What is Citalopram?

Introduction

Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.

It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and social phobia. The antidepressant effects may take one to four weeks to occur. It is taken by mouth.

Common side effects include nausea, trouble sleeping, sexual problems, shakiness, feeling tired, and sweating. Serious side effects include an increased risk of suicide in those under the age of 25, serotonin syndrome, glaucoma, and QT prolongation. It should not be used in persons who take or have recently taken a MAO inhibitor. Antidepressant discontinuation syndrome may occur when stopped. There are concerns that use during pregnancy may harm the foetus.

Citalopram was approved for medical use in the United States in 1998. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2019, it was the 30th most commonly prescribed medication in the United States, with more than 21 million prescriptions.

Brief History

Citalopram was first synthesized in 1972 by chemist Klaus Bøgesø and his research group at the pharmaceutical company Lundbeck and was first marketed in 1989 in Denmark. It was first marketed in the US in 1998. The original patent expired in 2003, allowing other companies to legally produce and market generic versions.

Medical Uses

Depression

In the United States, citalopram is approved to treat major depressive disorder. Citalopram appears to have comparable efficacy and superior tolerability relative to other antidepressants. In the National Institute for Health and Clinical Excellence ranking of ten antidepressants for efficacy and cost-effectiveness, citalopram is fifth in effectiveness (after mirtazapine, escitalopram, venlafaxine, and sertraline) and fourth in cost-effectiveness. The ranking results were based on a 2009 meta-analysis by Andrea Cipriani; an update of the analysis in 2018 produced broadly similar results.

Evidence for effectiveness of citalopram for treating depression in children is uncertain.

Panic Disorder

Citalopram is licensed in the UK and other European countries for panic disorder, with or without agoraphobia.

Other

Citalopram may be used off-label to treat anxiety, and dysthymia, premenstrual dysphoric disorder, body dysmorphic disorder, and obsessive-compulsive disorder (OCD).

It appears to be as effective as fluvoxamine and paroxetine in OCD. Some data suggest the effectiveness of intravenous infusion of citalopram in resistant OCD. Citalopram is well tolerated and as effective as moclobemide in social anxiety disorder. There are studies suggesting that citalopram can be useful in reducing aggressive and impulsive behaviour. It appears to be superior to placebo for behavioural disturbances associated with dementia. It has also been used successfully for hypersexuality in early Alzheimer’s disease.

A meta-analysis, including studies with fluoxetine, paroxetine, sertraline, escitalopram, and citalopram versus placebo, showed SSRIs to be effective in reducing symptoms of premenstrual syndrome, whether taken continuously or just in the luteal phase. For alcoholism, citalopram has produced a modest reduction in alcoholic drink intake and increase in drink-free days in studies of alcoholics, possibly by decreasing desire or reducing the reward.

While on its own citalopram is less effective than amitriptyline in the prevention of migraines, in refractory cases, combination therapy may be more effective.

Citalopram and other SSRIs can be used to treat hot flashes.

A 2009 multisite randomised controlled study found no benefit and some adverse effects in autistic children from citalopram, raising doubts whether SSRIs are effective for treating repetitive behaviour in children with autism.

Some research suggests citalopram interacts with cannabinoid protein-couplings in the rat brain, and this is put forward as a potential cause of some of the drug’s antidepressant effect.

Administration

Citalopram is typically taken in one dose, either in the morning or evening. It can be taken with or without food. Its absorption does not increase when taken with food, but doing so can help prevent nausea. Nausea is often caused when the 5HT3 receptors actively absorb free serotonin, as this receptor is present within the digestive tract. The 5HT3 receptors stimulate vomiting. This side effect, if present, should subside as the body adjusts to the medication.

Citalopram is considered safe and well tolerated in the therapeutic dose range. Distinct from some other agents in its class, it exhibits linear pharmacokinetics and minimal drug interaction potential, making it a better choice for the elderly or comorbid patients.

Adverse Effects

Sexual dysfunction is often a side effect with SSRIs.

Citalopram theoretically causes side effects by increasing the concentration of serotonin in other parts of the body (e.g. the intestines). Other side effects, such as increased apathy and emotional flattening, may be caused by the decrease in dopamine release associated with increased serotonin. Citalopram is also a mild antihistamine, which may be responsible for some of its sedating properties.

Other common side effects of citalopram include drowsiness, insomnia, nausea, weight changes (usually weight gain), increase in appetite, vivid dreaming, frequent urination, dry mouth, increased sweating, trembling, diarrhoea, excessive yawning, severe tinnitus, and fatigue. Less common side effects include bruxism, vomiting, cardiac arrhythmia, blood pressure changes, dilated pupils, anxiety, mood swings, headache, hyperactivity and dizziness. Rare side effects include convulsions, hallucinations, severe allergic reactions and photosensitivity. If sedation occurs, the dose may be taken at bedtime rather than in the morning. Some data suggests citalopram may cause nightmares. Citalopram is associated with a higher risk of arrhythmia than other SSRIs.

Withdrawal symptoms can occur when this medicine is suddenly stopped, such as paraesthesia, sleeping problems (difficulty sleeping and intense dreams), feeling dizzy, agitated or anxious, nausea, vomiting, tremors, confusion, sweating, headache, diarrhoea, palpitations, changes in emotions, irritability, and eye or eyesight problems. Treatment with citalopram should be reduced gradually when treatment is finished.

Citalopram and other SSRIs can induce a mixed state, especially in those with undiagnosed bipolar disorder.  According to an article published in 2020, one of the other rare side effects of Citalopram could be triggering visual snow syndrome; which does not resolve after the discontinuation of the medicine.

Sexual Dysfunction

Some people experience persistent sexual side effects after they stop taking SSRIs. This is known as Post-SSRI Sexual Dysfunction (PSSD). Common symptoms in these cases include genital anaesthesia, erectile dysfunction, anhedonia, decreased libido, premature ejaculation, vaginal lubrication issues, and nipple insensitivity in women. The prevalence of PSSD is unknown, and there is no established treatment.

Abnormal Heart Rhythm

In August 2011, the US Food and Drug Administration (FDA) announced, “Citalopram causes dose-dependent QT interval prolongation. Citalopram should no longer be prescribed at doses greater than 40 mg per day”. A further clarification issued in March 2012, restricted the maximum dose to 20 mg for subgroups of patients, including those older than 60 years and those taking an inhibitor of cytochrome P450 2C19.7.

Endocrine Effects

As with other SSRIs, citalopram can cause an increase in serum prolactin level. Citalopram has no significant effect on insulin sensitivity in women of reproductive age and no changes in glycaemic control were seen in another trial.

Exposure in Pregnancy

Antidepressant exposure (including citalopram) during pregnancy is associated with shorter duration of gestation (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). Antidepressant exposure is not associated with an increased risk of spontaneous abortion. It is uncertain whether there is an increased prevalence of septal heart defects among children whose mothers were prescribed an SSRI in early pregnancy.

Interactions

Citalopram should not be taken with St John’s wort, tryptophan or 5-HTP as the resulting drug interaction could lead to serotonin syndrome. With St John’s wort, this may be caused by compounds in the plant extract reducing the efficacy of the hepatic cytochrome P450 enzymes that process citalopram. It has also been suggested that such compounds, including hypericin, hyperforin and flavonoids, could have SSRI-mimetic effects on the nervous system, although this is still subject to debate. One study found that Hypericum extracts had similar effects in treating moderate depression as citalopram, with fewer side effects.

Tryptophan and 5-HTP are precursors to serotonin. When taken with an SSRI, such as citalopram, this can lead to levels of serotonin that can be lethal. This may also be the case when SSRIs are taken with SRAs (serotonin releasing agents) such as in the case of MDMA. It is possible that SSRIs could reduce the effects associated due to an SRA, since SSRIs stop the reuptake of Serotonin by blocking SERT. This would allow less serotonin in and out of the transporters, thus decreasing the likelihood of neurotoxic effects. However, these concerns are still disputed as the exact pharmacodynamic effects of citalopram and MDMA have yet to be fully identified.[citation needed]

SSRIs, including citalopram, can increase the risk of bleeding, especially when coupled with aspirin, NSAIDs, warfarin, or other anticoagulants. Citalopram is contraindicated in individuals taking MAOIs, owing to a potential for serotonin syndrome.

Taking citalopram with omeprazole may cause higher blood levels of citalopram. This is a potentially dangerous interaction, so dosage adjustments may be needed or alternatives may be prescribed.

SSRI discontinuation syndrome has been reported when treatment is stopped. It includes sensory, gastrointestinal symptoms, dizziness, lethargy, and sleep disturbances, as well as psychological symptoms such as anxiety/agitation, irritability, and poor concentration. Electric shock-like sensations are typical for SSRI discontinuation. Tapering off citalopram therapy, as opposed to abrupt discontinuation, is recommended in order to diminish the occurrence and severity of discontinuation symptoms. Some doctors choose to switch a patient to Prozac (fluoxetine) when discontinuing citalopram as fluoxetine has a much longer half-life (i.e. stays in the body longer compared to citalopram). This may avoid many of the severe withdrawal symptoms associated with citalopram discontinuation. This can be done either by administering a single 20 mg dose of fluoxetine or by beginning on a low dosage of fluoxetine and slowly tapering down. Either of these prescriptions may be written in liquid form to allow a very slow and gradual tapering down in dosage. Alternatively, a patient wishing to stop taking citalopram may visit a compounding pharmacy where their prescription may be re-arranged into progressively smaller dosages.

Overdose

Overdosage may result in vomiting, sedation, disturbances in heart rhythm, dizziness, sweating, nausea, tremor, and rarely amnesia, confusion, coma, or convulsions.  Overdose deaths have occurred, sometimes involving other drugs, but also with citalopram as the sole agent. Citalopram and N-desmethylcitalopram may be quantified in blood or plasma to confirm a diagnosis of poisoning in hospitalised patients or to assist in a medicolegal death investigation. Blood or plasma citalopram concentrations are usually in a range of 50-400 μg/l in persons receiving the drug therapeutically, 1000-3000 μg/l in patients who survive acute overdosage and 3-30 mg/l in those who do not survive. It is the most dangerous of SSRIs in overdose.

Suicidality

In the United States, citalopram carries a boxed warning stating it may increase suicidal thinking and behaviour in those under age 24.

