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Singulair side effects anxiety. Singulair Side Effects: Understanding the Risks of Depression and Anxiety

How can Singulair cause mental health issues. What are the potential side effects of this allergy medication. Why did the FDA issue a box warning for Singulair. How should patients safely discontinue Singulair if side effects occur.

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The Hidden Dangers of Singulair: A Family’s Harrowing Experience

Kammy Pany’s world turned upside down when her 7-year-old son Tyson began exhibiting alarming behavioral changes. Once a happy and active child, Tyson suddenly transformed into a volatile and aggressive boy, prone to explosive temper tantrums that left his family struggling to cope. Little did they know, the culprit behind this drastic change was a seemingly innocuous allergy medication – Singulair.

Tyson’s story is not unique. Countless families have found themselves grappling with unexpected and severe side effects after taking Singulair or its generic form, montelukast. These side effects range from anxiety and depression to suicidal thoughts and actions, leaving many to question the true cost of allergy relief.

Understanding Singulair: More Than Just an Allergy Medication

Singulair, known generically as montelukast, is a medication primarily used to treat allergies and asthma. It works by blocking certain natural substances that cause inflammation in the airways, helping to prevent asthma attacks and alleviate allergy symptoms. However, its impact on the body extends beyond the respiratory system, potentially affecting the brain and mental health.

How does Singulair work?

Singulair is a leukotriene receptor antagonist. It blocks the action of substances in the body called leukotrienes, which are responsible for causing inflammation in the airways. By inhibiting these substances, Singulair helps to reduce swelling and constriction in the airways, making breathing easier for those with asthma or allergies.

The Dark Side of Singulair: Unexpected Mental Health Effects

While Singulair has been effective in managing allergies and asthma for many patients, a growing body of evidence suggests that it can have serious neuropsychiatric side effects. These effects can be particularly pronounced in children and young adults, though adults are not immune to the risks.

  • Depression
  • Anxiety
  • Aggression
  • Suicidal thoughts and actions
  • Attention problems
  • Vivid dreams and nightmares
  • Hallucinations
  • Memory issues

These side effects can occur suddenly and without warning, often catching patients and their families off guard. In Tyson’s case, the change was dramatic and life-altering for the entire family.

FDA Warnings: A Timeline of Concerns

The U.S. Food and Drug Administration (FDA) has been aware of the potential neuropsychiatric side effects of Singulair for over a decade. However, the journey to fully acknowledging and addressing these risks has been a long one.

When did the FDA first acknowledge Singulair’s mental health risks?

The FDA began including warnings about potential mental health side effects in Singulair’s package insert in 2008, a full decade after the drug was initially approved for use in the United States. However, these early warnings were not widely publicized, and many patients and healthcare providers remained unaware of the risks.

What prompted the FDA to issue a boxed warning for Singulair?

In September 2019, the FDA held a public meeting titled “Neuropsychiatric Events with the Use of Montelukast in Pediatric Patients.” During this meeting, the agency presented data showing over 10,000 reported nervous system and psychotic events attributed to Singulair. This staggering number, likely representing only a fraction of actual cases, prompted the FDA to take more decisive action.

In March 2020, the FDA issued a boxed warning for Singulair and its generic equivalents. A boxed warning, also known as a “black box” warning, is the agency’s strongest warning label, reserved for drugs that carry the risk of serious side effects or death.

Decoding the FDA’s Boxed Warning for Singulair

The FDA’s boxed warning for Singulair contains crucial information for patients and healthcare providers. Understanding this warning is essential for making informed decisions about the use of this medication.

What are the key points of the FDA’s boxed warning for Singulair?

  1. Serious mental health side effects have been reported in patients taking Singulair.
  2. The benefits of montelukast may not outweigh the risks for some patients.
  3. Singulair should be reserved for treating allergies only in patients who cannot tolerate other medicines.
  4. Discontinue Singulair immediately if a mental health side effect occurs.

This last point, however, has become a subject of debate among healthcare professionals and patients alike.

The Withdrawal Dilemma: Balancing Risks and Benefits

While the FDA recommends immediate discontinuation of Singulair if mental health side effects occur, some patients and healthcare providers have reported that abrupt cessation can lead to its own set of problems.

Can stopping Singulair suddenly cause withdrawal symptoms?

Some patients have reported experiencing withdrawal symptoms when stopping Singulair abruptly. These symptoms can include increased anxiety, depression, and even suicidal thoughts. This presents a challenging dilemma for patients and healthcare providers: how to balance the risks of continuing the medication against the potential dangers of sudden withdrawal.

Katie Johnson, an adult patient, experienced sudden problems controlling her temper after taking Singulair for just a few weeks. Her story highlights the complexity of managing Singulair’s side effects and the importance of careful monitoring and individualized care.

Beyond Children: Singulair’s Impact on Adults

While much of the focus on Singulair’s side effects has been on children, adults are not immune to these risks. In fact, the neuropsychiatric effects of Singulair can be just as severe and life-altering for adult patients.

How do Singulair’s side effects manifest in adults?

Adults taking Singulair may experience a range of neuropsychiatric symptoms, including:

  • Mood swings
  • Increased irritability
  • Difficulty concentrating
  • Sleep disturbances
  • Anxiety and panic attacks
  • Depression
  • Suicidal thoughts

These symptoms can develop gradually or appear suddenly, even in patients who have been taking the medication for an extended period without previous issues.

The Importance of Awareness and Vigilance

Given the potential severity of Singulair’s side effects, it’s crucial for patients, caregivers, and healthcare providers to be aware of the risks and remain vigilant for any signs of neuropsychiatric symptoms.

What should patients and caregivers watch for when taking Singulair?

Key warning signs to be aware of include:

  • Sudden changes in mood or behavior
  • Increased aggression or irritability
  • New or worsening anxiety or depression
  • Sleep disturbances, including vivid dreams or nightmares
  • Difficulty concentrating or memory problems
  • Any thoughts of self-harm or suicide

If any of these symptoms occur, it’s essential to contact a healthcare provider immediately. Do not stop taking the medication without medical guidance, as sudden discontinuation may lead to withdrawal symptoms.

Alternatives to Singulair: Exploring Other Options

Given the potential risks associated with Singulair, many patients and healthcare providers are exploring alternative treatments for allergies and asthma. While Singulair may still be the best option for some patients, it’s important to consider all available alternatives.

What are some alternatives to Singulair for treating allergies and asthma?

