, it is obvious that only complex pharmacotherapy with a flexible dynamic approach to the choice of therapeutic tactics depending on the clinical picture existing at a particular stage of the disease can stabilize the state and maintain the social adaptation of this contingent of patients.
Currently, there is no “ideal” drug that, in monotherapy, could provide all the clinical effects necessary for bipolar disorder, namely, antidepressant in the treatment of the next depressive phase, antimanic in the treatment of mania, antipsychotic in the treatment of affective-delusional states, prophylactic in regarding the prevention of recurrence of both poles.
At the same time, properly selected therapy using drugs of different pharmacological groups (normotimics, antipsychotics, antidepressants) can significantly reduce the severity of symptoms inherent in this disease.
In bipolar disorder, regardless of the phase and stage of the disease, the first choice drugs are normotimics, which must be prescribed already at the initial stages, followed by continuous use throughout life. This group includes the traditionally used lithium carbonate, sodium valproate and carbamazepine, as well as the new drug lamotrigine.
Each of these drugs has its own spectrum, which differs from the others, as a normotimal activity (i.e., a greater or lesser prophylactic effect in relation to the phases of the opposite pole), and a more or less pronounced suppressing effect in relation to depressive and manic symptoms.They also prevent the development of phase inversion caused by the additional prescription of antidepressants, which is often inevitable during periods of depressive conditions.
The parent group of normotimics is lithium carbonate, the prophylactic efficacy of which in bipolar disorder, especially with respect to manic phases, is well known, as is its anti-manic relief. At the same time, the effectiveness of lithium as a topical therapy for depression is not so obvious. It is shown in several placebo-controlled studies, but their number is small, and the group of subjects includes both patients with bipolar and recurrent depression [13, 25, 28, 31].The antidepressant effect of lithium develops much more slowly than the antimanic effect. When lithium is prescribed during the depressive phase, it takes, on average, six to eight weeks to achieve a distinct clinical effect, therefore, lithium monotherapy in the acute period of the depressive phase in most cases is insufficient. Long-term studies confirm its ability to prevent manic phases, but show less efficiency in relation to the development of depression [2-4, 6, 7, 18, 27, 50-52].Despite the fact that lithium carbonate is still a traditional treatment for bipolar disorder, the risk of toxic reactions, side effects and complications, as well as the need for constant monitoring of the drug in the blood, significantly limit the possibility of its long-term use.
Sodium valproate was the first drug to be used as an alternative to lithium. Over the past 20 years, its effectiveness has been studied in numerous open and controlled studies involving several hundred patients.Their results prove the effectiveness of valproate in bipolar disorder. The spectrum of its normotimal action is similar to the spectrum of lithium: it prevents the development of manic phases to a greater extent than depressive ones [3, 4, 6-8, 19, 24]. Its actual stopping effect is also more pronounced in relation to manic phases as compared to depressive ones [20, 46]. There have been no controlled studies of the efficacy of valproate in bipolar depression, and clinically it appears to be less effective in treating depression compared to mania [44].
Carbamazepine is another drug widely used to treat bipolar disorder. Despite its more than twenty years of widespread practical use, there have been no studies of its efficacy involving placebo control, randomization, and double-blind design. However, summarizing the data of numerous studies, we can say that their results convincingly prove a clear normotimic effect of carbamazepine [1-3, 5, 6, 15, 45, 54, 57]. In terms of overall effectiveness, carbamazepine is not inferior to lithium carbonate and sodium valproate, but it has a different spectrum of normotimal action, since its effect is more fully manifested in relation to the reduction of depression compared to manias.The effectiveness of carbamazepine in the relief of manic states is inferior to the effectiveness of lithium. However, according to most studies of the anti-manic effect of carbamazepine, the number of responders to therapy is 50-70%. The antidepressant effect of carbamazepine is less pronounced than the antimanic effect [38, 53], but more than that of lithium and valproate. At the same time, well-designed placebo-controlled studies are needed to confirm the antidepressant effect of carbamazepine in bipolar depression, as for sodium valproate.In addition, the side effects of these drugs, as well as the risk of drug interactions, in some cases prevent long-term therapy.