Stereochemistry

Citalopram has one stereocentre, to which a 4-fluoro phenyl group and an N, N-dimethyl-3-aminopropyl group bind. As a result of this chirality, the molecule exists in (two) enantiomeric forms (mirror images). They are termed S-(+)-citalopram and R-(–)-citalopram.

Citalopram is sold as a racemic mixture, consisting of 50% (R)-(−)-citalopram and 50% (S)-(+)-citalopram. Only the (S)-(+) enantiomer has the desired antidepressant effect. Lundbeck now markets the (S)-(+) enantiomer, the generic name of which is escitalopram. Whereas citalopram is supplied as the hydrobromide, escitalopram is sold as the oxalate salt (hydrooxalate). In both cases, the salt forms of the amine make these otherwise lipophilic compounds water-soluble.

Metabolism

Citalopram is metabolised in the liver mostly by CYP2C19, but also by CYP3A4 and CYP2D6. Metabolites desmethylcitalopram and didesmethylcitalopram are significantly less energetic and their contribution to the overall action of citalopram is negligible. The half-life of citalopram is about 35 hours. Approximately 80% is cleared by the liver and 20% by the kidneys. The elimination process is slower in the elderly and in patients with liver or kidney failure. With once-daily dosing, steady plasma concentrations are achieved in about a week. Potent inhibitors of CYP2C19 and 3A4 might decrease citalopram clearance. Tobacco smoke exposure was found to inhibit the biotransformation of citalopram in animals, suggesting that the elimination rate of citalopram is decreased after tobacco smoke exposure. After intragastric administration, the half-life of the racemic mixture of citalopram was increased by about 287%.

Society and Culture

Brand Names

Citalopram is sold under these brand names:

  • Akarin (Denmark, Nycomed).
  • C Pram S (India).
  • Celapram (Australia and New Zealand).
  • Celexa (US and Canada, Forest Laboratories, Inc.).
  • Celica (Australia).
  • Ciazil (Australia and New Zealand).
  • Cilate (South Africa).
  • Cilift (South Africa).
  • Cimal (South America, by Roemmers and Recalcine).
  • Cipralex (South Africa).
  • Cipram (Denmark and Turkey, H. Lundbeck A/S).
  • Cipramil (Australia, Brazil, Belgium, Chile, Finland, Germany, Netherlands, Iceland, Ireland, Israel, New Zealand, Norway, Russia, South Africa, Sweden, and the United Kingdom).
  • Cipraned, Cinapen (Greece).
  • Ciprapine (Ireland).
  • Ciprotan (Ireland).
  • Citabax, Citaxin (Poland).
  • Cital (Poland).
  • Citalec (Czech Republic and Slovakia).
  • Citalex (Iran and Serbia).
  • Citalo (Australia, Egypt, and Pakistan).
  • Citalopram (Canada, Denmark, Finland, Germany, Ireland, New Zealand, Spain, Sweden, Switzerland, United Kingdom, the US).
  • Citol (Russia).
  • Citox (Mexico).
  • Citrol (Europe and Australia).
  • Citta (Brazil).
  • Dalsan (Eastern Europe).
  • Denyl (Brazil).
  • Elopram (Italy).
  • Estar (Pakistan).
  • Humorup (Argentina).
  • Humorap (Peru, Bolivia).
  • Lopraxer (Greece).
  • Oropram (Iceland, Actavis).
  • Opra (Russia).
  • Pram (Russia).
  • Pramcit (Pakistan).
  • Procimax (Brazil).
  • Recital (Israel, Thrima Inc. for Unipharm Ltd.).
  • Sepram (Finland).
  • Seropram (various European countries, including Czech Republic).
  • Szetalo (India).
  • Talam (Europe and Australia).
  • Temperax (Argentina, Chile, and Peru).
  • Vodelax (Turkey).
  • Zentius (South America, by Roemmers and Recalcine).
  • Zetalo (India).
  • Cipratal (Kuwait, GCC).
  • Zylotex (Portugal).

European Commission Fine

On 19 June 2013, the European Commission imposed a fine of €93.8 million on the Danish pharmaceutical company Lundbeck, plus a total of €52.2 million on several generic pharmaceutical-producing companies. This was in response to Lundbeck entering an agreement with the companies to delay their sales of generic citalopram after Lundbeck’s patent on the drug had expired, thus reducing competition in breach of European antitrust law.

What is a Second-Generation Antidepressant?

Introduction

The second-generation antidepressants are a class of antidepressants characterised primarily by the era of their introduction, approximately coinciding with the 1970s and 1980s, rather than by their chemical structure or by their pharmacological effect. As a consequence, there is some controversy over which treatments actually belong in this class.

Refer to Atypical Antidepressant, Tricyclic Antidepressant, and Tetracyclic Antidepressant.

The term “third generation antidepressant” is sometimes used to refer to newer antidepressants, from the 1990s and 2000s, often selective serotonin reuptake inhibitors (SSRIs) such as; fluoxetine (Prozac), paroxetine (Paxil) and sertraline (Zoloft), as well as some non-SSRI antidepressants such as mirtazapine, nefazodone, venlafaxine, duloxetine and reboxetine. However, this usage is not universal.

Examples

This list is not exhaustive, and different sources vary upon which items should be considered second-generation.

  • Amineptine.
  • Amoxapine.
  • Bupropion.
  • Iprindole.
  • Maprotiline.
  • Medifoxamine.
  • Mianserin.
  • Nomifensine.
  • Tianeptine.
  • Trazodone.
  • Venlafaxine.
  • Viloxazine.

What is Seproxetine?

Introduction

Seproxetine, also known as (S)-norfluoxetine, is a selective serotonin reuptake inhibitor (SSRI).

Background

It is the S enantiomer of norfluoxetine, the main active metabolite of the widely used antidepressant fluoxetine; but little is known about its pharmacological actions. Seproxetine was being investigated by Eli Lilly and Company as an antidepressant; however, cardiac side effects were discovered and development was discontinued.

What is RTI-353?

Introduction

RTI(-4229)-353 is a phenyltropane derived drug which acts as an SSRI (Navarro et al., 2001).

Tamagnan et al. (2006) also made some phenyltropanes with high activity and selectivity for the SERT (pM affinity).

References

Navarro, H.A., Xu, H., Zhong, D., Blough, B.E., Ross, W.P., Kuhar, M.J. & Carroll, F.I. (2001) [(125)I]3beta-(4-ethyl-3-iodophenyl)nortropane-2beta-carboxylic acid methyl ester ([(125)I]EINT): a potent and selective radioligand for the brain serotonin transporter. Synapse: New York, N.Y. 41(3), pp.241-247.

Tamagnan, G., Alagille, D., Fu, X., Kula, N.S., Baldessarini, R.J., Innis, R.B. & Baldwin, R.M. (2006) Synthesis and monoamine transporter affinity of new 2beta-carbomethoxy-3beta-[aryl or heteroaryl]phenyltropanes. Bioorganic & Medicinal Chemistry Letters. 16(1), pp.217-220.

What is Olanzapine/Fluoxetine?

Introduction

Olanzapine/fluoxetine (trade name Symbyax, created by Eli Lilly and Company) is a fixed-dose combination medication containing olanzapine (Zyprexa), an atypical antipsychotic, and fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI). Olanzapine/fluoxetine is primarily used to treat the depressive episodes of bipolar I disorder as well as treatment-resistant depression.

Medical Uses

Olanzapine/fluoxetine was approved by the US Food and Drug Administration (FDA) to treat the depressive episodes of bipolar I disorder in 2003. In 2009, it was granted approval for the treatment of treatment-resistant depression.

Olanzapine/fluoxetine, or other antidepressant/antipsychotic combinations, are sometimes prescribed off-label for anxiety disorders, eating disorders, obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD).

Side Effects

Possible side effects of olanzapine/fluoxetine include all those of the two component drugs: olanzapine (side effects) and fluoxetine (side effects). Common side effects include suicidal thoughts, increased appetite, weight gain, drowsiness, fatigue, dry mouth, swelling, tremor, blurred vision, and difficulty concentrating.

Olanzapine/fluoxetine could produce a severe allergic reaction and should not be used if the patient has previously experienced an allergic reaction to either fluoxetine or olanzapine.

Olanzapine is correlated with an increase in blood sugar. Patients with diabetes, or those at risk for developing it, require careful monitoring.

In rare cases, olanzapine/fluoxetine may cause neuroleptic malignant syndrome.

Like other SSRIs, olanzapine/fluoxetine carries a boxed warning stating that it could increase the risk of suicidal thoughts and behaviours in patients aged 24 and under. The warning also states that olanzapine/fluoxetine may increase the risk of death in elderly patients with dementia-related psychosis.

What is Paroxetine?

Introduction

Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.

It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder, social anxiety disorder, posttraumatic stress disorder (PTSD), generalised anxiety disorder (GAD) and premenstrual dysphoric disorder. It has also been used in the treatment of premature ejaculation and hot flashes due to menopause. It is taken by mouth.

Common side effects include drowsiness, dry mouth, loss of appetite, sweating, trouble sleeping, and sexual dysfunction. Serious side effects may include suicidal thoughts in those under the age of 25, serotonin syndrome, and mania. While the rate of side effects appears similar compared to other SSRIs and SNRIs, antidepressant discontinuation syndromes may occur more often. Use in pregnancy is not recommended, while use during breastfeeding is relatively safe. It is believed to work by blocking the re-uptake of the chemical serotonin by neurons in the brain.

Paroxetine was approved for medical use in the United States in 1992 and initially sold by GlaxoSmithKline. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2019, it was the 78th most commonly prescribed medication in the United States, with more than 9 million prescriptions. In 2018, it was in the top 10 of most prescribed antidepressants in the United States. In 2012, the United States Department of Justice fined GlaxoSmithKline $3 billion for withholding data, unlawfully promoting use in those under 18, and preparing an article that misleadingly reported the effects of paroxetine in adolescents with depression following its clinical trial study 329.

Medical Uses

Paroxetine is primarily used to treat major depressive disorder (MDD), obsessive-compulsive disorder (OCD), PTSD, social anxiety disorder, and panic disorder. It is also occasionally used for agoraphobia, GAD, premenstrual dysphoric disorder and menopausal hot flashes.