Some potential alternatives include:

  • Inhaled corticosteroids
  • Long-acting beta-agonists (LABAs)
  • Combination inhalers (containing both a corticosteroid and a LABA)
  • Antihistamines
  • Nasal corticosteroid sprays
  • Allergy shots (immunotherapy)

The best alternative will depend on the individual patient’s specific condition, symptoms, and overall health. It’s crucial to work closely with a healthcare provider to determine the most appropriate treatment plan.

The Road Ahead: Advocating for Patient Safety

The story of Singulair’s side effects serves as a stark reminder of the importance of ongoing drug safety monitoring and patient advocacy. As more information comes to light about the potential risks of this widely prescribed medication, patients, healthcare providers, and regulatory agencies must work together to ensure the safest possible use of Singulair and other similar drugs.

How can patients advocate for their safety when taking medications like Singulair?

To protect themselves and their loved ones, patients can:

  • Stay informed about the potential risks and side effects of their medications
  • Communicate openly and honestly with their healthcare providers about any concerns or symptoms
  • Report any adverse effects to the FDA through the MedWatch program
  • Seek second opinions when necessary
  • Explore alternative treatments when appropriate

By remaining vigilant and proactive, patients can play a crucial role in safeguarding their own health and contributing to the broader understanding of medication safety.

The story of Singulair serves as a cautionary tale about the hidden risks that can lurk within even commonly prescribed medications. As research continues and our understanding of these risks evolves, it’s crucial for patients, healthcare providers, and regulatory agencies to remain vigilant and prioritize patient safety above all else. While Singulair may continue to be an effective treatment option for some, the potential for severe neuropsychiatric side effects underscores the need for careful consideration and ongoing monitoring in its use.

allergy medicine can cause depression and suicides

PHOENIX (3TV/CBS 5) — She could feel the stares. Kammy Pany would have been embarrassed, but she was consumed with concern as she held down her 7-year-old, trying to stop him from hurting himself or someone else. Tyson’s explosive temper was why Kammy accompanied him on a field trip to LEGOLAND Discovery Center in Tempe, Arizona.

Noise from the rides and kids playing on a nearby jungle gym could not drown out Tyson’s screams. Other parents on the field trip stood by watching, wanting to help but helpless. Trying not to hurt him, Kammy pinned Tyson down using a technique recently taught to her by his psychiatrist. One hand pressed on his chest, her other holding both of his hands. The second-grader was small enough that she could still control him. He didn’t use to be like this. Just a couple of months earlier, Tyson was a happy, active little boy. His transformation was heartbreaking and all-consuming for the family. His once expressive eyes seemed vacant. Tyson began routinely flying into fits of rage over the smallest things. The engaging, inquisitive child, who had been a wonderful big brother, would now erupt into fits of rage at the sound of little sisters’ voices. Every moment for Kammy and her husband Mike was spent preparing for Tyson’s next meltdown. Tyson’s temper became so volatile that his father arranged to come home from his job at a moment’s notice if the situation at home got out of control, which it frequently did.

As Kammy held Tyson down, she had no idea the little pill she was giving him daily, prescribed by his doctor, could be causing her son’s mental and emotional problems. Nearly three years later, Tyson sits calmly on the back patio at the family’s Arizona home. He lets out an embarrassed little laugh when asked if he remembers what happened to him. “You mean when I lost my mind?” he asks with a little giggle.

Tyson is now a sweet, well-mannered kid. Much closer to the same child Kammy says he was before a prescription for Singulair to treat his allergies and asthma threw the family’s life into chaos. Montelukast is the generic form of Singulair. For families like Tyson’s, Singulair may trigger a journey of confusion, concern, and turmoil. For others, it ends in death. Suicidal thoughts and actions are one of the known side effects families say they didn’t find out about until after their loved ones killed themselves.

New Warnings, Little Awareness

Warnings the drug could cause depression, aggression, and suicide began appearing in the package insert for Singulair in 2008, a decade after the drug was put on the market, but the risks were not generally advertised. According to the FDA, side effects of Singulair and its generics include suicidal thoughts and actions, agitation, aggressive behavior or hostility, attention problems, bad or vivid dreams, depression, disorientation, or confusion, feeling anxious, hallucinations including seeing or hearing things that are not there, irritability, memory problems, obsessive-compulsive symptoms, restlessness, sleepwalking, stuttering, tremor or shakiness, trouble sleeping, and uncontrolled muscle movements. In September of 2019, the FDA held a public meeting titled ‘Neuropsychiatric Events with the Use of Montelukast in Pediatric Patients.’ Montelukast is the generic of Singulair.

The FDA provided data showing more than 10,000 nervous system and psychotic events attributed to Singulair had been reported to the agency through their ‘FDA Adverse Event Reporting System.” FAERS is a database where the public and health care professionals can report problems with medication. Some health experts at the meeting believe the thousands of reports represent only a fraction of the actual number of problems experienced by patients. Acknowledging that many health care professionals and patients are not aware of the risk of mental health side effects, the FDA issued a ‘box warning’ for Singulair and its generic Montelukast in March of 2020. A box warning is the agency’s strongest warning and alerts patients that a drug carries the potential for serious side effects or death.

Included in the FDA’s warning:
  • Serious mental health side effects have been reported in patients taking Singulair.
  • Because of the risk of mental health side effects, the benefits of Montelukast may not outweigh the risk in some patients.
  • Singulair should be reserved to treat allergies only in patients who cannot tolerate other medicines.
  • Discontinue Singulair immediately if a mental health side effect occurs.

The last warning is the source of debate.

This is the box warning issued by the FDA.(FDA)

Withdrawl Debate

Risks are not limited to children. Katie Johnson was taking Singulair for a matter of weeks when she noticed sudden problems controlling her temper. She describes it as being short with her husband and coworkers. Her issues progressed to daily suicidal thoughts as she drove to work. “There were times I wanted to drive my car off a bridge,” says Katie. According to Katie, her doctor did not warn her about any potential side effects. Looking for the cause behind the change in her personality, Katie read the warnings for Singulair and found they include the risk of depression and suicide. Katie says as soon she stopped taking the medication, “It was like a switch went off,” and almost instantly, she was back to her old self. Katie had no problem going off Singulair. The process was much different for Tyson. Months of doctor’s appointments left Kammy with no answers about the source of Tyson’s emotional issues. Desperate for answers, Kammy took Tyson to doctor after doctor. One diagnosed him with ADHD; other doctors blamed his age.

