What is Desvenlafaxine?

Introduction

Desvenlafaxine, sold under the brand name Pristiq among others, is a medication used to treat depression.

It is recommended that the need for further treatment be occasionally reassessed. It may be less effective than its parent compound venlafaxine, although some studies have found comparable efficacy. It is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class and is taken by mouth.

Common side effects include dizziness, trouble sleeping, increased sweating, constipation, sleepiness, anxiety, and sexual problems. Serious side effects may include suicide in those under the age of 25, serotonin syndrome, bleeding, mania, and high blood pressure. A withdrawal syndrome may occur if the dose is rapidly decreased. It is unclear if use during pregnancy or breastfeeding is safe.

Desvenlafaxine was approved for medical use in the United States in 2008. In Europe its application for use was denied in 2009. In 2017, it was the 235th most commonly prescribed medication in the United States, with more than two million prescriptions.

Medical Uses

Desvenlafaxine is primarily used as a treatment for major depressive disorder. Use has only been studied up to 8 weeks. It may be less effective than venlafaxine, although some studies have found comparable efficacy with a lower rate of nausea.

Doses of 50-400 mg/day appear effective for major depressive disorder, although no additional benefit was demonstrated at doses greater than 50 mg/day, and adverse events and discontinuations were more frequent at higher doses.

Desvenlafaxine improves the HAM-D17 score and measures of well being such as the Sheehan Disability Scale (SDS) and 5-item World Health Organisation Well-Being Index (WHO-5).

Adverse Effects

Frequency of adverse effects:

  • Very common adverse effects include:
    • Nausea.
    • Headache.
    • Dizziness.
    • Dry mouth.
    • Hyperhidrosis.
    • Diarrhoea.
    • Insomnia.
    • Constipation.
    • Fatigue.
  • Common adverse effects include:
    • Tremor.
    • Blurred vision.
    • Mydriasis.
    • Decreased appetite.
    • Sexual dysfunction.
    • Insomnia.
    • Anxiety.
    • Elevated cholesterol and triglycerides.
    • Proteinuria.
    • Vertigo.
    • Feeling jittery.
    • Asthenia.
    • Nervousness.
    • Hot flush.
    • Irritability.
    • Abnormal dreams.
    • Urinary hesitation.
    • Yawning.
    • Rash.
  • Uncommon adverse effects include:
  • Rare adverse effects include:
    • Hyponatraemia (low blood sodium).
    • Seizures.
    • Extrapyramidal side effects.
    • Hallucinations.
    • Angioedema.
    • Photosensitivity reaction.
    • Stevens-Johnson syndrome.
  • Common however unknown intensity of adverse effects include:
    • Abnormal bleeding (gastrointestinal bleeds).
    • Narrow-angle glaucoma.
    • Mania.
    • Interstitial lung disease.
    • Eosinophilic pneumonia.
    • Hypertension.
    • Suicidal behaviour and thoughts.
    • Serotonin syndrome.

Pharmacology

Desvenlafaxine is a synthetic form of the isolated major active metabolite of venlafaxine, and is categorised as a serotonin-norepinephrine reuptake inhibitor (SNRI). When most normal metabolisers take venlafaxine, approximately 70% of the dose is metabolised into desvenlafaxine, so the effects of the two drugs are expected to be very similar. It works by blocking the “reuptake” transporters for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin (5-hydroxytryptamine) and norepinephrine (noradrenaline). It is approximately 10 times more potent at inhibiting serotonin uptake than norepinephrine uptake.

Approval Status

United States

Wyeth announced on 23 January 2007 that it received an approvable letter from the Food and Drug Administration (FDA) for desvenlafaxine. Final approval to sell the drug was contingent on a number of things, including:

  • A satisfactory FDA inspection of Wyeth’s Guayama, Puerto Rico facility, where the drug is to be manufactured;
  • Several postmarketing surveillance commitments, and follow-up studies on low-dose use, relapse, and use in children;
  • Clarity by Wyeth around the company’s product education plan for physicians and patients;
  • Approval of desvenlafaxine’s proprietary name, Pristiq.