Lamotrigine is a modern anticonvulsant that has long been used in the treatment of epilepsy, and is now also registered as a prophylactic agent for recurrent affective episodes (mainly depressive) in bipolar disorder. It should be noted that today lamotrigine is the only normotimic agent, the effectiveness of which, incl.including and in patients with “rapid phase change” [24], has been proven in methodologically accurately planned blind placebo- and lithium-controlled studies [21, 22]. Lamotrigine is close to carbamazepine in terms of its normotimal action spectrum. At the same time, its stopping effect in relation to the symptoms of the depressive phase in bipolar disorder seems to be more proven in comparison with other normotimics. The good tolerance of lamotrigine, both with short-term and long-term use, is its significant advantage over other drugs in this group.A meta-analysis of the results of a study of its tolerance in comparison with lithium and placebo shows that adverse events developed in only 10% of patients receiving lamotrigine, and, unlike lithium, the frequency of their development did not differ significantly compared with placebo.
Normotimics provide, first of all, a prophylactic effect and allow to prolong the euthymic period. The success of preventive therapy determines the global effectiveness of treatment for bipolar disorder and can significantly reduce or prevent social maladjustment of patients associated with the frequent development of exacerbations.Given the continuous long-term, almost lifelong nature of such therapy, it is necessary to minimize the manifestations of side effects, since they are often the reason for the spontaneous withdrawal of the drug and the patient’s refusal of preventive treatment.
The use of antidepressants and antipsychotics as a means of relieving depressive, manic and psychotic symptoms is inevitable during periods of exacerbation of bipolar disorder. Moreover, their influence on the course of the disease has its own characteristics.It has been shown that the use of antidepressants in the relief of bipolar depression is associated with a high risk of phase inversion, i.e., with the development of a hypomanic or manic state. In recurrent depression, the risk of phase inversion is extremely low (Fig. 2).
Pharmacogenic phase inversion is considered an unfavorable factor that aggravates the overall course of bipolar disorder. According to modern concepts, the number of previous episodes may be associated with a greater risk of subsequent exacerbations [30, 47, 48], ie, “the phase provokes the phase.”According to various studies, tricyclic antidepressants provoke phase inversion in bipolar disorder in 11-74% of cases [32, 50]. In this case, the frequency of inversions has a dose-dependent nature and the higher, the higher the level of applied dosages.
Timely diagnosis of mixed and manic-delusional states is undoubtedly very important for choosing the right therapeutic tactics and predicting the subsequent course of the disease. Probably, it is precisely such states, along with manias that have psychotic features in their structure, that are mistakenly regarded as psychomotor agitation in schizophrenia.Such an erroneous diagnosis leads to the prescription for a long term of powerful classical antipsychotics, often in a depot form, which in itself contributes to the development of protracted states with the leveling of the affective radical and the formation of a frozen manic-delusional structure that does not undergo transformation, or causes an inversion of affect with prolonged adynamic depressions … In addition, it has been shown that patients with bipolar disorder are more sensitive to the development of extrapyramidal side effects of classical antipsychotics.
Extrapyramidal symptoms caused by long-term use of classical antipsychotics in patients with bipolar disorder are sometimes the main reason for their disability. At the same time, the use of antipsychotics in manic states is inevitable in most cases and is determined by the high frequency of development of psychotic symptoms in its structure. About 50% of manic episodes are accompanied by delusional symptoms, 15% – hallucinatory and 20% – formal thinking disorders [32].
As in cases of inadequate prescription of antidepressants in bipolar disorder, prolonged and not justified by the need to control psychotic symptoms, the use of classical antipsychotics, which, in addition to a negative somatotropic effect, have their own depressogenic effect, can lead to a chronicity of affective-delusional disorders and rapid disability of patients.