Searching everywhere for answers, she put up a post in an online asthma group. A mother responded and told Kammy about Singulair’s potential side effects. Kammy and her husband immediately stopped giving Tyson his nightly dose. Some of Tyson’s issues started to resolve, and others intensified. The FDA’s Box Warning for Singulair advises people to stop taking the drug immediately if mental health problems develop. That approach is disputed by some people who claim to stop the medication caused withdrawals and, in some cases, the onset or worsening of symptoms. After taking Singulair for more than a year, Kammy says stopping the medication sent Tyson into extreme withdrawal. “He got to the point where I didn’t know if I needed to check him into the ER. We had to strap him into a car seat because his body was flailing out of control,” recalls Kammy.

The pharmaceutical company Merck, Singulair’s manufacturer, declined to be interviewed for this article.

A spokesperson for Merck provided a statement that reads in part, “We remain confident in the efficacy and safety of SINGULAIR (montelukast sodium), a medicine that has been prescribed to tens of millions of indicated patients with asthma and allergic rhinitis since its approval more than 20 years ago.” The company did not respond to a follow-up request to address specific questions, including whether the manufacturer has studied the effects of stopping the drug cold turkey versus tapering off. The FDA was more open to questions, responding the agency did not find enough evidence to support recommending tapering off the medication. CBS 5 Investigates dug deeper into what evidence the FDA considered in making that decision. After examining transcripts from the 2019 meeting, the FDA confirmed to CBS 5 that their recommendation was based on examining just 17 cases of withdrawal reported to the FAERS database.

Kammy is now an administrator for the Facebook group ‘Montelukast (Singulair) Side Effects Support and Discussion Group.’ During the FDA’s meeting, Kammy gave a detailed presentation. She highlighted the group’s experience that withdrawal may not be as rare as believed. At the time of the 2019 meeting, there were around 7,300 members of the Facebook group. Nearly 5 percent of the group, 362 people, reported going through withdrawal, of which 267 were children. The Facebook support group focuses on members sharing their experiences about the side effects of Singulair during treatment and recovery. Administrators post the warning in bold letters, “NO MEDICAL ADVICE IS PROVIDED ON THIS PAGE.” In posts, members detail a wide variety of experiences with tapering off versus suddenly stopping the medication. Some report no reaction; others say effects suddenly developed or increased in severity. Families also detail experiences of withdrawal, sometimes lasting weeks to months.

Kammy says Tyson’s withdrawal lasted 6 months.

Effects on the Brain

Shortly after the box warning was issued, CBS 5 began investigating claims Singulair’s manufacturer, Merck, had evidence more than 20 years ago, before the drug went to market, that it could affect the brain. Attorney Kim Beck, with Beck Law Center, is connected to lawsuits based on those same claims. When the black box warning was announced, she says one question stood out, “Why, after twentysomething years, are we just now putting this significant warning on this drug?” Documents submitted to the FDA for Singulair’s approval included animal testing, which showed 24 hours after a dose of the medication was administered, the amount of drug decreased in the lungs but increased in the brain. Beck says, “These rat studies demonstrate the drug does pass the blood-brain-barrier and Merck had an obligation to, at the very least say, ‘Is this a problem?’” Based on the evidence she has seen, Beck says it appears the drug manufacturer failed to investigate what effect the drug has on the brain.

Not all drugs cross the blood-brain barrier, a membrane surrounding the brain which prevents harmful substances from entering.

According to the FDA, at the time of approval, although animal testing showed the drug crossed the blood-brain barrier, there were no signs it affected the central nervous system, so the agency did not require Merck to conduct further studies. A subtle but significant change has now been made to the information and warnings provided in the drug’s packaging. The word “minimal” has been removed in describing the amount of drug that crosses the blood-brain barrier. According to FDA spokesperson Chanapa Tantibanchachai, the change was made “so as not to understate the animal findings and to remove as much ambiguity from the labeling as possible.”

Details on Singulair’s distribution by the FDA.(FDA)FDA details on Singulair’s distribution(FDA)

Also pointed out in lawsuits, Merck applied for a patent for the drug to treat cerebral spasms, a narrowing of the blood vessels in the brain. According to Beck, applying for the patent showed the drug manufacturer knew the drug could have an effect on the brain. The patent was filed in 1996, two years before Singulair’s approval to treat allergies and asthma in 1998.

No New Studies

Excitement over the FDA issuing the box warning has led to disappointment for advocates fighting to raise awareness on the side effects associated with Singulair. Laura Marotta helped lead the charge for stronger warnings after her son Nicholas was prescribed the generic form of Singulair for asthma. After less than a year of taking the drug, Nicholas began experiencing severe symptoms of anxiety, depression, and hallucinations. In the FDA’s 2019 meeting, there was excitement as the agency acknowledged Singulair not only acts on the lungs, for which it is prescribed but also on the brain.

For Laura, that excitement faded within minutes, as the FDA acknowledged they most likely could not force Merck to conduct further studies on the drug’s effects on the brain. The reason may come down to money.

Before the availability of generic versions, Singulair was Merck’s top-selling product bringing in $4.2 billion in sales in 2007, $4.3 billion in 2008, and $4.6 billion in 2009. With the FDA, Dr. Sally Seymour said it was her opinion that because Singulair is now available as a generic, the company no longer makes a significant profit from the brand name version. If the FDA required Merck to conduct additional studies on safety, which are expensive, Merck could let its New Drug Application (NDA) expire. That move would leave only generic versions on the market. The FDA cannot force companies who make generic versions of drugs to do studies. Laura says the system is broken. “We have a medication that is being prescribed for asthma/allergies with an acknowledged direct action on the brain, with no hope for further studies because Merck doesn’t have to study it for the brain effects,” she said.

Another disappointment for families who say they have been affected by Singulair is the lack of impact from the box warning. The warning was issued in March 2020 and overshadowed by the COVID-19 pandemic. Posts in the Singulair support group detail doctors continuing to ignore, not recognize, or downplay side effects. In a Facebook post, Holly Davis expressed concern over her 2-year-old son being prescribed Singulair. She says her pediatrician responded, “Did you Google it? Don’t ever Google it. That will just scare you.” Holly says risks were also played down by her pharmacist, who told her, “almost no one has side effects from this.” Advocates, while frustrated, continue to fight to raise awareness that Singulair can have life-altering side effects. It’s a warning they hope will make it not just to the public but also to doctors.

Consult a Doctor

A wide range of doctors routinely prescribes Singulair, from allergists and pulmonologists to pediatricians and general practitioners. CBS 5 Investigates spoke with more than a half dozen doctors. Ten months after the box warning was issued, only one was aware of the increased warning. Dr. Aaron Wilson, a specialist in mental health and addiction, recommends changes to medication should always be made under a doctor’s supervision. From the viewpoint of a psychiatrist, he says a cardinal rule in mental health is to avoid treating a condition that is caused by something else. He cautions against the loop of adding medication on top of medication without first looking for the source of the problem.