Depression

A variety of meta analyses have been conducted to evaluate the efficacy of paroxetine in depression. They have variously concluded that paroxetine is superior or equivalent to placebo and that it is equivalent or inferior to other antidepressants. Despite this, there was no clear evidence that paroxetine was better or worse compared with other antidepressants at increasing response to treatment at any point in time.

Anxiety Disorders

Paroxetine was the first antidepressant approved in the United States for the treatment of panic disorder. Several studies have concluded that paroxetine is superior to placebo in the treatment of panic disorder.

Paroxetine has demonstrated efficacy for the treatment of social anxiety disorder in adults and children. It is also beneficial for people with co-occurring social anxiety disorder and alcohol use disorder. It appears to be similar to a number of other SSRIs.

Paroxetine is used in the treatment of OCD. Comparative efficacy of paroxetine is equivalent to that of clomipramine and venlafaxine. Paroxetine is also effective for children with OCD.

Paroxetine is approved for treatment of PTSD in the United States, Japan and Europe. In the United States it is approved for short-term use.

Paroxetine is also Food and Drug Administration (FDA)-approved for GAD.

Menopausal Hot Flashes

In 2013, low-dose paroxetine was approved in the US for the treatment of moderate-to-severe vasomotor symptoms such as hot flashes and night sweats associated with menopause. At the low dose used for menopausal hot flashes, side effects are similar to placebo and dose tapering is not required for discontinuation.

Fibromyalgia

Studies have also shown paroxetine “appears to be well-tolerated and improve the overall symptomatology in patients with fibromyalgia” but is less robust in helping with the pain involved.

Adverse Effects

Common side effects include drowsiness, dry mouth, loss of appetite, sweating, trouble sleeping, and sexual dysfunction. Serious side effects may include suicide in those under the age of 25, serotonin syndrome, and mania. While the rate of side effects appears similar compared to other SSRIs and SNRIs, antidepressant discontinuation syndromes may occur more often. Use in pregnancy is not recommended while use during breastfeeding is relatively safe.

Paroxetine shares many of the common adverse effects of SSRIs, including (with the corresponding rates seen in people treated with placebo in parentheses):

  • Nausea 26% (9%).
  • Diarrhoea 12% (8%).
  • Constipation 14% (9%).
  • Dry mouth 18% (12%).
  • Somnolence 23% (9%).
  • Insomnia 13% (6%).
  • Headache 18% (17%).
  • Hypomania 1% (0.3%).
  • Blurred vision 4% (1%).
  • Loss of appetite 6% (2%).
  • Nervousness 5% (3%).
  • Paraesthesia 4% (2%).
  • Dizziness 13% (6%).
  • Asthenia (weakness; 15% (6%)).
  • Tremor 8% (2%).
  • Sweating 11% (2%).
  • Sexual dysfunction (≥10% incidence).

Most of these adverse effects are transient and go away with continued treatment. Central and peripheral 5-HT3 receptor stimulation is believed to result in the gastrointestinal effects observed with SSRI treatment. Compared to other SSRIs, it has a lower incidence of diarrhoea, but a higher incidence of anticholinergic effects (e.g. dry mouth, constipation, blurred vision, etc.), sedation/somnolence/drowsiness, sexual side effects, and weight gain.

Due to reports of adverse withdrawal reactions upon terminating treatment, the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency recommends gradually reducing over several weeks or months if the decision to withdraw is made (Refer to discontinuation syndrome below).

Mania or hypomania may occur in 1% of patients with depression and up to 12% of patients with bipolar disorder. This side effect can occur in individuals with no history of mania but it may be more likely to occur in those with bipolar or with a family history of mania.

Suicide

Like other antidepressants, paroxetine may increase the risk of suicidal thinking and behaviour in people under the age of 25. The FDA conducted a statistical analysis of paroxetine clinical trials in children and adolescents in 2004 and found an increase in suicidality and ideation as compared to placebo, which was observed in trials for both depression and anxiety disorders. In 2015 a paper published in The BMJ that reanalysed the original case notes argued that in Study 329, assessing paroxetine and imipramine against placebo in adolescents with depression, the incidence of suicidal behaviour had been under-reported and the efficacy exaggerated for paroxetine.

Sexual Dysfunction

Sexual dysfunction, including loss of libido, anorgasmia, lack of vaginal lubrication, and erectile dysfunction, is one of the most commonly encountered adverse effects of treatment with paroxetine and other SSRIs. While early clinical trials suggested a relatively low rate of sexual dysfunction, more recent studies in which the investigator actively inquires about sexual problems suggest that the incidence is higher than 70%. Symptoms of sexual dysfunction have been reported to persist after discontinuing SSRIs, although this is thought to be occasional.

Pregnancy

Antidepressant exposure (including paroxetine) is associated with shorter duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g or 2.6 oz), and lower Apgar scores (by <0.4 points). The American College of Obstetricians and Gynaecologists recommends that for pregnant women and women planning to become pregnant, paroxetine “be avoided, if possible”, as it may be associated with increased risk of birth defects.

Babies born to women who used paroxetine during the first trimester have an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs). Unless the benefits of paroxetine justify continuing treatment, consideration should be given to stopping or switching to another antidepressant. Paroxetine use during pregnancy is associated with about 1.5-1.7-fold increase in congenital birth defects, in particular, heart defects, cleft lip and palate, clubbed feet or any birth defects.

Antidepressant Discontinuation Syndrome

Refer to Antidepressant Discontinuation Syndrome.

Many psychoactive medications can cause withdrawal symptoms upon discontinuation from administration. Evidence has shown that paroxetine has among the highest incidence rates and severity of withdrawal syndrome of any medication of its class. Common withdrawal symptoms for paroxetine include nausea, dizziness, lightheadedness and vertigo; insomnia, nightmares and vivid dreams; feelings of electricity in the body, as well as rebound depression and anxiety. Liquid formulation of paroxetine is available and allows a very gradual decrease of the dose, which may prevent discontinuation syndrome. Another recommendation is to temporarily switch to fluoxetine, which has a longer half-life and thus decreases the severity of discontinuation syndrome.

In 2002, the FDA published a warning regarding “severe” discontinuation symptoms among those terminating paroxetine treatment, including paraesthesia, nightmares, and dizziness. The FDA also warned of case reports describing agitation, sweating, and nausea. In connection with a Glaxo spokesperson’s statement that withdrawal reactions occur only in 0.2% of patients and are “mild and short-lived”, the International Federation of Pharmaceutical Manufacturers Associations said GSK had breached two of the Federation’s codes of practice.

Paroxetine prescribing information posted at GlaxoSmithKline has been updated related to the occurrence of a discontinuation syndrome, including serious discontinuation symptoms.

Overdose

Acute overdosage is often manifested by emesis, lethargy, ataxia, tachycardia, and seizures. Plasma, serum, or blood concentrations of paroxetine may be measured to monitor therapeutic administration, confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities. Plasma paroxetine concentrations are generally in a range of 40-400 μg/L in persons receiving daily therapeutic doses and 200-2,000 μg/L in poisoned patients. Postmortem blood levels have ranged from 1-4 mg/L in acute lethal overdose situations. Along with the other SSRIs, sertraline and fluoxetine, paroxetine is considered a low-risk drug in cases of overdose.

Interactions

Interactions with other drugs acting on the serotonin system or impairing the metabolism of serotonin may increase the risk of serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reaction. Such reactions have been observed with SNRIs and SSRIs alone, but particularly with concurrent use of triptans, MAO inhibitors, antipsychotics, or other dopamine antagonists.

The prescribing information states that paroxetine should “not be used in combination with an MAOI (including linezolid, an antibiotic which is a reversible non-selective MAOI), or within 14 days of discontinuing treatment with an MAOI”, and should not be used in combination with pimozide, thioridazine, tryptophan, or warfarin.

Paroxetine interacts with the following cytochrome P450 enzymes:

  • CYP2D6 for which it is both a substrate and a potent inhibitor.
  • CYP2B6 (strong) inhibitor.
  • CYP3A4 (weak) inhibitor.
  • CYP1A2 (weak) inhibitor.
  • CYP2C9 (weak) inhibitor.
  • CYP2C19 (weak) inhibitor.

Paroxetine has been shown to be an inhibitor of G protein-coupled receptor kinase 2 (GRK2).

Pharmacology

Pharmacodynamics

Paroxetine is the most potent and one of the most specific selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs). It also binds to the allosteric site of the serotonin transporter, similarly, but less potently, than escitalopram. Paroxetine also inhibits the reuptake of norepinephrine to a lesser extent (<50 nmol/L). Based on evidence from four weeks of administration in rats, the equivalent of 20 mg paroxetine taken once daily occupies approximately 88% of serotonin transporters in the prefrontal cortex.

Pharmacokinetics

Paroxetine is well-absorbed following oral administration. It has an absolute bioavailability of about 50%, with evidence of a saturable first pass effect. When taken orally, it achieves maximum concentration in about 6-10 hours and reaches steady-state in 7-14 days. Paroxetine exhibits significant interindividual variations in volume of distribution and clearance. Less than 2% of an oral dose is excreted in urine unchanged.

Paroxetine is a mechanism-based inhibitor of CYP2D6.

Society and Culture

GlaxoSmithKline has paid substantial fines, paid settlements in class-action lawsuits, and become the subject of several highly critical books about its marketing of paroxetine, in particular the off-label marketing of paroxetine for children, the suppression of negative research results relating to its use in children, and allegations that it failed to warn consumers of substantial withdrawal effects associated with use of the drug. Paroxetine was approved for medical use in the United States in 1992 and initially sold by GlaxoSmithKline. It is currently available as a generic medication. In 2017, it was the 68th most commonly prescribed medication in the United States, with more than eleven million prescriptions. The United States Department of Justice fined GlaxoSmithKline $3 billion in 2012, for withholding data, unlawfully promoting use in those under 18, and preparing an article that misleadingly reported the effects of paroxetine in adolescents with depression following its clinical trial study 329.

Marketing

In early 2004, GSK agreed to settle charges of consumer fraud for $2.5 million. The legal discovery process also uncovered evidence of deliberate, systematic suppression of unfavourable Paxil research results. One of GSK’s internal documents read, “It would be commercially unacceptable to include a statement that efficacy [in children] had not been demonstrated, as this would undermine the profile of paroxetine”.

In 2012 the US Justice Department announced that GSK agreed to plead guilty and pay a $3 billion fine, in part for promoting the use of Paxil for children.