The FDA approved the drug for antidepressant use in February 2008, and was to be available in US pharmacies in May 2008.

In March 2017, the generic form of the drug was made available in the US.

Canada

On 04 February 2009, Health Canada approved use of desvenlafaxine for treatment of depression.

European Union

In 2009, an application to market desvenlafaxine for major depressive disorder in the European Union was declined. In 2012, Pfizer received authorization in Spain to market desvenlafaxine for the disorder but it is not being sold.

Australia

Desvenlafaxine is classified as a schedule 4 (prescription only) drug in Australia. It was listed on the PBS (Pharmaceutical Benefits Scheme) in 2008 for the treatment of major depressive disorders.

What is Agomelatine?

Introduction

Agomelatine is an atypical antidepressant used to treat major depressive disorder.

One review found that it is as effective as other antidepressants with similar discontinuation rates overall but less discontinuations due to side effects. Another review also found it was similarly effective to many other antidepressants.

Common side effects include weight gain, fatigue, liver problems, nausea, headaches, and anxiety. Due to potential liver problems ongoing blood tests are recommended. Its use is not recommended in people with dementia or over the age of 75. There is tentative evidence that it may have fewer side effects than some other antidepressants. It works by stimulating melatonin receptors and blocking serotonin receptors.

Agomelatine was approved for medical use in Europe in 2009 and Australia in 2010. Its use is not approved in the United States and efforts to get approval were ended in 2011. It was developed by the pharmaceutical company Servier.

Brief History

Agomelatine was discovered and developed by the European pharmaceutical company Servier Laboratories Ltd. Servier continued to develop the drug and conduct phase III trials in the European Union.

In March 2005, Servier submitted agomelatine to the European Medicines Agency (EMA) under the trade names Valdoxan and Thymanax. On 27 July 2006, the Committee for Medical Products for Human Use (CHMP) of the EMA recommended a refusal of the marketing authorisation. The major concern was that efficacy had not been sufficiently shown, while there were no special concerns about side effects. In September 2007, Servier submitted a new marketing application to the EMA.

In March 2006, Servier announced it had sold the rights to market agomelatine in the United States to Novartis. It was undergoing several phase III clinical trials in the US, and until October 2011 Novartis listed the drug as scheduled for submission to the FDA no earlier than 2012. However, the development for the US market was discontinued in October 2011, when the results from the last of those trials became available.

It received approval from the European Medicines Agency (EMA) for marketing in the European Union in February 2009 and approval from the Therapeutic Goods Administration (TGA) for marketing in Australia in August 2010.

Medical Uses

Major Depressive Disorder

Agomelatine is used for the treatment of major depressive episodes in adults in Europe. Ten placebo controlled trials have been performed to investigate the short term efficacy of agomelatine in major depressive disorder. At the end of treatment, significant efficacy was demonstrated in six of the ten short-term double-blind placebo-controlled studies. Two were considered “failed” trials, as comparators of established efficacy failed to differentiate from placebo. Efficacy was also observed in more severely depressed patients in all positive placebo-controlled studies. The maintenance of antidepressant efficacy was demonstrated in a relapse prevention study. One meta-analysis found agomelatine to be as effective as standard antidepressants.

A meta-analysis found that agomelatine is effective in treating severe depression. Its antidepressant effect is greater for more severe depression. In people with a greater baseline score (>30 on HAMD17 scale), the agomelatine-placebo difference was of 4.53 points. Controlled studies in humans have shown that agomelatine is at least as effective as the SSRI antidepressants paroxetine, sertraline, escitalopram, and fluoxetine in the treatment of major depression. A 2018 meta-study comparing 21 antidepressants found agomelatine was one of the more tolerable, yet effective antidepressants.