The foregoing determines the ongoing search for a drug that could provide all the effects necessary for bipolar disorder. In this regard, the focus of special attention at the moment are drugs of new generations, among which atypical antipsychotics occupy a special place. Moreover, theoretical views on bipolar disorder and schizophrenia as diseases with a common biological basis stimulate a new round of research on the efficacy of atypical antipsychotics as drugs, on the one hand, with proven efficacy in schizophrenia and, therefore, likely efficacy in bipolar disorder, and on the other hand, which differ from classical antipsychotics in good tolerance.Recent studies show that the spectrum of their clinical action in bipolar disorder is close to the spectrum of action of normotimics. At the same time suppressing the development of symptoms of both poles and, above all, manic, they, like normotimics, do not cause phase inversion, while each of them has a more or less pronounced stopping effect in mania or depression. At the same time, atypical antipsychotics, in contrast to normotimics, have proven antipsychotic efficacy. The spectrum of clinical action of atypical antipsychotics in comparison with drugs from other groups to the greatest extent meets the requirements for this kind of “ideal” drug.Despite the undoubted promise of the use of atypical antipsychotics in bipolar disorder, further research is needed to prove their prophylactic efficacy and clarify the characteristics of clinical action.
Expansion of the arsenal of normotimic drugs with different spectrum of psychotropic action, in modern conditions, allows for more differentiated preventive therapy for bipolar disorder. Since there are no clearly verified clinical or laboratory predictors of the effectiveness of this or that normotimal therapy, the doctor should rely on various other signs when choosing a therapy.The choice of the drug is carried out, first of all, taking into account the peculiarities of the course of the disease, namely the predominant polarity of the phases: lithium carbonate and sodium valproate are the drugs of the first choice in cases where manic symptoms dominate during the course of the disease, and carbamazepine and lamotrigine – with prevailing depressive symptoms. In the case of a rapidly cyclic course, priority remains with carbamazepine, valproate and lamotrigine.
In addition, one should take into account the effectiveness of a particular drug in previous exacerbations or in the patient’s relatives, the presence of comorbid disorders (for example, drug addiction), signs of “organically defective soil”, etc.
Another important aspect when choosing a drug for long-term, almost lifelong therapy is the patient’s somatoneurological status and taking into account the spectrum of side effects of the prescribed drug. When relieving depressive and manic symptoms during periods of exacerbation, the drugs of first choice are also normotimics. In the case of their insufficient effectiveness, antidepressants (for depression) or antipsychotics (for manias and affective-delusional states) are added, and further stopping therapy is carried out against the background of normotimics.The appointment of antidepressants and classical antipsychotics should be justified and limited to the period of cupping therapy. When stopping manic and mixed states, as well as, if necessary, to influence psychotic symptoms in the structure of depression or mania, preference should be given to atypical antipsychotics.
Effective prophylactic therapy requires the use of adequate dosages of the prescribed drug. The drug regimen of treatment should be selected taking into account the patient’s individual tolerance of drugs in such a way as, on the one hand, to ensure their maximum effectiveness, and on the other hand, to neutralize possible side effects, which often in themselves are the reason for the patient’s refusal from any preventive therapy.In addition, throughout the course of treatment, it is necessary to adhere to the principle of a flexible dynamic approach to the choice of drug dosages with the possibility of correcting them in the event of relapse or pre-relapse disorders, and if such correction is impossible, it is necessary to timely switch to changing therapy using a different normotimic or their combination.
Psychosocial support can be of significant help in the treatment of the depressive phase and reduce the rate of relapse. Some psychosocial techniques developed specifically for bipolar disorder are capable of reducing interpersonal conflicts, leveling potential trigger mechanisms for phase development, and / or smoothing out circadian rhythm.
Thus, BAD represents a wide layer of urgent and insufficiently studied problems of modern psychiatry that require close attention of researchers of various specialties, practitioners and a wide range of medical community. Only such interaction can support the existing theories with an evidence base on the way to establishing the truth and ensure the development of methods of therapy and social support that will ensure the preservation of the quality of life of a wide range of one of the most intact contingents of the mentally ill.

Literature
1. Vovin R.Ya., Digilov A.G., Skorik A.I. Preventive treatment of affective psychoses with finlepsin // Journal of Neuropathology and Psychiatry. S.S. Korsakov. 1984. No. 8. S. 1226-1230.