On 12 February 2016, the UK Competition and Markets Authority imposed record fines of £45 million on companies which were found to have infringed European Union and UK Competition law by entering into agreements to delay the market entry of generic versions of the drug in the UK. GlaxoSmithKline received the bulk of the fines, being fined £37,600,757. Other companies, which produce generics, were issued fines which collectively total £7,384,146. UK public health services are likely to claim damages for being overcharged in the period where the generic versions of the drug were illegally blocked from the market, as the generics are over 70% less expensive. GlaxoSmithKline may also face actions from other generics manufacturers who incurred loss as a result of the anticompetitive conduct. On 18 April 2016, appeals were lodged with the Competition Appeal Tribunal by the companies which were fined.

GSK marketed paroxetine through television advertisements throughout the late 1990s and early 2000s. Commercials also aired for the CR version of the drug beginning in 2003.

Sales

In 2007, paroxetine was ranked 94th on the list of bestselling drugs, with over $1 billion in sales. In 2006, paroxetine was the fifth-most prescribed antidepressant in the US retail market, with more than 19.7 million prescriptions. In 2007, sales had dropped slightly to 18.1 million but paroxetine remained the fifth-most prescribed antidepressant in the US.

Trade Names

Trade names include Aropax, Brisdelle, Deroxat, Paxil, Pexeva, Paxtine, Paxetin, Paroxat, Paraxyl, Sereupin, Daparox and Seroxat.

Research

Several studies have suggested that paroxetine can be used in the treatment of premature ejaculation. In particular, intravaginal ejaculation latency time (IELT) was found to increase with 6- to 13-fold, which was somewhat longer than the delay achieved by the treatment with other SSRIs (fluvoxamine, fluoxetine, sertraline, and citalopram). However, paroxetine taken acutely (“on demand”) 3-10 hours before coitus resulted only in a “clinically irrelevant and sexually unsatisfactory” 1.5-fold delay of ejaculation and was inferior to clomipramine, which induced a fourfold delay.

There is also evidence that paroxetine may be effective in the treatment of compulsive gambling and hot flashes.

Benefits of paroxetine prescription for diabetic neuropathy or chronic tension headache are uncertain.

Although the evidence is conflicting, paroxetine may be effective for the treatment of dysthymia, a chronic disorder involving depressive symptoms for most days of the year.

There is evidence to support that paroxetine selectively binds to and inhibits G protein-coupled receptor kinase 2 (GRK2). Since GRK2 regulates the activity of the beta adrenergic receptor, which becomes desensitised in cases of heart failure, paroxetine (or a paroxetine derivative) could be used as a heart failure treatment in the future.

Paroxetine has been deemed to have dmoad activity.

What is Imipramine?

Introduction

Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression.

It is also effective in treating anxiety and panic disorder. The drug is also used to treat bedwetting. Imipramine is taken by mouth.

Common side effects of imipramine include dry mouth, drowsiness, dizziness, low blood pressure, rapid heart rate, urinary retention, and electrocardiogram changes. Overdose of the medication can result in death. Imipramine appears to work by increasing levels of serotonin and norepinephrine and by blocking certain serotonin, adrenergic, histamine, and cholinergic receptors.

Imipramine was discovered in 1951 and was introduced for medical use in 1957. It was the first TCA to be marketed. Imipramine and the other TCAs have decreased in use in recent decades, due to the introduction of the selective serotonin reuptake inhibitors (SSRIs), which have fewer side effects and are safer in overdose.

Brief History

The parent compound of imipramine, 10,11-dihydro-5H-dibenz[b,f]azepine (dibenzazepine), was first synthesized in 1899, but no pharmacological assessment of this compound or any substituted derivatives was undertaken until the late 1940s. Imipramine was first synthesized in 1951, as an antihistamine. The antipsychotic effects of chlorpromazine were discovered in 1952, and imipramine was then developed and studied as an antipsychotic for use in patients with schizophrenia. The medication was tested in several hundred patients with psychosis, but showed little effectiveness. However, imipramine was serendipitously found to possess antidepressant effects in the mid-1950s following a case report of symptom improvement in a woman with severe depression who had been treated with it. This was followed by similar observations in other patients and further clinical research. Subsequently, imipramine was introduced for the treatment of depression in Europe in 1958 and in the United States in 1959. Along with the discovery and introduction of the monoamine oxidase inhibitor iproniazid as an antidepressant around the same time, imipramine resulted in the establishment of monoaminergic drugs as antidepressants.

In the late 1950s, imipramine was the first TCA to be developed (by Ciba). At the first international congress of neuropharmacology in Rome, September 1958 Dr Freyhan from the University of Pennsylvania discussed as one of the first clinicians the effects of imipramine in a group of 46 patients, most of them diagnosed as “depressive psychosis”. The patients were selected for this study based on symptoms such as depressive apathy, kinetic retardation and feelings of hopelessness and despair. In 30% of all patients, he reported optimal results, and in around 20%, failure. The side effects noted were atropine-like, and most patients suffered from dizziness. Imipramine was first tried against psychotic disorders such as schizophrenia, but proved ineffective. As an antidepressant, it did well in clinical studies and it is known to work well in even the most severe cases of depression. It is not surprising, therefore, that imipramine may cause a high rate of manic and hypomanic reactions in hospitalised patients with pre-existing bipolar disorder, with one study showing that up to 25% of such patients maintained on Imipramine switched into mania or hypomania. Such powerful antidepressant properties have made it favourable in the treatment of treatment-resistant depression.

Before the advent of SSRIs, its sometimes intolerable side-effect profile was considered more tolerable. Therefore, it became extensively used as a standard antidepressant and later served as a prototypical drug for the development of the later-released TCAs. Since the 1990s, it has no longer been used as commonly, but is sometimes still prescribed as a second-line treatment for treating major depression . It has also seen limited use in the treatment of migraines, ADHD, and post-concussive syndrome. Imipramine has additional indications for the treatment of panic attacks, chronic pain, and Kleine-Levin syndrome. In paediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis.

Medical Uses

Imipramine is used in the treatment of depression and certain anxiety disorders. It is similar in efficacy to the antidepressant drug moclobemide. It has also been used to treat nocturnal enuresis because of its ability to shorten the time of delta wave stage sleep, where wetting occurs. In veterinary medicine, imipramine is used with xylazine to induce pharmacologic ejaculation in stallions. Blood levels between 150-250 ng/mL of imipramine plus its metabolite desipramine generally correspond to antidepressant efficacy.

Available Forms

Imipramine is available in the form of oral tablets and capsules.

Contraindications

Combining it with alcohol consumption causes excessive drowsiness. It may be unsafe during pregnancy.

Side Effects

Those listed in italics below denote common side effects.

  • Central nervous system: dizziness, drowsiness, confusion, seizures, headache, anxiety, tremors, stimulation, weakness, insomnia, nightmares, extrapyramidal symptoms in geriatric patients, increased psychiatric symptoms, paraesthesia.
  • Cardiovascular: orthostatic hypotension, ECG changes, tachycardia, hypertension, palpitations, dysrhythmias
  • Eyes, ears, nose and throat: blurred vision, tinnitus, mydriasis.
  • Gastrointestinal: dry mouth, nausea, vomiting, paralytic ileus, increased appetite, cramps, epigastric distress, jaundice, hepatitis, stomatitis, constipation, taste change.
  • Genitourinary: urinary retention.
  • Hematological: agranulocytosis, thrombocytopenia, eosinophilia, leukopenia.
  • Skin: rash, urticaria, diaphoresis, pruritus, photosensitivity.

Overdose

Refer to Tricyclic Antidepressant Overdose.

Pharmacology

Pharmacodynamics

Imipramine affects numerous neurotransmitter systems known to be involved in the aetiology of depression, anxiety, attention-deficit hyperactivity disorder (ADHD), enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions.

The mechanisms of imipramine’s actions include, but are not limited to, effects on:

  • Serotonin: very strong reuptake inhibition.
  • Norepinephrine: strong reuptake inhibition.
    • Desipramine has more affinity to norepinephrine transporter than imipramine.
  • Dopamine:
    • Imipramine blocks D2 receptors.
    • Imipramine, and its metabolite desipramine, have no appreciable affinity for the dopamine transporter (Ki = 8,500 and >10,000 nM, respectively).
  • Acetylcholine:
    • Imipramine is an anticholinergic, specifically an antagonist of the muscarinic acetylcholine receptors.
    • Thus, it is prescribed with caution to the elderly and with extreme caution to those with psychosis, as the general brain activity enhancement in combination with the “dementing” effects of anticholinergics increases the potential of imipramine to cause hallucinations, confusion and delirium in this population.
  • Epinephrine:
    • Imipramine antagonises adrenergic receptors, thus sometimes causing orthostatic hypotension.
  • Sigma receptor:
    • Activity on sigma receptors is present, but it is very weak (Ki = 520 nM) and it is about half that of amitriptyline (Ki = 300 nM).
  • Histamine:
    • Imipramine is an antagonist of the histamine H1 receptors.
  • BDNF:
    • BDNF is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis.
    • It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours.
    • Chronic imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promoter, and also reduced expression of hippocampal HDAC5.

Pharmacokinetics

Within the body, imipramine is converted into desipramine (desmethylimipramine) as a metabolite.

Chemistry

Imipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include desipramine (N-desmethylimipramine), clomipramine (3-chloroimipramine), trimipramine (2′-methylimipramine or β-methylimipramine), and lofepramine (N-(4-chlorobenzoylmethyl)desipramine). Imipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine. The chemical name of imipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C19H24N2 with a molecular weight of 280.407 g/mol. The drug is used commercially mostly as the hydrochloride salt; the embonate (pamoate) salt is used for intramuscular administration and the free base form is not used. The CAS Registry Number of the free base is 50-49-7, of the hydrochloride is 113-52-0, and of the embonate is 10075-24-8.

Society and Culture

Generic Names

Imipramine is the English and French generic name of the drug and its INN, BAN, and DCF, while imipramine hydrochloride is its USAN, USP, BANM, and JAN. Its generic name in Spanish and Italian and its DCIT are imipramina, in German is imipramin, and in Latin is imipraminum. The embonate salt is known as imipramine pamoate.

Brand Names

Imipramine is marketed throughout the world mainly under the brand name Tofranil. Imipramine pamoate is marketed under the brand name Tofranil-PM for intramuscular injection.