“If a medication is causing significant depression and anxiety and we put an antidepressant on that, you end up kind of chasing your tail,” says Dr. Wilson. Dr. Wilson suggests patients may need to provide information to their doctors. A recent poll in the online support group asked members prescribed Montelukast after the box warning was issued if the doctor warned them about possible mental health side effects; 2 members received verbal warnings, 90 members responded they were not given warnings.

The FDA points out there are a number of safe, effective medications that can be used as alternatives to Singulair. The agency recommends health care professionals prescribe montelukast only if patients don’t respond to or cannot tolerate other therapies: “We have reevaluated the risks and benefits of montelukast and have determined it should not be the first choice treatment, particularly when allergic rhinitis symptoms are mild. In addition, many health care professionals and patients/caregivers are not aware of the risk of mental health side effects despite the existing warnings in the prescribing information.” -FDA. The FDA provides extensive information on its website detailing potential side effects and warnings. Patients may want to bring the information with them to their appointment or send their doctors the link.

Adverse effects linked to medications should be reported to the FDA’s FAERS database.

Copyright 2022 KTVK/KPHO. All rights reserved.

Montelukast (Singulair) and Mental Health Warnings

Written by
Juhi Modi

Medically reviewed by
HaVy Ngo-Hamilton, Pharm. D.
| Jul 26, 2022

Montelukast (sold under the brand name Singulair and in generic form) is a medication used to prevent asthma attacks, thus reducing asthmatic symptoms such as breathing difficulty, wheezing, coughing, and chest tightness. Many health care professionals also prescribe montelukast to treat allergic rhinitis (hay fever), which can be seasonal or year-round; however, montelukast should only be used after other treatments have been tried and not proven effective. 

In 2020, the U.S. Food and Drug Administration (FDA) issued a black box warning (the strongest type of FDA warning) about the potential risks of taking this medication. 

Specifically, the black box warning indicates that the asthma and allergy drug montelukast (Singulair) can have severe neuropsychiatric effects. The FDA boxed warning was issued to strengthen existing warnings for montelukast users.

Please continue reading to learn more about some of the serious mental health side effects and psychiatric disorders that can occur after taking montelukast (Singulair).

What are the mental health side effects of Singulair?

Taking montelukast can lead to serious mental health side effects such as sleep problems, dream abnormalities, depression, agitation, or even suicidal thoughts and actions. 

Given the increased risk of these reported neuropsychiatric events, the FDA boxed warning advises healthcare providers to avoid prescribing montelukast (Singulair) for mild symptoms, especially for mild allergic rhinitis, and to use alternative therapies instead. 

Does Singulair affect your mood?

Singulair can cause changes in behavior as well as mood related changes, such as aggressive behavior, agitation, confusion, anxiety, hallucinations, vivid dreams, depression, disorientation, irritability, memory problems, obsessive-compulsive symptoms, restlessness, and suicidal thinking. In addition to the mental side effects, some people also experience uncontrolled muscle movements and tremors while on Singulair. 

These serious neuropsychiatric events can make patients receiving montelukast appear unstable to their friends and loved ones. This serious behavior and mood change mimics mental illness symptoms. If someone experiences unusual changes in mood while on Singulair, they are possibly experiencing the adverse events associated with montelukast and should be evaluated by a health care professional without delay.

Can montelukast cause psychosis?

The allergy and asthma drug montelukast (Singulair), the oral granule dosage form,  can be prescribed to children as young as 6 months old. Studies have shown that the main adverse effects in infants under the age of 2 years are sleep disturbances. In children between the ages of 2 and 11 years, the main mental health side effects of montelukast are depression and anxiety. In adolescents between the ages of 12 and 17 years, suicidal ideation, depression, and anxiety are the main mental health side effects of this asthma and allergy drug. 

Generally speaking, neuropsychiatric events caused by montelukast are more frequently reported in children than adults. Infants and children seem to be most likely to suffer from sleep disorders, whereas adolescents and adults have a higher likelihood of suffering from neuropsychiatric events such as depression, anxiety, suicidal thoughts, and psychosis. However, there have been no reports of completed suicides related to Singulair use.

Can Singulair make depression worse?

Singulair should be reserved as the last treatment option for asthma, even for healthy patients with no history of a mental health disorder. If you or your loved ones start taking Singulair for the first time, keep in mind that the risk of serious mental health side effects is higher for patients with concomitant neuropsychiatric symptoms prior to starting montelukast. People with pre-existing mental health issues such as depression should discuss other effective allergy medicines with their medical professionals. 

If you notice worsening depression or any other serious mental health side effects of montelukast in yourself or a family member, make sure you or your loved one is evaluated immediately by a health care professional.

Important Prescribing Information About the Allergy Drug Montelukast (Singulair) for Health Care Professionals and Patients

After extensive review and case reports, the FDA requires boxed warning for the asthma drug montelukast because it can cause serious mental health adverse events. 

Given the warning about serious mental health side effects associated with taking montelukast, the U.S. Food and Drug Administration (FDA) advises restricting the use of this asthma and allergy drug. More specifically, healthcare providers should avoid prescribing Singulair to treat mild symptoms, especially those with allergic rhinitis.  

The boxed warning about serious mental health effects means that healthcare providers and patients should be more cautious with the utilization of this commonly-prescribed medication. Keep in mind that mild allergy symptoms can usually be treated effectively and safely with other alternatives, both over-the-counter products or prescription medications. 

Health care professionals can use their clinical judgment to continue their patients on montelukast (Singulair). In these instances, the FDA requires stronger warnings about the risk of neuropsychiatric events to be communicated thoroughly to the patients and their families. It is very important that patients and their loved ones are well-informed about these mental health side effects so that they can notify their doctors immediately or seek emergency medical attention if they observe any changes in mood or behavior, including thoughts of self-harm. 