2. Kostyukova E.G. Comparative features of the preventive action of carbamazepine and lithium carbonate in affective and schizoaffective psychoses // Journal of Neuropathology and Psychiatry. S.S. Korsakov. 1989. T. 88. V. 12.
3. Kuzavkova M.V. Clinical and pharmacokinetic prognosis of the effectiveness of normotimics in secondary prevention of phase-occurring endogenous psychoses / Diss.for a job. learned. step. Cand. honey. sciences. M., 2001.
4. Mosolov S.N. The use of lithium salts in psychiatric practice. M., 1983.38 p.
5. S. N. Mosolov Break of the continual course of affective fluctuations with the help of carbamazepine and sodium valproate in patients with endogenous psychoses resistant to treatment with lithium salts // Psychopathological and pathogenetic aspects of the prognosis and therapy of depression. M., 1986.S. 75-80.
6. Mosolov S.N. Comparative efficacy of the prophylactic use of lithium carbonate, carbamazepine and sodium valproate in affective and schizoaffective psychoses // Journal of Neuropathology and Psychiatry.S.S. Korsakov. 1991. No. 4. S. 78-83.
7. Mosolov S.N., Kostyukova E.G., Kuzavkova M.V. Prophylactic use of anticonvulsants in phasic endogenous psychoses (comparative study of carbamazepine, sodium valproate and lithium salts) // Anticonvulsants in psychiatric and neurological practice / ed. Vein A.M., Mosolova S.N. Medical Information Agency, St. Petersburg, 1994. S. 72-128.
8. S. N. Mosolov Fundamentals of psychopharmacotherapy // East. 1996.374 p.
9. Angst J, Preisig M.(1995). Course of a clinical cohort of unipolar, bipolar and schizoaffective patients. Results of a prospective study from 1959 to 1985. Schweiz Arch Neurol Psychiatry 14a 5-16.
10. Angst J. (1998). The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord 50.143-151.
11. Angst J, Sellaro R. (2000). Historical perspectives and natural history of bipolar disorder. Biol Psychiatry 48.445-457.
12. Angst J., Gamma A., Benazzi F., Ajdacic V., Eich D., Rbssler W.Diagnostic issues in bipolar disorder // Europ. Neuropsychopharm. 2003. Vol. 13. S43-S50.
13. Baastrup P.C., Schou M. Lithium as a prophylactic agent. Its effects against recurrent depression and manic-depressive psychosis // Arch. Gen. Psychiat. 1967. Vol.16. P.162-172.
14. Bain M, Juszczak E, Mclnneny K, Kendell R.E. (2000). Obstetric complications and affective psychoses, two case-control studies based on structured obstetric records. Br J Psychiatry 176 523-526.
15. Ballenger J.C., Post R.M. Carbamazepine in manic-depressive illness: A new treatment // Am. J. Psychiatry. 1980. Vol. 137. P. 782-790.
16. Bauer MS, Calabrese JR, Dunner DL, et al. Multisite data reanalysis of the validity of rapid cycling as a course modifier for bipolar disorder in DSM-IV. Am J Psychiatry 1999; 151: 506-515.
17. Bebbington P., Ramana R. The epidemiology of bipolar affective disorder // Soc. Psychiatry Psychiatr. Epidemiol. 1995. Vol. 30. P. 279-92.
18. Bowden C.L. Key treatment studies of lithium in manic-depressive illness: efficacy and side effects // J.Clin. Psychiatry 1998 V.59. Suppl 6. P. 13-19, discussion 20.
19. Bowden CL, Calabrese JR, Mcelroy SL et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch. Gen. Psychiat. (2000) 57: 481-489.
20. Bowden C.L. Novel treatments for bipolar disorder // Exp. Opin. Invest. Drugs. 2001. Vol. 10.N 4. P. 661-671.
21. Bowden C. L., Calabrese J. R., Sachs G., et al. A randomized, placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder.In: Scientific Abstracts of the 40th Annual Meeting of the American College of Neuropsychopharmacology; December 9-13, 2001; Waikoloa, HI, p. 238.