Availability

Imipramine is available for medical use widely throughout the world, including in the United States, the United Kingdom, elsewhere in Europe, Brazil, South Africa, Australia, and New Zealand.

What is a Monoamine Oxidase Inhibitor?

Introduction

Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B).

They are best known as highly efficacious antidepressants, as well as effective therapeutic agents for panic disorder and social phobia. They are particularly effective in treatment-resistant depression and atypical depression. They are also used in the treatment of Parkinson’s disease and several other disorders.

Reversible inhibitors of monoamine oxidase A (RIMAs) are a subclass of MAOIs that selectively and reversibly inhibit the MAO-A enzyme. RIMAs are used clinically in the treatment of depression and dysthymia. Due to their reversibility, they are safer in single-drug overdose than the older, irreversible MAOIs, and weaker in increasing the monoamines important in depressive disorder. RIMAs have not gained widespread market share in the United States.

New research into MAOIs indicates that much of the concern over their supposed dangerous dietary side effects stems from misconceptions and misinformation, and that they are still underutilised despite demonstrated efficacy. New research also questions the validity of the perceived severity of dietary reactions, which has been based on outdated research. Despite this, many psychiatrists, who have little or no knowledge of and experience with monoamine oxidase inhibitors (and are thus unaware of their significant benefits), still reserve them as a last line of treatment, used only when other classes of antidepressant drugs (for example, selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants) have failed.

Brief History

MAOIs started off due to the serendipitous discovery that iproniazid was a potent MAO inhibitor (MAOI). Originally intended for the treatment of tuberculosis, in 1952, iproniazid’s antidepressant properties were discovered when researchers noted that the depressed patients given iproniazid experienced a relief of their depression. Subsequent in vitro work led to the discovery that it inhibited MAO and eventually to the monoamine theory of depression. MAOIs became widely used as antidepressants in the early 1950s. The discovery of the 2 isoenzymes of MAO has led to the development of selective MAOIs that may have a more favourable side-effect profile.

The older MAOIs’ heyday was mostly between the years 1957 and 1970. The initial popularity of the ‘classic’ non-selective irreversible MAO inhibitors began to wane due to their serious interactions with sympathomimetic drugs and tyramine-containing foods that could lead to dangerous hypertensive emergencies. As a result, the use by medical practitioners of these older MAOIs declined. When scientists discovered that there are two different MAO enzymes (MAO-A and MAO-B), they developed selective compounds for MAO-B, (for example, selegiline, which is used for Parkinson’s disease), to reduce the side-effects and serious interactions. Further improvement occurred with the development of compounds (moclobemide and toloxatone) that not only are selective but cause reversible MAO-A inhibition and a reduction in dietary and drug interactions. Moclobemide, was the first reversible inhibitor of MAO-A to enter widespread clinical practice.

A transdermal patch form of the MAOI selegiline, called Emsam, was approved for use in depression by the US Food and Drug Administration (FDA) on 28 February 2006.

Medical Uses

MAOIs have been found to be effective in the treatment of panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety disorder and depression, bulimia, and post-traumatic stress disorder, as well as borderline personality disorder, and obsessive compulsive disorder (OCD). MAOIs appear to be particularly effective in the management of bipolar depression according to a retrospective-analysis from 2009. There are reports of MAOI efficacy in OCD, trichotillomania, body dysmorphic disorder, and avoidant personality disorder, but these reports are from uncontrolled case reports.

MAOIs can also be used in the treatment of Parkinson’s disease by targeting MAO-B in particular (therefore affecting dopaminergic neurons), as well as providing an alternative for migraine prophylaxis. Inhibition of both MAO-A and MAO-B is used in the treatment of clinical depression and anxiety.

MAOIs appear to be particularly indicated for outpatients with dysthymia complicated by panic disorder or hysteroid dysphoria.

Newer MAOIs such as selegiline (typically used in the treatment of Parkinson’s disease) and the reversible MAOI moclobemide provide a safer alternative and are now sometimes used as first-line therapy.

Side Effects

Hypertensive Crisis

People taking MAOIs generally need to change their diets to limit or avoid foods and beverages containing tyramine, which is found in products such as cheese, soy sauce, and salami. If large amounts of tyramine are consumed, they may suffer a hypertensive crisis, which can be fatal. Examples of foods and beverages with potentially high levels of tyramine include animal liver and fermented substances, such as alcoholic beverages and aged cheeses. Excessive concentrations of tyramine in blood plasma can lead to hypertensive crisis by increasing the release of norepinephrine (NE), which causes blood vessels to constrict by activating alpha-1 adrenergic receptors. Ordinarily, MAO-A would destroy the excess NE; when MAO-A is inhibited, however, NE levels get too high, leading to dangerous increases in blood pressure.

RIMAs are displaced from MAO-A in the presence of tyramine, rather than inhibiting its breakdown in the liver as general MAOIs do. Additionally, MAO-B remains free and continues to metabolise tyramine in the stomach, although this is less significant than the liver action. Thus, RIMAs are unlikely to elicit tyramine-mediated hypertensive crisis; moreover, dietary modifications are not usually necessary when taking a reversible inhibitor of MAO-A (i.e. moclobemide) or low doses of selective MAO-B inhibitors (e.g. selegiline 6 mg/24 hours transdermal patch).

Drug Interactions

The most significant risk associated with the use of MAOIs is the potential for drug interactions with over-the-counter, prescription, or illegally obtained medications, and some dietary supplements (e.g. St. John’s wort, tryptophan). It is vital that a doctor supervise such combinations to avoid adverse reactions. For this reason, many users carry an MAOI-card, which lets emergency medical personnel know what drugs to avoid (e.g. adrenaline (epinephrine) dosage should be reduced by 75%, and duration is extended).

Tryptophan supplements should not be consumed with MAOIs as the potentially fatal serotonin syndrome may result.

MAOIs should not be combined with other psychoactive substances (antidepressants, painkillers, stimulants, including prescribed, OTC and illegally acquired drugs, etc.) except under expert care. Certain combinations can cause lethal reactions, common examples including SSRIs, tricyclics, MDMA, meperidine, tramadol, and dextromethorphan. Drugs that affect the release or reuptake of epinephrine, norepinephrine, or dopamine typically need to be administered at lower doses due to the resulting potentiated and prolonged effect. MAOIs also interact with tobacco-containing products (e.g. cigarettes) and may potentiate the effects of certain compounds in tobacco. This may be reflected in the difficulty of smoking cessation, as tobacco contains naturally occurring MAOI compounds in addition to the nicotine.

While safer than general MAOIs, RIMAs still possess significant and potentially serious drug interactions with many common drugs; in particular, they can cause serotonin syndrome or hypertensive crisis when combined with almost any antidepressant or stimulant, common migraine medications, certain herbs, or most cold medicines (including decongestants, antihistamines, and cough syrup).

Ocular alpha-2 agonists such as brimonidine and apraclonidine are glaucoma medications which reduce intraocular pressure by decreasing aqueous production. These alpha-2 agonists should not be given with oral MAOIs due to the risk of hypertensive crisis.

Withdrawal

Antidepressants including MAOIs have some dependence-producing effects, the most notable one being a discontinuation syndrome, which may be severe especially if MAOIs are discontinued abruptly or too rapidly. The dependence-producing potential of MAOIs or antidepressants in general is not as significant as benzodiazepines, however. Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks, months or years to minimise or prevent withdrawal symptoms.

MAOIs, as with most antidepressant medication, may not alter the course of the disorder in a significant, permanent way, so it is possible that discontinuation can return the patient to the pre-treatment state. This consideration complicates prescribing between a MAOI and a SSRI, because it is necessary to clear the system completely of one drug before starting another. One physician organisation recommends the dose to be tapered down over a minimum of four weeks, followed by a two week washout period. The result is that a depressed patient will have to bear the depression without chemical help during the drug-free interval. This may be preferable to risking the effects of an interaction between the two drugs.

Interactions

The MAOIs are infamous for their numerous drug interactions, including the following kinds of substances:

  • Substances that are metabolised by monoamine oxidase, as they can be boosted by up to several-fold.
  • Substances that increase serotonin, norepinephrine, or dopamine activity, as too much of any of these neurochemicals can result in severe acute consequences, including serotonin syndrome, hypertensive crisis, and psychosis, respectively.

Such substances that can react with MAOIs include:

  • Phenethylamines: 2C-B, mescaline, phenethylamine (PEA), etc.
    • Amphetamines: amphetamine, MDMA, dextroamphetamine, methamphetamine, DOM, etc.
  • Tryptamines: DMT (MAOIs prevent oxidisation of DMT in the digestive tract, which renders it biologically inert. This allows it to be absorbed in the stomach and small intestine, allowing one to experience the effects of DMT by taking it orally i.e. by Ayahuasca. This anti-oxidation effect can also be observed when administering DMT by inhalation, and it can serve to potentiate the length of the experience.)
  • Norepinephrine, and/or dopamine reuptake inhibitors:
    • Serotonin-norepinephrine reuptake inhibitors (SNRIs): desvenlafaxine, duloxetine, milnacipran, venlafaxine.
    • Norepinephrine-dopamine reuptake inhibitors (NDRIs): amineptine, bupropion, methylphenidate, nomifensine.
    • Norepinephrine reuptake inhibitors (NRIs): atomoxetine, mazindol, reboxetine.
    • Tricyclic antidepressants (TCAs): amitriptyline, butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, protriptyline, trimipramine.
    • Tetracyclic antidepressants (TeCAs): amoxapine, maprotiline.
    • Phenylpiperidine derivative opioids: meperidine/pethidine, tramadol, methadone, fentanyl, dextropropoxyphene, propoxyphene.
    • Others: brompheniramine, chlorpheniramine, cocaine, cyclobenzaprine, dextromethorphan (DXM), ketamine, MDPV, nefazodone, phencyclidine (PCP), pheniramine, sibutramine, trazodone
  • Serotonin, norepinephrine, and/or dopamine releasers: 4-methylaminorex (4-MAR), amphetamine, benzphetamine, cathine, cathinone, diethylcathinone, ephedrine, levmetamfetamine, lisdexamfetamine, MDMA (“Ecstasy”), methamphetamine, pemoline, phendimetrazine, phenethylamine (PEA), phentermine, propylhexedrine, pseudoephedrine, phenylephrine, tyramine.
  • Local and general anaesthetic in surgery and dentistry, in particular those containing epinephrine. There is no universally taught or accepted practice regarding dentistry and use of MAOIs such as phenelzine, and therefore it is vital to inform all clinicians, especially dentists, of the potential effect of MAOIs and local anaesthesia. In preparation for dental work, withdrawal from phenelzine is specifically advised; since this takes two weeks, however, it is not always a desirable or practical option. Dentists using local anaesthesia are advised to use a non-epinephrine anaesthetic such as mepivacaine at a level of 3%. Specific attention should be paid to blood pressure during the procedure, and the level of the anaesthetic should be regularly and appropriately topped-up, for non-epinephrine anaesthetics take longer to come into effect and wear off faster. Patients taking phenelzine are advised to notify their psychiatrist prior to any dental treatment.
  • Certain other supplements may exhibit below-therapeutic-level MAOI activity: Hypericum perforatum (“St John’s wort”), inositol, Rhodiola rosea, S-adenosyl-L-methionine (SAMe).
  • Antibiotics such as linezolid.
  • Other monoamine oxidase inhibitors.