However, the body of research on agomelatine has been substantially affected by publication bias, prompting analyses which take into account both published and unpublished studies. These have confirmed that agomelatine is approximately as effective as more commonly used antidepressants (e.g. SSRIs), but some qualified this as “marginally clinically relevant”, being only slightly above placebo. According to a 2013 review, agomelatine did not seem to provide an advantage in efficacy over other antidepressants for the acute-phase treatment of major depression.

Use in Special Populations

It is not recommended in Europe for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. However, a study reported in September, 2020, showed greater efficacy vs. placebo for agomelatine 25mg per day in youth age 7-18 years. Only limited data is available on use in elderly people ≥ 75 years old with major depressive episodes.

It is not recommended during pregnancy or breastfeeding.

Contraindications

Agomelatine is contraindicated in patients with kidney or liver impairment. According to information disclosed by Servier in 2012, guidelines for the follow-up of patients treated with Valdoxan have been modified in concert with the European Medicines Agency. As some patients may experience increased levels of liver enzymes in their blood during treatment with Valdoxan, doctors have to run laboratory tests to check that the liver is working properly at the initiation of the treatment and then periodically during treatment, and subsequently decide whether to pursue the treatment or not. No relevant modification in agomelatine pharmacokinetic parameters in patients with severe renal impairment has been observed. However, only limited clinical data on its use in depressed patients with severe or moderate renal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing agomelatine to these patients.

Adverse Effects

Agomelatine does not alter daytime vigilance and memory in healthy volunteers. In depressed patients, treatment with the drug increased slow wave sleep without modification of REM (Rapid Eye Movement) sleep amount or REM latency. Agomelatine also induced an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients.

Agomelatine appears to cause fewer sexual side effects and discontinuation effects than paroxetine.

  • Common (1-10% incidence) adverse effects include:
    • Hyperhidrosis (excess sweating that is not proportionate to the ambient temperature).
    • Abdominal pain.
    • Nausea.
    • Vomiting.
    • Diarrhoea.
    • Constipation.
    • Back pain.
    • Fatigue.
    • Increased ALAT and ASAT (liver enzymes).
    • Headache.
    • Dizziness.
    • Somnolence.
    • Insomnia.
    • Migraine.
    • Anxiety.
  • Uncommon (0.1-1%) adverse effects include:
    • Paraesthesia (abnormal sensations [e.g. itching, burning, tingling, etc.] due to malfunctioning of the peripheral nerves).
    • Blurred vision.
    • Eczema.
    • Pruritus (itching).
    • Urticaria.
    • Agitation.
    • Irritability.
    • Restlessness.
    • Aggression.
    • Nightmares.
    • Abnormal dreams.
  • Rare (0.01-0.1%) adverse effects include:
    • Mania.
    • Hypomania.
    • Suicidal ideation.
    • Suicidal behaviour.
    • Hallucinations.
    • Steatohepatitis.
    • Increased GGT and/or alkaline phosphatase.
    • Liver failure.
    • Jaundice.
    • Erythematous rash.
    • Face oedema and angioedema.
    • Weight gain or loss, which tends to be less significant than with SSRIs.

Dependence and Withdrawal

No dosage tapering is needed on treatment discontinuation. Agomelatine has no abuse potential as measured in healthy volunteer studies.

Overdose

Agomelatine is expected to be relatively safe in overdose.

Interactions

Agomelatine is a substrate of CYP1A2, CYP2C9 and CYP2C19. Inhibitors of these enzymes, e.g. the SSRI antidepressant fluvoxamine, reduce its clearance and can therefore lead to an increase in agomelatine exposure. There is also the potential for agomelatine to interact with alcohol to increase the risk of hepatotoxicity.