 

References:

  1. https://www.fda.gov/news-events/press-announcements/fda-requires-stronger-warning-about-risk-neuropsychiatric-events-associated-asthma-and-allergy?utm_campaign=030420_PR_FDA
  2. https://medlineplus. gov/druginfo/meds/a600014.html
  3. https://pubmed.ncbi.nlm.nih.gov/26620206/#
  4. https://pubmed.ncbi.nlm.nih.gov/19815114/

Treatment of psychotic major depressive disorder with antidepressants: a possible role for sigma receptors. Extended abstract

The psychotic (delusional) form of major depressive disorder (MDD) is characterized by depressive symptoms combined with delusions and sometimes hallucinations. It affects about a quarter of all patients hospitalized for depressive disorders. It is characterized by more frequent exacerbations and hospitalizations, longer duration of attacks, severity of disability, and risk of suicide than non-psychotic MDD. Some studies have shown that over a fifteen-year follow-up period, mortality in the psychotic form of MDD was 41% versus 20% in patients with the non-psychotic form. Unfortunately, this form of MDD is difficult to treat. Electroconvulsive therapy (ECT), as well as atypical antipsychotics such as olanzapine and risperidone, are recognized as effective, but limited in use due to the large number of negative effects. The most commonly used combination of tricyclic antidepressants (TAD) with antipsychotics. There are data on the use of selective serotonin reuptake inhibitors (SSRIs), including in combination with antipsychotic drugs. Currently, the effect of antagonists of glucocorticoid receptors, such as miferpistone, is being studied, the use of which is based on the facts of an increase in the activity of the hypothalamic-pituitary-adrenal interaction in patients. Their long-term use, however, is limited in women due to progesterone antagonism.

Approximately 30-40% of patients with PFMD are known to respond to TAD treatment. When antipsychotics are added to TADs, the response to treatment is greater than with either drug alone. For example, TAD monotherapy and antipsychotics alone gave a positive result in 34% and 51% of respondents, respectively, while their combined use increased the response to 77%. Recent data on the use of SSRIs instead of TADs show that when using fluoxetine, citalopram or paroxetine in combination with olanzapine or perphenazine, the number of responders reached 70%. Negative symptoms in schizophrenia responded well to the combination of olanzapine and fluvoxamine. Equally effective and safe is the combination of fluvoxamine with typical antipsychotics.

SSRIs are more effective in the psychotic form of MDD as monotherapy compared to TADs. The most studied here is fluvoxamine. Thus, in one of the studies, the dosage of fluvoxamine 300 mg per day made it possible to reach the level of responders of 84.2% after 6 weeks. In another six-week study, similar data were obtained comparing fluvoxamine in combination with either placebo or pindolol – 80 and 85%, respectively, with an earlier onset of action (at 3 and 4 weeks) in the group receiving the combination with pindolol; p < 0.05 (Fig. 1). In all these cases, the HAM-D depression score was < 8, and the DDERS psychotic symptom score was 0.

A six-week, double-blind comparison study of fluvoxamine 300 mg daily with the same dose of venlafaxine showed a response rate of 78. 6% versus 58.3%, respectively (Fig. 2).

The ability of fluvoxamine to prevent relapse of the psychotic form of MDD was also studied (dose of 300 mg/day for 6 weeks and a 30-month follow-up period, during which patients continued to receive 300 mg/day of fluvoxamine or 200 mg/day for 6 months. fluvoxamine for 24 months). During the first 6 months there were no relapses. Over the next 24 months. remission was maintained in 80% of patients, and 20% had a single relapse during this period. At the same time, the safety and tolerability profile of fluvoxamine was comparable in these patients with that in the non-psychotic form of MDD. Thus, SSRI monotherapy has been shown to be a good alternative to both ECT and the combination of TAD with antipsychotics. The latter is known to increase the risk of adverse drug interactions and side effects, to which (when using typical antipsychotics) patients with mood disorders are especially susceptible.

Modern studies of the effect of antidepressants on psychotic forms of MDD are aimed at elucidating the features of their interaction with σ-receptors. These receptors, which regulate the activity of glutaminergic systems, were first referred to as opiate and then as phenocyclidine receptors. Although their receptor connections can be established, it is rather difficult to think of them in terms of agonism/antagonism. Compared to most receptors located only in cell membranes, σ-receptors are found in dynamic proteins of the endoplasmic reticulum, which are believed to disrupt secondary intercellular communication systems, especially calcium binding. σ-receptors are abundant in the brain, lungs, heart, muscles, liver, and kidneys. Despite the fact that only two receptor subtypes are mentioned in the literature: σ 1 and σ 2 – there are probably more of them. σ 1 receptors are found in the granular layer of the cerebellum, singular nuclei, in the CA3 region of the hippocampus, the hypothalamus, and the pons. A large accumulation of σ 2 receptors is observed in the cortex, hippocampus, habenular nucleus, paraventricular and supraoptic nuclei of the hypothalamus, and some cranial nuclei. σ 1 receptors are involved in the processes of memorization and learning, stress, anxiety, depression, aggression, drug dependence, as well as in psychotic and neuroprotective processes. Thus, the antipsychotic haloperidol is a potent σ-antagonist.

Studies have shown the degree of affinity of some antidepressants for σ-receptors in the rat brain (Table 1), the severity of which determines their clinical activity. As can be seen from Table. 1, fluvoxamine has the highest affinity (when comparing two types of receptors), followed by sertraline, fluoxetine, citalopram, etc. It is not clear whether SSRIs are agonists, antagonists, or partial agonists of σ-receptors. Clinical studies also support data on the effectiveness of fluvoxamine in the treatment of psychotic MDD and the enhanced effect of antipsychotics when combined with it in the treatment of negative symptoms of schizophrenia.

Thus, in the psychotic form of MDD, SSRIs outperform TADs both in terms of efficacy and tolerability, and, unlike TADs, can also be used as monotherapy.

The effectiveness of fluvoxamine monotherapy in the psychotic form of MDD compared with other antidepressants is probably due to the high affinity of this drug for σ-receptors.

CNS Spectr. – 2005. – 10(4). — 319-323

References

1. Coryell W., Pfohl B., Zimmerman M. The clinical and neuroendocrine features of psychotic depression // J. Nerv. Ment. Dis. 1984; 172:521-528.

2. Basso M.R., Bornstein R.A. Neuropsychological deficits in psychotic versus nonpsychotic unipolar depression // Neuropsychology. 1999; 13:69-75.

3. Thakur M., Hays J., Ranga K., Krishnan R. Clinical, demographic and social characteristics of psychotic depression // Psychiatry Res. 1999; 86:99-106.

4. Hori M., Shiraishi H., Koizumi J. Delusional depression and suicide // Jpn. J. Psychiatry Neurol. 1993; 47:811-817.

5. Schatzberg A.F., Rothschild A.J. Psychotic (delusional) major depression: should it be included as a distinct syndrome in DSM-IV? // Am. J. Psychiatry. 1992; 149:733-745.

6. Vythilingam M., Chen J., Bremner J.D., Mazure C.M., Maciejewski P.K., Nelson J.C. Psychotic depression and mortality // Am. J. Psychiatry. 2003; 160:574-576.