Mechanism of Action

MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine. MAO-B preferentially deaminates phenethylamine and certain other trace amines; in contrast, MAO-A preferentially deaminates other trace amines, like tyramine, whereas dopamine is equally deaminated by both types.

Reversibility

The early MAOIs covalently bound to the monoamine oxidase enzymes, thus inhibiting them irreversibly; the bound enzyme could not function and thus enzyme activity was blocked until the cell made new enzymes. The enzymes turn over approximately every two weeks. A few newer MAOIs, a notable one being moclobemide, are reversible, meaning that they are able to detach from the enzyme to facilitate usual catabolism of the substrate. The level of inhibition in this way is governed by the concentrations of the substrate and the MAOI.

Harmaline found in Peganum harmala, Banisteriopsis caapi, and Passiflora incarnata is a reversible inhibitor of monoamine oxidase A (RIMA).

Selectivity

In addition to reversibility, MAOIs differ by their selectivity of the MAO enzyme subtype. Some MAOIs inhibit both MAO-A and MAO-B equally, other MAOIs have been developed to target one over the other.

MAO-A inhibition reduces the breakdown of primarily serotonin, norepinephrine, and dopamine; selective inhibition of MAO-A allows for tyramine to be metabolised via MAO-B. Agents that act on serotonin if taken with another serotonin-enhancing agent may result in a potentially fatal interaction called serotonin syndrome or with irreversible and unselective inhibitors (such as older MAOIs), of MAO a hypertensive crisis as a result of tyramine food interactions is particularly problematic with older MAOIs. Tyramine is broken down by MAO-A and MAO-B, therefore inhibiting this action may result in its excessive build-up, so diet must be monitored for tyramine intake.

MAO-B inhibition reduces the breakdown mainly of dopamine and phenethylamine so there are no dietary restrictions associated with this. MAO-B would also metabolize tyramine, as the only differences between dopamine, phenethylamine, and tyramine are two phenylhydroxyl groups on carbons 3 and 4. The 4-OH would not be a steric hindrance to MAO-B on tyramine. Selegiline is selective for MAO-B at low doses, but non-selective at higher doses.

List of MAO Inhibiting Drugs

Marketed MAOIs

  • Nonselective MAO-A/MAO-B inhibitors.
    • Hydrazine (antidepressant).
      • Isocarboxazid (Marplan).
      • Hydracarbazine.
      • Phenelzine (Nardil).
    • Non-hydrazines.
      • Tranylcypromine (Parnate, Jatrosom).
  • Selective MAO-A inhibitors.
    • Bifemelane (Alnert, Celeport) (available in Japan).
    • Moclobemide (Aurorix, Manerix).
    • Pirlindole (Pirazidol) (available in Russia).
  • Selective MAO-B inhibitors.
    • Rasagiline (Azilect).
    • Selegiline (Deprenyl, Eldepryl, Emsam, Zelapar).
    • Safinamide (Xadago).

Linezolid is an antibiotic drug with weak, reversible MAO-inhibiting activity.

Methylene blue, the antidote indicated for drug-induced methemoglobinemia, among a plethora of other off-label uses, is a highly potent, reversible MAO inhibitor.

MAOIs that have been Withdrawn from the Market

  • Nonselective MAO-A/MAO-B inhibitors:
    • Hydrazines.
      • Benmoxin (Nerusil, Neuralex).
      • Iproclozide (Sursum).
      • Iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida) (discontinued worldwide except for France).
      • Mebanazine (Actomol).
      • Nialamide (Niamid).
      • Octamoxin (Ximaol, Nimaol).
      • Pheniprazine (Catron).
      • Phenoxypropazine (Drazine).
      • Pivalylbenzhydrazine (Tersavid).
      • Safrazine (Safra) (discontinued worldwide except for Japan).
    • Non-hydrazines.
      • Caroxazone (Surodil, Timostenil).
  • Selective MAO-A inhibitors:
    • Minaprine (Cantor).
    • Toloxatone (Humoryl).

List of RIMAs

  • Marketed pharmaceuticals:
    • Moclobemide (Aurorix, Manerix).
  • Other pharmaceuticals.
    • Brofaromine (Consonar).
    • Caroxazone (Surodil, Timostenil).
    • Eprobemide (Befol).
    • Methylene blue.
    • Metralindole (Inkazan).
    • Minaprine (Cantor).
    • Pirlindole (Pirazidol).
  • Naturally occurring RIMAs in plants:
    • Curcumin (selectivity for MAO-A and reliability of research on curcumin are disputed).
    • Harmaline.
    • Harmine.
  • Research compounds:
    • Amiflamine (FLA-336).
    • Befloxatone (MD-370,503).
    • Cimoxatone (MD-780,515).
    • Esuprone.
    • Sercloremine (CGP-4718-A).
    • Tetrindole.
    • CX157 (TriRima).

What is Serotonin Syndrome?

Introduction

Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs.

Not to be confused with Antidepressant Discontinuation Syndrome.

The degree of symptoms can range from mild to severe, including a potentiality of death. Symptoms in mild cases include high blood pressure and a fast heart rate; usually without a fever. Symptoms in moderate cases include high body temperature, agitation, increased reflexes, tremor, sweating, dilated pupils, and diarrhoea. In severe cases body temperature can increase to greater than 41.1 °C (106.0 °F). Complications may include seizures and extensive muscle breakdown.

Serotonin syndrome is typically caused by the use of two or more serotonergic medications or drugs. This may include selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), monoamine oxidase inhibitor (MAOI), tricyclic antidepressants (TCAs), amphetamines, pethidine (meperidine), tramadol, dextromethorphan, buspirone, L-tryptophan, 5-HTP, St. John’s wort, triptans, ecstasy (MDMA), metoclopramide, or cocaine. It occurs in about 15% of SSRI overdoses. It is a predictable consequence of excess serotonin on the central nervous system (CNS). Onset of symptoms is typically within a day of the extra serotonin.

Diagnosis is based on a person’s symptoms and history of medication use. Other conditions that can produce similar symptoms such as neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic toxicity, heat stroke, and meningitis should be ruled out. No laboratory tests can confirm the diagnosis.

Initial treatment consists of discontinuing medications which may be contributing. In those who are agitated, benzodiazepines may be used. If this is not sufficient, a serotonin antagonist such as cyproheptadine may be used. In those with a high body temperature active cooling measures may be needed. The number of cases of serotonin syndrome that occur each year is unclear. With appropriate treatment the risk of death is less than one percent. The high-profile case of Libby Zion, who is generally accepted to have died from serotonin syndrome, resulted in changes to graduate medical education in New York State.

Signs and Symptoms

Symptom onset is usually rapid, often occurring within minutes of elevated serotonin levels. Serotonin syndrome encompasses a wide range of clinical findings. Mild symptoms may consist of increased heart rate, shivering, sweating, dilated pupils, myoclonus (intermittent jerking or twitching), as well as overresponsive reflexes. However, many of these symptoms may be side effects of the drug or drug interaction causing excessive levels of serotonin; not an effect of elevated serotonin itself. Tremor is a common side effect of MDMA’s action on dopamine, whereas hyperreflexia is symptomatic of exposure to serotonin agonists. Moderate intoxication includes additional abnormalities such as hyperactive bowel sounds, high blood pressure and hyperthermia; a temperature as high as 40 °C (104 °F). The overactive reflexes and clonus in moderate cases may be greater in the lower limbs than in the upper limbs. Mental changes include hypervigilance or insomnia and agitation. Severe symptoms include severe increases in heart rate and blood pressure that may lead to shock. Temperature may rise to above 41.1 °C (106.0 °F) in life-threatening cases. Other abnormalities include metabolic acidosis, rhabdomyolysis, seizures, kidney failure, and disseminated intravascular coagulation; these effects usually arising as a consequence of hyperthermia.

The symptoms are often described as a clinical triad of abnormalities:

  • Cognitive effects: headache, agitation, hypomania, mental confusion, hallucinations, coma.
  • Autonomic effects: shivering, sweating, hyperthermia, vasoconstriction, tachycardia, nausea, diarrhoea.
  • Somatic effects: myoclonus (muscle twitching), hyperreflexia (manifested by clonus), tremor.

Cause

A large number of medications and street drugs can cause serotonin syndrome when taken alone at high doses or in combination with other serotonergic drugs. The table below lists some of these drugs.

ClassDrugs
AntidepressantsMAOIs, TCAs, SSRIs, SNRIs, nefazodone, and trazodone.
OpioidsDextropropoxyphene, tramadol, tapentadol, pethidine (meperidine), fentanyl, pentazocine, buprenorphine oxycodone, and hydrocodone.
Central Nervous System StimulantsMDMA, MDA, methamphetamine, lisdexamfetamine, amphetamine, phentermine, amfepramone (diethylpropion), serotonin releasing agents like hallucinogenic substituted amphetamines, sibutramine, methylphenidate, and cocaine.
5-HT1 AgonistsTriptans
Psychedelics5-Methoxy-diisopropyltryptamine, alpha-methyltryptamine, and LSD.
HerbsSt John’s Wort, Syrian rue, Panax ginseng, Nutmeg, and Yohimbe.
OthersTryptophan, L-Dopa, valproate, buspirone, lithium, linezolid, dextromethorphan, 5-hydroxytryptophan, chlorpheniramine, risperidone, olanzapine, ondansetron, granisetron, metoclopramide, ritonavir, and metaxalone.