Pharmacology

Pharmacodynamics

Agomelatine is a melatonin receptor agonist (MT1 (Ki 0.1 nM) and MT2 (Ki = 0.12 nM)) and serotonin 5-HT2C (Ki = 631 nM) and 5-HT2B receptor (Ki = 660 nM) antagonist. Binding studies indicate that it has no effect on monoamine uptake and no affinity for adrenergic, histamine, cholinergic, dopamine, and benzodiazepine receptors, nor other serotonin receptors.

Agomelatine resynchronizes circadian rhythms in animal models of delayed sleep phase syndrome. By antagonising 5-HT2C, it disinhibits/increases noradrenaline and dopamine release specifically in the frontal cortex. Therefore, it is sometimes classified as a norepinephrine-dopamine disinhibitor. It has no influence on the extracellular levels of serotonin. Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset.

Antagonism of 5-HT2B is an antidepressant property agomelatine shares with several atypical antipsychotics, such as aripiprazole, which are themselves used as atypical antidepressants. 5-HT2B antagonists are currently being investigated for their usefulness in reducing cardiotoxicity of drugs as well as being effective in reducing headache. Hence this particular receptor antagonism of agomelatine is useful for its antidepressant effectiveness as well as reducing the drug’s adverse effects.

Chemistry

Structure

The chemical structure of agomelatine is very similar to that of melatonin. Where melatonin has an indole ring system, agomelatine has a naphthalene bioisostere instead.

Research

Agomelatine is under development by Servier for the treatment of generalised anxiety disorder and has reached phase III clinical trials for this indication, but in August 2017, Servier communicated that development for this indication is suspended.

Agomelatine is also studied for its effects on sleep regulation. Studies report various improvements in general quality of sleep metrics, as well as benefits in circadian rhythm disorders. It has been found more effective than placebo in the treatment of generalised anxiety disorder. A 2019 review suggested no recommendations of agomelatine in support of, or against, its use to treat individuals with seasonal affective disorder.

What is Quetiapine?

Introduction

Quetiapine, sold under the brand name Seroquel among others, is an atypical antipsychotic medication used for the treatment of schizophrenia, bipolar disorder, and major depressive disorder. Despite being widely used as a sleep aid due its sedating effect, the benefits of such use do not appear to generally outweigh the side effects. It is taken by mouth.

Common side effects include sleepiness, constipation, weight gain, and dry mouth. Other side effects include low blood pressure with standing, seizures, a prolonged erection, high blood sugar, tardive dyskinesia, and neuroleptic malignant syndrome. In older people with dementia, its use increases the risk of death. Use in the third trimester of pregnancy may result in a movement disorder in the baby for some time after birth. Quetiapine is believed to work by blocking a number of receptors including serotonin and dopamine.

Quetiapine was developed in 1985 and approved for medical use in the United States in 1997. It is available as a generic medication. In 2018, it was the 59th most commonly prescribed medication in the United States, with more than 12 million prescriptions.

Brief History

AstraZeneca submitted a new drug application for a sustained-release version of quetiapine in the United States, Canada, and the European Union in the second half of 2006 for treatment of schizophrenia. AstraZeneca was to retain the exclusive right to market sustained-release quetiapine until 2017. The sustained-release quetiapine is marketed mainly as Seroquel XR. Other marketing names are Seroquel Prolong, Seroquel Depot and Seroquel XL

On 18 May 2007, AstraZeneca announced that the US Food and Drug Administration (FDA) had approved Seroquel XR for acute treatment of schizophrenia. During its 2007 Q2 earnings conference, AstraZeneca announced plans to launch Seroquel XR in the US during August 2007. However, Seroquel XR has become available in US pharmacies only after the FDA had approved Seroquel XR for use as maintenance treatment for schizophrenia, in addition to acute treatment of the illness, on 16 November 2007. The company has not provided a reason for the delay of Seroquel XR’s launch.

Health Canada approved sale of Seroquel XR on 27 September 2007.