7. Perry P.J., Morgan D.E., Smith R.E. et al. Treatment of unipolar depression accompanied by delusions: ECT versus tricyclic antidepressant-antipsychotic combinations // J. Affect Disord. 1982; 4:195-200.

8. Parker G., Roy K., Hadzi-Pavlovic D. et al. Psychotic (delusional) depression: a meta-analysis of physical treatments // J. Affect Disord. 1992; 24:17-24.

9. Muller-Siecheneder F., Muller M.J., Hillert A. et al. Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome // J. Clin. Psychopharmacol. 1998; 18:111-120.

10. DeBattista C., Solvason H.B., Belanoff J. et al. Treatment of psychotic depression // Am. J. Psychiatry. 1997; 154: 1625-1626.

11. Kroessler D. Relative efficacy rates for therapies of delusional depression // Convuls. Ther. 1985; 1:173-182.

12. Coryell W. The treatment of psychotic depression // J. Clin. Psychiatry. 1998; 59 (Suppl. 1): 22-29.

13. Khan A., Noonan C., Healey W. Is a single tricyclic antidepressant trial and active treatment for psychotic depression? // Prog. Neuropsychopharmacol Biol. Psychiatry. 1991; 15:765-770.

14. O’Neal B.L., Smith C.L., Trivedi M. Evaluation of newer treatment interventions for psychotic depression // Curr. Psychiatry Rep. 2000; 2:305-309.

15. Schatzberg A.F. New approaches to managing psychotic depression // J. Clin. Psychiatry. 2003; 64 (Suppl. 1): 19-23.

16. Dub e S., Rothschild A.J., Andersen S.W., Sanger T.M., Hostetler J., Tohen M.F., Tollefson G.D. Olanzapine-fluoxetine combination for psychotic major depression // Eur. Neuropsychopharmacol. 2002: 12 (Suppl. 3): S.180.

17. Matthews J.D., Bottonari K.A., Polania L.M. et al. An open study of olanzapine and fluoxetine for psychotic major depressive disorder: an interim analysis // J. Clin. Psychiatry. 2002; 63:1164-1170.

18. Belanoff J.K., Rothschild A.J., Cassidy F. et al. An open label trial of C-1073 (mifepristone) for psychotic major depression // Biol. Psychiatry. 2001; 52:386-392.

19. Belanoff J.K., Flores B.H., Kalezhan M. et al. Rapid reversal of psychotic depression using mifepristone // J. Clin. psychopharmacol. 2001; 21:516-521.

20. Schatzberg A.F., Posener J.A., DeBattista C. et al. Neuropsychological deficits in psychotic versus nonpsychotic major depression and no mental illness // Am. J. Psychiatry. 2000; 157:1095-1100.

21. Horden A., Holt N.F., Burt C.G. Amitriptyline in depressive states // Br. J. Psychiatry. 1963; 109:815-825.

22. Kantor S.J., Glassman A.H. Delusional depression: natural history and response to treatment // Br. J. Psychiatry. 1977; 133:351-360.

23. Nelson J.C., Bowers M.B. Delusional unipolar depression: description and drug response // Arch. Gen. Psychiatry. 1978; 35:1321-1328.

24. Spiker D.G., Weiss J.C., Dealy R.S. et al. The pharmacological treatment of delusional depression // Am. J. Psychiatry. 1985; 142:430-436.

25. Kroessler D. Relative efficacy rates for therapies of delusional depression // Convuls. Ther. 1985; 1:173-182.

26. Minter R.E., Mandel M.R. The treatment of psychotic major depressive disorder with drugs and electroconvulsive therapy // J. Nerv. Ment. Dis. 1979; 167:726-733.

27. Konig F., von Hippel C., Petersdorff T., Neuhoffer-Weiss M., Wolfersdorf M., Kaschka W.P. First experiences in combination therapy using olanzapine with SSRIs (citalopram, paroxetine) in delusional depression // Neuropsychobiology. 2001; 43:170-174.

28. Rothschild A.J., Samson J.A., Bessette M. P., Carter-Campbell J.T. Efficacy of the combination of fluoxetine and perphenazine in the treatment of psychotic depression // J. Clin. Psychiatry. 1993; 54:338-342.

29. Lammers C.H., Deuschle M., Weigmann H. et al. Coadministration of clozapine and fluvoxamine in psychotic patients clinical experience // Pharmacopsychiatry. 1999; 32:76-77.

30. Hiemke C., Peled A., Jabarin M. et al. Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects // J. Clin. Psychopharmacol. 2002; 22:502-506.

31. Silver H. Fluvoxamine as an adjunctive agent in schizophrenia // CNS Drug. Rev. 2001; 7:283-304.

32. Silver H. Selective serotonin reuptake inhibitor augmentation in the treatment of negative symptoms of schizophrenia // Int. Clin. Psychopharmacol. 2003; 18:305-313.

33. Zanardi R., Franchini L., Gasperini M., Perez J., Smeraldi E. Double-blind controlled trial of sertraline versus paroxetine in the treatment of delusional depression // Am. J. Psychiatry. 1996; 153: 1631-1633.

34. Gatti F., Bellini L., Gasperini M., Perez J., Zanardi R., Smeraldi E. Fluvoxamine alone in the treatment of delusional depression // Am. J. Psychiatry. 1996; 153:414-416.

35. Zanardi R., Franchini L., Gasperini M., Lucca A., Smeraldi E., Perez J. Faster onset of action of fluvoxamine in combination with pindolol in the treatment of delusional depression: a controlled study // J. Clin. Psychopharmacol. 1998; 18:441-446.

36. Simpson G.M., El Sheshai A., Rady A., Kingsbury S.J., Fayek M. Sertraline as monotherapy in the treatment of psychotic and nonpsychotic depression // J. Clin. Psychiatry. 2003; 64:959-965.

37. Zanardi R., Franchini L., Serretti A., Perez J., Smeraldi E. Venlafaxine versus fluvoxamine in the treatment of delusional depression: a pilot double-blind controlled study // J. Clin. Psychiatry. 2000; 61:26-29.

38. Zanardi R., Franchini L., Gasperini M. , Smeraldi E., Perez J. Long-term treatment of psychotic (delusional) depression with fluvoxamine: an open pilot study // Int. Clin. Psychopharmacol. 1997; 12:195-197.

39. Spiker D.G., Kupfer D.J. Placebo response rates in psychotic and nonpsychotic depression // J. Affect. Discord. 1988; 14:21-23.

40. Glassman A.H., Roose S.P. Delusional depression: a distinct clinical entity? // Arch. Gen. Psychiatry. 1981; 38:424-427.