Many cases of serotonin toxicity occur in people who have ingested drug combinations that synergistically increase synaptic serotonin. It may also occur due to an overdose of a single serotonergic agent. The combination of MAOIs with precursors such as L-tryptophan or 5-HTP pose a particularly acute risk of life-threatening serotonin syndrome. The case of combination of MAOIs with tryptamine agonists (commonly known as ayahuasca) can present similar dangers as their combination with precursors, but this phenomenon has been described in general terms as the “cheese effect”. Many MAOIs irreversibly inhibit monoamine oxidase. It can take at least four weeks for this enzyme to be replaced by the body in the instance of irreversible inhibitors. With respect to tricyclic antidepressants only clomipramine and imipramine have a risk of causing SS.

Many medications may have been incorrectly thought to cause serotonin syndrome. For example, some case reports have implicated atypical antipsychotics in serotonin syndrome, but it appears based on their pharmacology that they are unlikely to cause the syndrome. It has also been suggested that mirtazapine has no significant serotonergic effects, and is therefore not a dual action drug. Bupropion has also been suggested to cause serotonin syndrome, although as there is no evidence that it has any significant serotonergic activity, it is thought unlikely to produce the syndrome. In 2006 the United States Food and Drug Administration (FDA) issued an alert suggesting that the combined use of SSRIs or SNRIs and triptan medications or sibutramine could potentially lead to severe cases of serotonin syndrome. This has been disputed by other researchers as none of the cases reported by the FDA met the Hunter criteria for serotonin syndrome. The condition has however occurred in surprising clinical situations, and because of phenotypic variations among individuals, it has been associated with unexpected drugs, including mirtazapine.

The relative risk and severity of serotonergic side effects and serotonin toxicity, with individual drugs and combinations, is complex. Serotonin syndrome has been reported in patients of all ages, including the elderly, children, and even newborn infants due to in utero exposure. The serotonergic toxicity of SSRIs increases with dose, but even in over-dose it is insufficient to cause fatalities from serotonin syndrome in healthy adults. Elevations of central nervous system serotonin will typically only reach potentially fatal levels when drugs with different mechanisms of action are mixed together. Various drugs, other than SSRIs, also have clinically significant potency as serotonin reuptake inhibitors, (e.g. tramadol, amphetamine, and MDMA) and are associated with severe cases of the syndrome.

Although the most significant health risk associated with opioid overdoses is respiratory depression, it is still possible for an individual to develop serotonin syndrome from certain opioids without the loss of consciousness. However, most cases of opioid-related serotonin syndrome involve the concurrent use of a serotergenic drug such as antidepressants. Nonetheless, it is not uncommon for individuals taking opioids to also be taking antidepressants due to the comorbidity of pain and depression.

Cases where opioids alone are the cause of serotonin syndrome are typically seen with tramadol, because of its dual mechanism as a serotonin-norepinephrine reuptake inhibitor. Serotonin syndrome caused by tramadol can be particularly problematic if an individual taking the drug is unaware of the risks associated with it and attempts to self-medicate symptoms such as headache, agitation, and tremors with more opioids, further exacerbating the condition.

Pathophysiology

Serotonin is a neurotransmitter involved in multiple complex biological processes including aggression, pain, sleep, appetite, anxiety, depression, migraine, and vomiting. In humans the effects of excess serotonin were first noted in 1960 in patients receiving a monoamine oxidase inhibitor (MAOI) and tryptophan. The syndrome is caused by increased serotonin in the central nervous system. It was originally suspected that agonism of 5-HT1A receptors in central grey nuclei and the medulla was responsible for the development of the syndrome. Further study has determined that overstimulation of primarily the 5-HT2A receptors appears to contribute substantially to the condition. The 5-HT1A receptor may still contribute through a pharmacodynamic interaction in which increased synaptic concentrations of a serotonin agonist saturate all receptor subtypes. Additionally, noradrenergic CNS hyperactivity may play a role as CNS norepinephrine concentrations are increased in serotonin syndrome and levels appear to correlate with the clinical outcome. Other neurotransmitters may also play a role; NMDA receptor antagonists and GABA have been suggested as affecting the development of the syndrome. Serotonin toxicity is more pronounced following supra-therapeutic doses and overdoses, and they merge in a continuum with the toxic effects of overdose.

Spectrum Concept

A postulated “spectrum concept” of serotonin toxicity emphasises the role that progressively increasing serotonin levels play in mediating the clinical picture as side effects merge into toxicity. The dose-effect relationship is the effects of progressive elevation of serotonin, either by raising the dose of one drug, or combining it with another serotonergic drug which may produce large elevations in serotonin levels. Some experts prefer the terms serotonin toxicity or serotonin toxidrome, to more accurately reflect that it is a form of poisoning.

Diagnosis

There is no specific test for serotonin syndrome. Diagnosis is by symptom observation and investigation of the person’s history. Several criteria have been proposed. The first evaluated criteria were introduced in 1991 by Harvey Sternbach. Researchers later developed the Hunter Toxicity Criteria Decision Rules, which have better sensitivity and specificity, 84% and 97%, respectively, when compared with the gold standard of diagnosis by a medical toxicologist. As of 2007, Sternbach’s criteria were still the most commonly used.

The most important symptoms for diagnosing serotonin syndrome are tremor, extreme aggressiveness, akathisia, or clonus (spontaneous, inducible and ocular). Physical examination of the patient should include assessment of deep-tendon reflexes and muscle rigidity, the dryness of the mucosa of the mouth, the size and reactivity of the pupils, the intensity of bowel sounds, skin colour, and the presence or absence of sweating. The patient’s history also plays an important role in diagnosis, investigations should include inquiries about the use of prescription and over-the-counter drugs, illicit substances, and dietary supplements, as all these agents have been implicated in the development of serotonin syndrome. To fulfil the Hunter Criteria, a patient must have taken a serotonergic agent and meet one of the following conditions:

  • Spontaneous clonus, or
  • Inducible clonus plus agitation or diaphoresis, or
  • Ocular clonus plus agitation or diaphoresis, or
  • Tremor plus hyperreflexia, or
  • Hypertonism plus temperature > 38 °C (100 °F) plus ocular clonus or inducible clonus.

Differential Diagnosis

Serotonin toxicity has a characteristic picture which is generally hard to confuse with other medical conditions, but in some situations it may go unrecognized because it may be mistaken for a viral illness, anxiety disorders, neurological disorder, anticholinergic poisoning, sympathomimetic toxicity, or worsening psychiatric condition. The condition most often confused with serotonin syndrome is neuroleptic malignant syndrome (NMS). The clinical features of neuroleptic malignant syndrome and serotonin syndrome share some features which can make differentiating them difficult. In both conditions, autonomic dysfunction and altered mental status develop. However, they are actually very different conditions with different underlying dysfunction (serotonin excess vs dopamine blockade). Both the time course and the clinical features of NMS differ significantly from those of serotonin toxicity. Serotonin toxicity has a rapid onset after the administration of a serotonergic drug and responds to serotonin blockade such as drugs like chlorpromazine and cyproheptadine. Dopamine receptor blockade (NMS) has a slow onset, typically evolves over several days after administration of a neuroleptic drug, and responds to dopamine agonists such as bromocriptine.

Differential diagnosis may become difficult in patients recently exposed to both serotonergic and neuroleptic drugs. Bradykinesia and extrapyramidal “lead pipe” rigidity are classically present in NMS, whereas serotonin syndrome causes hyperkinesia and clonus; these distinct symptoms can aid in differentiation.

Management

Management is based primarily on stopping the usage of the precipitating drugs, the administration of serotonin antagonists such as cyproheptadine, and supportive care including the control of agitation, the control of autonomic instability, and the control of hyperthermia. Additionally, those who ingest large doses of serotonergic agents may benefit from gastrointestinal decontamination with activated charcoal if it can be administered within an hour of overdose. The intensity of therapy depends on the severity of symptoms. If the symptoms are mild, treatment may only consist of discontinuation of the offending medication or medications, offering supportive measures, giving benzodiazepines for myoclonus, and waiting for the symptoms to resolve. Moderate cases should have all thermal and cardiorespiratory abnormalities corrected and can benefit from serotonin antagonists. The serotonin antagonist cyproheptadine is the recommended initial therapy, although there have been no controlled trials demonstrating its efficacy for serotonin syndrome. Despite the absence of controlled trials, there are a number of case reports detailing apparent improvement after people have been administered cyproheptadine. Animal experiments also suggest a benefit from serotonin antagonists. Cyproheptadine is only available as tablets and therefore can only be administered orally or via a nasogastric tube; it is unlikely to be effective in people administered activated charcoal and has limited use in severe cases. Cyproheptadine can be stopped when the person is no longer experiencing symptoms and the half life of serotonergic medications already passed.

Additional pharmacological treatment for severe case includes administering atypical antipsychotic drugs with serotonin antagonist activity such as olanzapine. Critically ill people should receive the above therapies as well as sedation or neuromuscular paralysis. People who have autonomic instability such as low blood pressure require treatment with direct-acting sympathomimetics such as epinephrine, norepinephrine, or phenylephrine.[6] Conversely, hypertension or tachycardia can be treated with short-acting antihypertensive drugs such as nitroprusside or esmolol; longer acting drugs such as propranolol should be avoided as they may lead to hypotension and shock. The cause of serotonin toxicity or accumulation is an important factor in determining the course of treatment. Serotonin is catabolized by monoamine oxidase A in the presence of oxygen, so if care is taken to prevent an unsafe spike in body temperature or metabolic acidosis, oxygenation will assist in dispatching the excess serotonin. The same principle applies to alcohol intoxication. In cases of serotonin syndrome caused by monoamine oxidase inhibitors oxygenation will not help to dispatch serotonin. In such instances, hydration is the main concern until the enzyme is regenerated.

Agitation

Specific treatment for some symptoms may be required. One of the most important treatments is the control of agitation due to the extreme possibility of injury to the person themselves or caregivers, benzodiazepines should be administered at first sign of this. Physical restraints are not recommended for agitation or delirium as they may contribute to mortality by enforcing isometric muscle contractions that are associated with severe lactic acidosis and hyperthermia. If physical restraints are necessary for severe agitation they must be rapidly replaced with pharmacological sedation. The agitation can cause a large amount of muscle breakdown. This breakdown can cause severe damage to the kidneys through a condition called rhabdomyolysis.