In early October 2008, the FDA approved Seroquel XR for the treatment of bipolar depression and bipolar mania. According to AstraZeneca, Seroquel XR is “the first medication approved by the FDA for the once-daily acute treatment of both depressive and manic episodes associated with bipolar.”

On 31 July, 2008, Handa Pharmaceuticals, based in Fremont, California, announced that its abbreviated new drug application (“ANDA”) for quetiapine fumarate extended-release tablets, the generic version of AstraZeneca’s SEROQUEL XR, has been accepted by the FDA.

On 01 December 2008, Biovail announced that the FDA had accepted the company’s ANDA to market its own version of sustained-release quetiapine. Biovail’s sustained-release tablets will compete with AstraZeneca’s Seroquel XR.

On 24 December 2008, AstraZeneca notified shareholders that the FDA had asked for additional information on the company’s application to expand the use of sustained-release quetiapine for treatment of depression.

Medical Uses

Quetiapine is primarily used to treat schizophrenia or bipolar disorder. Quetiapine targets both positive and negative symptoms of schizophrenia.

Schizophrenia

In a 2013 comparison of 15 antipsychotics in effectiveness in treating schizophrenia, quetiapine demonstrated standard effectiveness. It was 13-16% more effective than ziprasidone, chlorpromazine, and asenapine and approximately as effective as haloperidol and aripiprazole.

There is tentative evidence of the benefit of quetiapine versus placebo in schizophrenia; however, definitive conclusions are not possible due to the high rate of attrition in trials (greater than 50%) and the lack of data on economic outcomes, social functioning, or quality of life.

It is debatable whether, as a class, typical or atypical antipsychotics are more effective. Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. While quetiapine has lower rates of extrapyramidal side effects, there is greater sleepiness and rates of dry mouth.

A Cochrane review comparing quetiapine to other atypical antipsychotic agents tentatively concluded that it may be less efficacious than olanzapine and risperidone; produce fewer movement related side effects than paliperidone, aripiprazole, ziprasidone, risperidone and olanzapine; and produce weight gain similar to risperidone, clozapine and aripiprazole. They concluded that it produces suicide attempt, suicide; death; QTc prolongation, low blood pressure; tachycardia; sedation; gynaecomastia; galactorrhoea, menstrual irregularity and white blood cell count at a rate similar to first generation antipsychotics.

Bipolar Disorder

In those with bipolar disorder, quetiapine is used to treat depressive episodes; acute manic episodes associated with bipolar I disorder (as either monotherapy or adjunct therapy to lithium; valproate or lamotrigine); acute mixed episodes; and maintenance treatment of bipolar I disorder (as adjunct therapy to lithium or divalproex).

Major Depressive Disorder

Quetiapine is effective when used by itself and when used along with other medications in major depressive disorder (MDD). However, sedation is often an undesirable side effect.

In the United States, the United Kingdom and Australia (while not subsidised by the Australian Pharmaceutical Benefits Scheme for treatment of MDD), quetiapine is licensed for use as an add-on treatment in MDD.

Alzheimer’s Disease

Quetiapine does not decrease agitation among people with Alzheimer’s. Quetiapine worsens intellectual functioning in the elderly with dementia and therefore is not recommended.

Others

The use of low doses of quetiapine for insomnia, while common, is not recommended; there is little evidence of benefit and concerns regarding adverse effects.

It is sometimes used off-label, often as an augmentation agent, to treat conditions such as Tourette syndrome, musical hallucinations and anxiety disorders.

Quetiapine and clozapine are the most widely used medications for the treatment of Parkinson’s disease psychosis due to their very low extrapyramidal side-effect liability. Owing to the risks associated with clozapine (e.g. agranulocytosis, diabetes mellitus, etc.), clinicians often attempt treatment with quetiapine first, although the evidence to support quetiapine’s use for this indication is significantly weaker than that of clozapine.