41. Smeraldi E., Cavallaro R., Di Rosa M., Della Maggiore P., Brancato V. Prevalence and risk factors of involuntary movement disorders in a neuroleptic-treated population: a comparison between schizophrenic spectrum and non-schizophrenic spectrum patients // Schizophr. Res. 1991; 4:367-368.

42. Debonnel G., de Montigny C. Modulation of NMDA and dopaminergic neurotransmissions by sigma ligands: possible implications for the treatment of psychiatric disorders // Life Sci. 1996; 58:721-734.

43. Takebayashi M., Hayashi T., Su T.P. Nerve growth factor-induced neurite sprouting in PC12 cells involves sigma1-receptors: implications for antidepressants // J. Pharmacol. Exp. Ther. 2002; 303: 1227-1237.

44. Guitart X., Codony X., Monroy X. Sigma receptors: biology and therapeutic potential // Psychopharmacology (Berl.). 2004; 174:301-319.

45. Waterhouse R.N., Mardon K., Giles K.M., Collier T.L., O’Brien J.C. Halogenated 4-(phenoxymethyl)piperidines as potential radiolabeled probes for sigma-1 receptors: in vivo evaluation of [123I]-1-(iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl]piperidine. J. Med. Chem. 1997; 40: 1657-1667.

46. John C.S., Lim B.B., Geyer B.C., Vilner B.J., Bowen W.D. 99mTc-labeled sigma-receptor-binding complex: synthesis, characterization, and specific binding to human ductal breast carcinoma (T47D) cells // Bioconjug. Chem. 1997; 8:304-309.

47. Bergeron R., Debonnel G. Effects of low and high doses of selective sigma ligands: further evidence suggesting the existence of different subtypes of sigma receptors // Psychopharmacology (Berl. ). 1997; 129:215-224.

48. Maurice T., Urani A., Phan V.L., Romieu P. The interaction between neuroactive steroids and the sigma1 receptor function: behavioral consquences and therapeutic opportunities // Brain Res. Rev. 2001; 37:116-132.

49. Maurice T., Lockhart B.P. Neuroprotective and anti-amnesic potentials of sigma receptor ligands // Prog. Neuropsychopharmacol Biol. Psychiatry. 1997; 21:69-102.

50. Ucar H., Cacciaguerra S., Spampinato S., et al. 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives: novel, potent and selective sigma1 receptor ligands // Eur. J Pharmacol. 1997; 335:267-273.

51. Senda T., Matsuno K., Okamoto K., Kobayashi T., Nakata K., Mita S. Ameliorating effect of SA4503, a novel sigma1 receptor agonist, on memory impairments induced by cholinergic dysfunction in rats, Eur. J Pharmacol. 1996; 315:1-10.

52. Wang H.H., Chien J.W., Chou Y.C., Liao J.F., Chen C.F. Anti-amnesic effect of dimemorfan in mice // Br. J Pharmacol. 2003; 138:941-949.

53. Phan V.L., Urani A., Romieu P., Maurice T. Strain differences in sigma1 receptor-mediated behaviors are related to neurosteroid levels // Eur. J. Neurosci. 2002; 15:1523-1534.

54. Urani A., Romieu P., Portales-Casamar E., Roman F.J., Maurice T. The antidepressant-like effect induced by the sigma1 receptor agonist igmesine involves modulation of intracellular calcium mobilization // Psychopharmacology (Berl.). 2002; 163:26-35.

55. Kamei H., Kameyama T., Nabeshima T. Effects of sigma receptor ligands on conditioned fear stress // Methods Find. Exp. Clin. Pharmacol. 1998; 20:613-618.

56. Schumacher M., Akwa Y., Guennoun R. et al. Steroid synthesis and metabolism in the nervous system: trophic and protective effects // J. Neurocytol. 2000; 29:307-326.

57. Urani A., Romieu P., Roman F.J., Maurice T. Enhanced antidepressant effect of sigma1 receptor agonists in beta(25-35)-amyloid peptide-treated mice // Behav. brain. Res. 2002; 21:239-247.

58. Reddy D.S., Kaur G., Kulkarni S.K. Sigma (sigma1) receptor-mediated antidepressant-like effects of neurosteroids in the Porsolt forced swim test // Neuroreport. 1998; 9:3069-3073.

59. Maurice T., Phan V.L., Urani A., Kamei H., Noda Y., Nabeshima T. Neuroactive neurosteroids as endogenous effectors for the sigma1 receptor: pharmacological evidence and therapeutic opportunities // Jpn. J Pharmacol. 1999; 81:125-155.

60. Akunne H.C., Whetzel S.Z., Wiley J.N., et al. The pharmacology of the novel and selective sigma ligand, PD 144418 // Neuropharmacology. 1997; 36:51-62.

61. Guitart X., Mendez R., Ovalle S. et al. Regulation of ionotropic glutamate receptor subunits in different rat brain areas by a preferential sigma1 receptor ligand and potential atypical antipsychotic // Neuropsychopharmacology. 2000; 23:539-546.

62. Tam S.W., Cook L. Sigma opiates and certain antipsychotic drugs mutually inhibit (+)-[3H] SKF 10,047 and [3H]haloperidol binding in guinea pig brain membranes // Proc. Natl. Acad. sci. USA. 1984; 81:5618-5621.

63. McCann D.J., Su T.P. Haloperidol competitively inhibits the binding of (+)-[3H]SKF-10,047 to sigma sites // Eur. J Pharmacol. 1990; 180:361-364.

64. Stahl S.M., Shayegan D.K. New discoveries in the development of antipsychotics with novel mechanisms of action: beyond the atypical antipsychotics with serotonin dopamine antagonism // Ellenbroek B.A., Cools R.A., eds. Atypical Antipsychotics. Boston, Mass: Birkhauser; 2000: 215-232.

65. Stahl S.M., Shayegan D.K. Novel mechanisms of action: beyond atypical antipsychotics // den Boer J.A., ter Horst G.J., George M., eds. Current and Future Developments in Psychopharmacology. Amsterdam, Netherlands: Benecke; In press.

66. Pharmaceutical Companies Analysis // Chichester, England: Epsicom Business Intelligence: 2003.

67. Gewirtz G.R., Gorman J.M., Volavka J. et al. BMY 14802, a sigma receptor ligand for the treatment of schizophrenia // Neuropsychopharmacology. 1994; 10:37-40.

68. Narita N., Hashimoto K., Tomitaka S., Minabe Y. Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain // Eur. J Pharmacol. 1996; 307:117-119.