22. Bowden C. L., Ghaemi N., Gyulai L., et al. Lamotrigine delays mood episodes in recently depressed bipolar I patients. In: New Research Abstracts of the 155th Annual Meeting of the American Psychiatric Association; May 18-23, 2002; Philadelphia, PA, p. 81.
23. Browne R. Byrne M, Mulryan N, Scully A, Morris M, Kinsella A, McNeil T F, Walsh D, O’Callaghan E (2000) Labor and delivery complications at birth and later mania.An Irish case register study. Br J Psychiatry 176: 369-372.
24. Calabrese J. R., Suppes T., Bowden C. L., et al. A double-blind, placebo-controlled prophylaxis study of lamotrigine in rapid-cycling bipolar disorder // J. Clin. Psychiatry. 2000. Vol. 61. P. 841-850.
25. Coppen A, Noguern R, Bailey J, et al. Prophylactic lithium in affective disorders: Controlled trial. Lancet, 1971, 2, 275-279.
26. Coryell W, Endicott J, Keller M. Rapidly cycling affective disorder: Demographics, diagnosis, family history, and course.Arch Gen Psychiatry 1992; 49: 126-131.
27. Cundall RL, Brooks PW, and Murray LG (1972). A controlled evaluation of lithium prophylaxis in affective disorders. Psychol Med 2, 308-311.
28. Dunner DL, Fleiss JL, and Fieve RR. Lithium carbonate prophylaxis failure. Br J Psychiatr (1976) 129, 40-44.
29. Dunner D., Patrick V., Fieve R. Rapid cycling manic-depressive patients. Comprehensive Psychiat. 1977. Vol.18. No. 6. P. 561-566.
30. Ehnvall A., Agren H. Patterns of sensitization in the course of affec-tive illness.A life-charting study of treatment-refractory depressed patients // J. Affect Disord. 2002. Vol. 70. P. 67-75.
31. Fieve RR, Kumbaraci R, and Dunner DL. Lithium prophylaxis of depression in bipolar I, bipolar II, and unipolar patients. Am J Psychiatr (1976), 133 (8), 925-929.
32. Goodwin F.K., Jamison K.R. Manic-Depressive Illness. // Oxford University Press, New York, 1990. P. 369-596.
33. Hiller W, Dichtl G, Hecht H. Hundt W, von Zerssen D (1993) An empirical comparison of diagnoses and reliabilities in ICD-10 and DSM-III-R.Eur Arch Psychiatry Clin Neurosci 242.209-217.
34. Hirschfeld R., Keck P., Karcher K., Kramer M., Grossman F. Rapid antimanic effect of risperidone monotherapy A 3-week multicenter, double-blind, placebo-controlled trial. // Bipolar Disorders. 2003. V.5. Sappl 1.
35. Hwu HG, Yeh EK, Chang LY. Prevalence of psychiatric disorders in Taiwan defined by the Chinese Diagnostic Interview Schedule. Acta Psychiatr Scand. 1989; 79: 136-147.
36. Jenner F. A., Goodwin F. K., Sheridan M. at al.The effect of altered time regime on biological rhythms in a 48 hour periodic psychosis – BritJ. Psychiat. 1968. Vol. l 14.P. 215-224.
37. Kessler R. C., McGonagle K. A., Zhao S., et al. Lifetime and 12-month prevalence of DMS-III-R psychiatric disorders in the United States: Results from the National Comorbidity Survey // Arch. Gen. Psychiatry. 1994. Vol. 51. P. 8-19.
38. Kravitz H. M., Fawcett J. Carbamazepine in the treatment of affective disorders. Med Sci Res 15; 1-8, 1987.
39.Kukopulos A, Reginaldi D, Laddomada G, et al. Course of the manic-depressive cycle and changes caused by treatments. Pharmakopsychiatr 1980; 13: 156-167.
40. Medical Practice Project. A state-of-the-science report for office of Assistant Secretary for the US Department of Health, Education Welfare. Baltimore, 1979.