Adverse Effects

  • Very common (>10% incidence) adverse effects:
    • Dry mouth.
    • Dizziness.
    • Headache.
    • Somnolence:
      • Drowsiness; of 15 antipsychotics quetiapine causes the 5th most sedation.
      • Extended release (XR) formulations tend to produce less sedation, dose-by-dose than the immediate release formulations.
  • Common (1–10% incidence) adverse effects:
    • High blood pressure.
    • Orthostatic hypotension.
    • High pulse rate.
    • High blood cholesterol.
    • Elevated serum triglycerides.
    • Abdominal pain.
    • Constipation.
    • Increased appetite.
    • Vomiting.
    • Increased liver enzymes.
    • Backache.
    • Asthenia.
    • Insomnia.
    • Lethargy.
    • Tremor.
    • Agitation.
    • Nasal congestion.
    • Pharyngitis.
    • Fatigue.
    • Pain.
    • Dyspepsia (Indigestion).
    • Peripheral oedema.
    • Dysphagia.
    • Extrapyramidal disease:
      • Quetiapine and clozapine are noted for their relative lack of extrapyramidal side effects.
    • Weight gain:
      • SMD 0.43 kg when compared to placebo. Produces roughly as much weight gain as risperidone, less weight gain than clozapine, olanzapine and zotepine and more weight gain than ziprasidone, lurasidone, aripiprazole and asenapine.
      • As with many other atypical antipsychotics, this action is likely due to its actions at the H1 histamine receptor and 5-HT2C receptor.
  • Rare (<1% incidence) adverse effects:
    • Prolonged QT interval.
    • Sudden cardiac death.
    • Syncope.
    • Diabetic ketoacidosis.
    • Restless legs syndrome.
    • Hyponatraemia, low blood sodium.
    • Jaundice, yellowing of the eyes, skin and mucous membranes due to an impaired ability of the body to clear bilirubin, a by product of haem breakdown.
    • Pancreatitis, pancreas swelling.
    • Agranulocytosis, a potentially fatal drop in white blood cell count.
    • Leukopenia, a drop in white blood cell count, not as severe as agranulocytosis.
    • Neutropenia, a drop in neutrophils, the cell of the immune cells that defends the body against bacterial infections.
    • Eosinophilia.
    • Anaphylaxis, a potentially fatal allergic reaction.
    • Seizure.
    • Hypothyroidism, underactive thyroid gland.
    • Myocarditis, swelling of the myocardium.
    • Cardiomyopathy.
    • Hepatitis, swelling of the liver.
    • Suicidal ideation.
    • Priapism:
      • A prolonged and painful erection.
    • Stevens-Johnson syndrome:
      • A potentially fatal skin reaction.
    • Neuroleptic malignant syndrome:
      • A rare and potentially fatal complication of antipsychotic drug treatment.
      • It is characterised by the following symptoms: tremor, rigidity, hyperthermia, tachycardia, mental status changes (e.g. confusion), etc.
    • Tardive Dyskinesia:
      • A rare and often irreversible neurological condition characterised by involuntary movements of the face, tongue, lips and rest of the body.
      • Most commonly occurs after prolonged treatment with antipsychotics.
      • It is believed to be particularly uncommon with atypical antipsychotics, especially quetiapine and clozapine

Both typical and atypical antipsychotics can cause tardive dyskinesia. According to one study, rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%. Although quetiapine and clozapine are atypical antipsychotics, switching to these atypicals is an option to minimise symptoms of tardive dyskinesia caused by other atypicals.

Weight gain can be a problem for some, with quetiapine causing more weight gain than fluphenazine, haloperidol, loxapine, molindone, olanzapine, pimozide, risperidone, thioridazine, thiothixene, trifluoperazine, and ziprasidone, but less than chlorpromazine, clozapine, perphenazine, and sertindole.

As with some other anti-psychotics, quetiapine may lower the seizure threshold, and should be taken with caution in combination with drugs such as bupropion.