Hyperthermia

Treatment for hyperthermia includes reducing muscle overactivity via sedation with a benzodiazepine. More severe cases may require muscular paralysis with vecuronium, intubation, and artificial ventilation. Suxamethonium is not recommended for muscular paralysis as it may increase the risk of cardiac dysrhythmia from hyperkalaemia associated with rhabdomyolysis. Antipyretic agents are not recommended as the increase in body temperature is due to muscular activity, not a hypothalamic temperature set point abnormality.

Prognosis

Upon the discontinuation of serotonergic drugs, most cases of serotonin syndrome resolve within 24 hours, although in some cases delirium may persist for a number of days. Symptoms typically persist for a longer time frame in patients taking drugs which have a long elimination half-life, active metabolites, or a protracted duration of action.

Cases have reported persisting chronic symptoms, and antidepressant discontinuation may contribute to ongoing features. Following appropriate medical management, serotonin syndrome is generally associated with a favourable prognosis.

Epidemiology

Epidemiological studies of serotonin syndrome are difficult as many physicians are unaware of the diagnosis or they may miss the syndrome due to its variable manifestations. In 1998 a survey conducted in England found that 85% of the general practitioners that had prescribed the antidepressant nefazodone were unaware of serotonin syndrome. The incidence may be increasing as a larger number of pro-serotonergic drugs (drugs which increase serotonin levels) are now being used in clinical practice. One post-marketing surveillance study identified an incidence of 0.4 cases per 1000 patient-months for patients who were taking nefazodone. Additionally, around 14 to 16 percent of persons who overdose on SSRIs are thought to develop serotonin syndrome.

Notable Cases

The most widely recognised example of serotonin syndrome was the death of Libby Zion in 1984. Zion was a freshman at Bennington College at her death on 05 March 1984, at age 18. She died within 8 hours of her emergency admission to the New York Hospital Cornell Medical Centre. She had an ongoing history of depression, and came to the Manhattan hospital on the evening of 04 March 1984, with a fever, agitation and “strange jerking motions” of her body. She also seemed disoriented at times. The emergency room physicians were unable to diagnose her condition definitively but admitted her for hydration and observation. Her death was caused by a combination of pethidine and phenelzine. A medical intern prescribed the pethidine. The case influenced graduate medical education and residency work hours. Limits were set on working hours for medical postgraduates, commonly referred to as interns or residents, in hospital training programmes, and they also now require closer senior physician supervision.

What is Antidepressant Discontinuation Syndrome?

Introduction

Antidepressant discontinuation syndrome (also known antidepressant withdrawal syndrome or SSRI discontinuation syndrome), is a condition that can occur following the interruption, reduction, or discontinuation of antidepressant medication following its continuous use of at least a month.

The symptoms may include flu-like symptoms, trouble sleeping, nausea, poor balance, sensory changes, anxiety, and depression. The problem usually begins within three days and may last for several months. Rarely psychosis may occur.

A discontinuation syndrome can occur after stopping any antidepressant including selective serotonin re-uptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). The risk is greater among those who have taken the medication for longer and when the medication in question has a short half-life. The underlying reason for its occurrence is unclear. The diagnosis is based on the symptoms.

Methods of prevention include gradually decreasing the dose among those who wish to stop, though it is possible for symptoms to occur with tapering. Treatment may include restarting the medication and slowly decreasing the dose. People may also be switched to the long acting antidepressant fluoxetine which can then be gradually decreased.

Approximately 20-50% of people who suddenly stop an antidepressant develop an antidepressant discontinuation syndrome. The condition is generally not serious, though about half of people with symptoms describe them as severe. Some restart antidepressants due to the severity of the symptoms.

Signs and Symptoms

People with antidepressant discontinuation syndrome have been on an antidepressant for at least four weeks and have recently stopped taking the medication, whether abruptly, after a fast taper, or each time the medication is reduced on a slow taper. Commonly reported symptoms include flu-like symptoms (nausea, vomiting, diarrhoea, headaches, sweating) and sleep disturbances (insomnia, nightmares, constant sleepiness). Sensory and movement disturbances have also been reported, including imbalance, tremors, vertigo, dizziness, and electric-shock-like experiences in the brain, often described by people who have them as “brain zaps”. These “brain zaps” have been described as an electric shock felt in the skull, potentially triggered by lateral eye movement, and at times accompanied by vertigo, pain, or dissociative symptoms. Some individuals consider it as a pleasant experience akin to an orgasm, however it is more often reported as an unpleasant experience that interferes with daily function. Mood disturbances such as dysphoria, anxiety, or agitation are also reported, as are cognitive disturbances such as confusion and hyperarousal.

In cases associated with sudden discontinuation of MAO inhibitors, acute psychosis has been observed. Over fifty symptoms have been reported.

A 2009 Advisory Committee to the US Food and Drug Administration (FDA) found that online anecdotal reports of discontinuation syndrome related to duloxetine included severe symptoms and exceeded prevalence of both paroxetine and venlafaxine reports by over 250% (although acknowledged this may have been influenced by duloxetine being a much newer drug). It also found that the safety information provided by the manufacturer not only neglected important information about managing discontinuation syndrome, but also explicitly advised against opening capsules, a practice required to gradually taper dosage.

Duration

Most cases of discontinuation syndrome may last between one and four weeks and resolve on their own. Occasionally symptoms can last up to one year. They typically resolve within a day of restoring the medication. Paroxetine and venlafaxine seem to be particularly difficult to discontinue, and prolonged withdrawal syndrome (post-acute-withdrawal syndrome, or PAWS) lasting over 18 months has been reported with paroxetine.

Mechanism

The underlying reason for its occurrence is unclear, though the syndrome appears similar to withdrawal from other psychotropic drugs such as benzodiazepines.

Prevention and Treatment

In some cases, withdrawal symptoms may be prevented by taking medication as directed, and when discontinuing, doing so gradually, although symptoms may appear while tapering. When discontinuing an antidepressant with a short half-life, switching to a drug with a longer half-life (e.g. fluoxetine or citalopram) and then tapering, and eventually discontinuing, from that drug can decrease the severity of symptoms in some cases.

Treatment is dependent on the severity of the discontinuation reaction and whether or not further antidepressant treatment is warranted. In cases where further antidepressant treatment is prescribed, then the only option suggested may be restarting the antidepressant. If antidepressants are no longer required, treatment depends on symptom severity. If symptoms of discontinuation are severe, or do not respond to symptom management, the antidepressant can be reinstated and then withdrawn more cautiously, or by switching to a drug with a longer half life, (such as Prozac), and then tapering and discontinuing that drug. In severe cases, hospitalisation may be required.

Pregnancy and Newborns

Antidepressants, including SSRIs, can cross the placenta and have the potential to affect the foetus and newborn, including an increased chance of miscarriage, presenting a dilemma for pregnant women to decide whether to continue to take antidepressants at all, or if they do, considering if tapering and discontinuing during pregnancy could have a protective effect for the newborn.

Postnatal adaptation syndrome (PNAS) (originally called “neonatal behavioural syndrome”, “poor neonatal adaptation syndrome”, or “neonatal withdrawal syndrome”) was first noticed in 1973 in newborns of mothers taking antidepressants; symptoms in the infant include irritability, rapid breathing, hypothermia, and blood sugar problems. The symptoms usually develop from birth to days after delivery and usually resolve within days or weeks of delivery.

Culture and History

Antidepressant discontinuation symptoms were first reported with imipramine, the first tricyclic antidepressant (TCA), in the late 1950s, and each new class of antidepressants has brought reports of similar conditions, including monoamine oxidase inhibitors (MAOIs), SSRIs, and SNRIs. As of 2001, at least 21 different antidepressants, covering all the major classes, were known to cause discontinuation syndromes. The problem has been poorly studied, and most of the literature has been case reports or small clinical studies; incidence is hard to determine and controversial.

With the explosion of use and interest in SSRIs in the late 1980s and early 1990s, focused especially on Prozac, interest grew as well in discontinuation syndromes. Some of the symptoms emerged from discussion boards where people with depression discussed their experiences with the disease and their medications; “brain zaps” or “brain shivers” was one symptom that emerged via these websites.

Heightened media attention and continuing public concerns led to the formation of an expert group on the safety of selective serotonin reuptake inhibitors in England, to evaluate all the research available prior to 2004. The group determined that the incidence of discontinuation symptoms are between 5% and 49%, depending on the particular SSRI, the length of time on the medicine and abrupt versus gradual cessation.

With the lack of a definition based on consensus criteria for the syndrome, a panel met in Phoenix, Arizona, in 1997 to form a draft definition, which other groups continued to refine.

In the late 1990s, some investigators thought that the fact that symptoms emerged when antidepressants were discontinued might mean that antidepressants were causing addiction, and some used the term “withdrawal syndrome” to describe the symptoms. While people taking antidepressants do not commonly exhibit drug-seeking behaviour, stopping antidepressants leads to similar symptoms as found in drug withdrawal from benzodiazapines, and other psychotropic drugs. As such, some researchers advocate the term withdrawal over discontinuation, to communicate the similar physiological dependence and negative outcomes. Due to pressure from pharmaceutical companies who make anti-depressants, the term “withdrawal syndrome” is no longer used by drug makers, and thus, most doctors, due to concerns that they may be compared to other drugs more commonly associated with withdrawal.

2013 Class Action Lawsuit

In 2013, a proposed class action lawsuit, Jennifer L Saavedra v. Eli Lilly and Company, was brought against Eli Lilly claiming that the Cymbalta label omitted important information about “brain zaps” and other symptoms upon cessation. Eli Lilly moved for dismissal per the “learned intermediary doctrine” as the doctors prescribing the drug were warned of the potential problems and are an intermediary medical judgement between Lilly and patients; in December 2013 Lilly’s motion to dismiss was denied.

Research

The mechanisms of antidepressant withdrawal syndrome have not yet been conclusively identified. The leading hypothesis is that after the antidepressant is discontinued, there is a temporary, but in some cases, long-lasting, deficiency in the brain of one or more essential neurotransmitters that regulate mood, such as serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid, and since neurotransmitters are an interrelated system, dysregulation of one affects the others.