41. Leverich GS, McElroy S L. Suppes T, Keck PE Jr, Denicoff KD, Nolen WA, Altshuler L L. Rush AJ, Kupka R, Frye MA, Autio KA, Post RM (2002) Early physical and sexual abuse associated with an adverse course of bipolar illness.Biol Psychiatry 51: 288-297.
42. Lish J. D., Dime-Meenan S., Whybrow P. C., et al. The national Depressive and Manic-Depressive Association (DMDA) survey of bipolar members // J. Affect Disord. 1994. Vol. 31. No. 4. P. 281-294.
43. Lloyd T, Jones PB. (2002). The epidemiology of first-onset mania. Textbook in psychiatric epidemiology, Tsuang M T, Tohen M (eds), pp. 445-458. Wiley-Liss, New York.
44. McElroy S.L., Keck Jr.P.E., Pope Jr.H.G. et al. Valproate in psychiatric disorders: literature review and clinical guidelines // J.Clin. Psychistry. 1989. Vol. 50. No. 3. P. 23-29.
45. Okuma T. Therapeutic and prophylactic efficasy of carbamazepine in manic depressive psychisis. In: Anticonvulsants in Affective Disorders, Emrich H. M., Okuma t., Muller A.A. (eds). Elsevier Science Publishers, Amsterdam, 1984.
46. Pope H.G., Jr., Mclroy S.L., Keck P.E., Jr., Hudson J.I. Valproate in the treatment of acute mania: a placebo-controlled study // Arch. Gen. Psychiat. 1991. Vol. 48. P. 62-68.
47. Post R., Leverich G.S., Altshuler L. et al. Lithium-discontinuation-induced refractoriness: iminary observations // Am. J. Psychiatr. 1992. Vol. 149. P. 1727-1729.
48. Post R. M., Denicoff K.D., Leverich G.S., Altshuler L. L., et al. Presentations of depression in bipolar illness. Clinical Neuroscience Research 2. 2002. P. 142-157.
49. Potash J B. DePaulo J-R Jr (2000). Searching high and low: a review of the genetics of bipolar disorder. Bipolar Disord 2. 8-26.
50. Prien R.F., Klett C.J., Caffey E.M.Lithium carbonate and imipramine in the prevention of affective episodes // Arch. Gen. Psychiatry. 1973. Vol. 29. P. 420-425.
51. Prien R.F., Kupfer D.J., Manskey P.A. et al. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders: Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine and lithium carbonate – imipramine carbonate combination // Arch. Gen. Psychiatry. 1984. Vol. 41. P. 1096-1104.
52. Secunda c S.K., Katz M.M., Swann A. et al. Mania: diagnosis, state vtasurment and prediction of treatment response // J. Affect. Disord. 1985. Vol. 8.P. 113-121.
53. Stromgren L., Boller S. Carbamazepine in treatment and prophylaxis of manic-depressive disorder // Psychiat. Dev. 1985. Vol. 4. P. 349-367.
54. Takezaki H., Hanaoka H. The use of carbamazepine (Tegretol) in the control of manic-depressive states // Clin. Psyhiat. 1971. Vol. 13.N 2.P. 173-183.
55. Tondo L., Laddomada P., Serra G. et al. Rapid cyclers and antidepressants // Pharmacopsychiatry.1981. Vol.16. No. 2. P. 119-123.
56. Tondo L, Baldessarini RJ. Rapid cycling in women and men with bipolar manic-depressive disorders. Am J Psychiatry 1998; 155: 1434-1436.
57. Uhde T.W., Post R.M., Ballenger J.C. et al. Carbamazepine in the treatment of neuropsychiatric disorders. In: Anticonvulsants in Affective Disorders, Emrich H. M., Okuma t., Muller A.A. (eds). Elsevier Science Publishes, Amsterdam, 1984.
58. Wehr T.A., Sack D.A., Duncan W.C. et al. Sleep and circadian rhythms in affective patients isolated from external time clues // Psychiat.Res. 1985. Vol.15. P.327-339.
59. Weissman MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA. 1996; 276: 293-299.
60. Winokur G, Coryell W, Keller M, Endicott J, Akiskal H (1993). A prospective follow-up of patients with bipolar and primary unipolar affective disorder.