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Pregnancy and Lactation

Placental exposure is least for quetiapine compared to other atypical antipsychotics. The evidence is insufficient to rule out any risk to the foetus but available data suggests it is unlikely to result in any major foetal malformations. It is secreted in breast milk and hence quetiapine-treated mothers are advised not to breastfeed.

Abuse Potential

In contrast to most other antipsychotic drugs, which tend to be somewhat aversive and often show problems with patient compliance with prescribed medication regimes, quetiapine is sometimes associated with drug misuse and abuse potential, for its hypnotic and sedative effects. It has a limited potential for misuse, usually only in individuals with a history of polysubstance abuse and/or mental illness, and especially in those incarcerated in prisons or secure psychiatric facilities where access to alternative intoxicants is more limited. To a significantly greater extent than other atypical antipsychotic drugs, quetiapine was found to be associated with drug-seeking behaviours, and to have standardised street prices and slang terms associated with it, either by itself or in combination with other drugs (such as “Q-ball” for the intravenous injection of quetiapine mixed with cocaine). The pharmacological basis for this distinction from other second generation antipsychotic drugs is unclear, though it has been suggested that quetiapine’s comparatively lower dopamine receptor affinity and strong antihistamine activity might mean it could be regarded as more similar to sedating antihistamines in this context. While these issues have not been regarded as sufficient cause for placing quetiapine under increased legal controls, prescribers have been urged to show caution when prescribing quetiapine to individuals with characteristics that might place them at increased risk for drug misuse.

Overdose

Most instances of acute overdosage result in only sedation, hypotension and tachycardia, but cardiac arrhythmia, coma and death have occurred in adults. Serum or plasma quetiapine concentrations are usually in the 1-10 mg/L range in overdose survivors, while postmortem blood levels of 10-25 mg/L are generally observed in fatal cases. Non-toxic levels in postmortem blood extend to around 0.8 mg/kg, but toxic levels in postmortem blood can begin at 0.35 mg/kg.

Pharmacology

Pharmacodynamics

Quetiapine has the following pharmacological actions:

  • Dopamine D1, D2, D3, D4, and D5 receptor antagonist.
  • Serotonin 5-HT1A receptor partial agonist, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptor antagonist, and 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F receptor ligand.
  • α1- and α2-adrenergic receptor antagonist.
  • Histamine H1 receptor antagonist.
  • Muscarinic acetylcholine receptor antagonist.

This means quetiapine is a dopamine, serotonin, and adrenergic antagonist, and a potent antihistamine with some anticholinergic properties. Quetiapine binds strongly to serotonin receptors; the drug acts as partial agonist at 5-HT1A receptors. Serial PET scans evaluating the D2 receptor occupancy of quetiapine have demonstrated that quetiapine very rapidly disassociates from the D2 receptor. Theoretically, this allows for normal physiological surges of dopamine to elicit normal effects in areas such as the nigrostriatal and tuberoinfundibular pathways, thus minimising the risk of side-effects such as pseudo-parkinsonism as well as elevations in prolactin. Some of the antagonised receptors (serotonin, norepinephrine) are actually autoreceptors whose blockade tends to increase the release of neurotransmitters.

At very low doses, quetiapine acts primarily as a histamine receptor blocker (antihistamine) and α1-adrenergic blocker. When the dose is increased, quetiapine activates the adrenergic system and binds strongly to serotonin receptors and autoreceptors. At high doses, quetiapine starts blocking significant amounts of dopamine receptors. Off-label prescriptions, e.g. for chronic insomnia, of low-dose quetiapine is not recommended due to the harmful side-effects.

When treating schizophrenia, antagonism of D2 receptor by quetiapine in the mesolimbic pathway relieves positive symptoms and antagonism of the 5HT2A receptor in the frontal cortex of the brain relieves negative symptoms. Quetiapine has fewer extrapyramidal side effects and is less likely to cause hyperprolactinemia when compared to other drugs used to treat schizophrenia, so is used as a first line treatment.