Treatment of the psychotic form of major depressive disorder with antidepressants: the possible role of the o-receptor (extended abstract) P.B. Gannushkina №06 2006



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Treatment of psychotic major depressive disorder with antidepressants: a possible role for the o-receptor (extended abstract) No. 06 2006

Author:S.M.Stahl

USA

Issue page numbers: 50-52

The psychotic (delusional) form of major depressive disorder (MDD) is characterized by depressive symptoms combined with delusions and sometimes hallucinations. It affects about a quarter of all patients hospitalized for depressive disorders. It is characterized by more frequent exacerbations and hospitalizations, a longer duration of attacks, the severity of disability and the risk of suicide than in the non-psychotic form of MDD.

The psychotic (delusional) form of major depressive disorder (MDD) is characterized by depressive symptoms combined with delusions and sometimes hallucinations. It affects about a quarter of all patients hospitalized for depressive disorders. It is characterized by more frequent exacerbations and hospitalizations, a longer duration of attacks, the severity of disability and the risk of suicide than in the non-psychotic form of MDD. Some studies have shown that, over a fifteen-year follow-up period, mortality in the psychotic form of MDD was 41% versus 20% in non-psychotic patients. Unfortunately, this form of MDD is poorly treated. Electroconvulsive therapy (ECT), as well as atypical antipsychotics such as olanzapine and risperidone, are recognized as effective, but limited due to the mass of negative effects. The most commonly used combination of tricyclic antidepressants (TAD) with antipsychotics. There are data on the use of selective serotonin reuptake inhibitors (SSRIs), including in combination with antipsychotic drugs. Currently, the action of glucocorticoid receptor antagonists, such as miferpistone, is being studied, whose use is based on the facts of an increase in the activity of the hypothalamic-pituitary-adrenal interaction in such patients. Their long-term use, however, is limited in women due to progesterone antagonism.

It is known that approximately 30-40% of patients with PFBD respond to TAD treatment. When antipsychotics are added to TADs, response to treatment is greater than with either drug alone. For example, TAD monotherapy and antipsychotics alone resulted in 34% and 51% responder rates, respectively, while their combined use increased the response rate to 77%. Recent data on the use of SSRIs instead of TADs show that the number of responders of the order of 70% was obtained with the use of fluoxetine, citalopram or paroxetine in combination with olanzapine or perphenazine. Negative symptoms in schizophrenia responded well to the combination of olanzapine and fluvoxamine. Equally effective and safe is the combination of fluvoxamine with typical antipsychotics.

SSRIs are more effective in the psychotic form of MDD as monotherapy compared to TADs. The most studied here is fluvoxamine. So, in one of the studies, the dosage of fluvoxamine 300 mg per day made it possible to reach the level of responders of 84.2% after 6 weeks. In another six-week study, similar data were obtained comparing fluvoxamine in combination with either placebo or pindolol – 80 and 85%, respectively, with an earlier onset of action (by 3 and 4 weeks) in the group receiving the combination with pindolol; p<0.05. In all these cases, the level of depression according to HAM-D was <8, and the severity of psychotic symptoms according to DDERS was 0.
A six-week double-blind comparison of fluvoxamine at a dose of 300 mg per day with the same dose of venlafaxine showed a response rate to treatment of 78.6% vs. 58.3%, respectively.

The ability of fluvoxamine to prevent relapse of the psychotic form of MDD was also studied (dose of 300 mg / day for 6 weeks and a 30-month follow-up, during which patients continued to receive 300 mg of fluvoxamine for 6 months or 200 mg / day of fluvoxamine for 24 months. B there were no relapses during the first 6 months.Over the next 24 months, remission was maintained in 80% of patients, and 20% had a single relapse during this period.At the same time, the safety and tolerability profile of fluvoxamine was comparable in these patients with that in the non-psychotic form of MDD. Thus, SSRIs alone have been shown to be a good alternative to both ECT and the combination of TADs with antipsychotics, the latter known to increase the risk of drug interactions and side effects, to which (with typical antipsychotics) patients with mood disorders are particularly susceptible.

Affinity of SSRIs and TADs for ǒ 1 – and ǒ 2 receptors

Substance

Ci (nM)

Ki-ratio
ǒ 1 ǒ 2 ǒ 1 /ǒ 9 0017 2
Fluvoxamine 36 8. 439 234
sertraline 57 5.297 93
fluoxetine 0348

68
Citalopram 292 5.410 19
Imipramine 9034 8

343 2.107 6
Paroxetine 1.893 22.870 12
Desipramine 1.987 11.430 6


Modern studies of the effect of antidepressants on psychotic forms of MDD are aimed at elucidating the features of their interaction with ǒ-receptors. These receptors, which regulate the activity of glutaminergic systems, were first referred to as opiate and then as phenocyclidine receptors. Although their receptor connections can be established, it is rather difficult to understand them in terms of agonism/antagonism. In contrast to most receptors located only in cell membranes, ǒ receptors are found in dynamic proteins of the endoplasmic reticulum, which are believed to disrupt secondary intercellular communication systems, especially calcium binding. ǒ-receptors are abundant in the brain, lungs, heart, muscles, liver, and kidneys. Although only two receptor subtypes are mentioned in the literature: ǒ 1 and ǒ 2 , there are probably more. ǒ 1 -Receptors are found in the granular layer of the cerebellum, singular nuclei, in the CA3 region of the hippocampus, the hypothalamus and the pons. In contrast, a high concentration of ǒ 2 receptors is observed in the cortex, hippocampus, habenular nucleus, paraventricular and supraoptic nuclei of the hypothalamus, and some cranial nuclei. ǒ 1 -Receptors are involved in the processes of memory and learning, stress, anxiety, depression, aggression, drug dependence, as well as psychotic and neuroprotective processes. Thus, the antipsychotic haloperidol is a potent ǒ-antagonist.

Studies have shown the degree of affinity of some antidepressants for rat brain ǒ-receptors (see table), the severity of which determines the degree of their clinical activity. As can be seen, fluvoxamine has the highest affinity (in terms of the ratio of two types of receptors), followed by sertraline, fluoxetine, citalopram, etc. It is not clear whether SSRIs are agonists, antagonists, or partial agonists of the ǒ receptor. Clinical studies also support data on the effectiveness of fluvoxamsin in the treatment of psychotic form of MDD and the enhancement of the effect of antipsychotics when combined with them in the treatment of negative symptoms of schizophrenia.

Thus, in the psychotic form of MDD, SSRIs outperform TADs both in terms of efficacy and tolerability, and, unlike TADs, can also be used as monotherapy.

The effectiveness of fluvoxamine monotherapy in the psychotic form of MDD compared with other antidepressants is probably due to the high affinity of this drug for o1 receptors.