Pharmacokinetics

Peak levels of quetiapine occur 1.5 hours after a dose. The plasma protein binding of quetiapine is 83%. The major active metabolite of quetiapine is norquetiapine (N-desalkylquetiapine). Quetiapine has an elimination half-life of 6 or 7 hours. Its metabolite, norquetiapine, has a half-life of 9 to 12 hours. Quetiapine is excreted primarily via the kidneys (73%) and in faeces (20%) after hepatic metabolism, the remainder (1%) is excreted as the drug in its unmetabolised form.

Chemistry

Quetiapine is a tetracyclic compound and is closely related structurally to clozapine, olanzapine, loxapine, and other tetracyclic antipsychotics.

Synthesis

The synthesis of quetiapine begins with a dibenzothiazepinone. The lactam is first treated with phosphoryl chloride to produce a dibenzothiazepine. A nucleophilic substitution is used to introduce the sidechain.

Society and Culture

Regulatory Status

In the United States, the FDA has approved quetiapine for the treatment of schizophrenia and of acute manic episodes associated with bipolar disorder (bipolar mania) and for treatment of bipolar depression. In 2009, quetiapine XR was approved as adjunctive treatment of major depressive disorder.

Quetiapine received its initial indication from the FDA for treatment of schizophrenia in 1997. In 2004, it received its second indication for the treatment of mania-associated bipolar disorder. In 2007 and 2008, studies were conducted on quetiapine’s efficacy in treating generalized anxiety disorder and major depression.

Patent protection for the product ended in 2012; however, in a number of regions, the long-acting version remained under patent until 2017.

Lawsuits

In April 2010, the US Department of Justice fined Astra-Zeneca $520 million for the company’s aggressive marketing of Seroquel for off-label uses. According to the Department of Justice, “the company recruited doctors to serve as authors of articles that were ghostwritten by medical literature companies and about studies the doctors in question did not conduct. AstraZeneca then used those studies and articles as the basis for promotional messages about unapproved uses of Seroquel.”

Multiple lawsuits have been filed in relation to quetiapine’s side-effects, in particular, diabetes.

Approximately 10,000 lawsuits have been filed against AstraZeneca, alleging that quetiapine caused problems ranging from slurred speech and chronic insomnia to deaths.

Controversy

In 2004, a young man named Dan Markingson committed suicide in a controversial Seroquel clinical trial at the University of Minnesota while under an involuntary commitment order. A group of University of Minnesota bioethicists charged that the trial involved an alarming number of ethical violations.

Nurofen Plus Tampering Case

In August 2011, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) issued a class-4 drug alert following reports that some batches of Nurofen plus contained Seroquel XL tablets instead.

Following the issue of the Class-4 Drug Alert, Reckitt Benckiser (UK) Ltd received further reports of rogue blister strips in cartons of two additional batches of Nurofen Plus tablets. One of the new batches contained Seroquel XL 50 mg tablets and one contained the Pfizer product Neurontin 100 mg capsules.

Following discussions with the MHRA’s Defective Medicines Report Centre (DMRC), Reckitt Benckiser (UK) Ltd decided to recall all remaining unexpired stock of Nurofen Plus tablets in any pack size, leading to a Class-1 Drug Alert. The contamination was later traced to in-store tampering by a customer.

What is Tranylcypromine/Trifluoperazine?

Introduction

Tranylcypromine/trifluoperazine (brand names Parstelin, Parmodalin, Jatrosom N, Stelapar) is a combination formulation of the monoamine oxidase inhibitor antidepressant drug tranylcypromine and the typical antipsychotic drug trifluoperazine that has been used in the treatment of major depressive disorder.

It contains 10 mg tranylcypromine and 1 mg trifluoperazine.

The drug has been in clinical use since at least 1961. It is still available in Italy with the name of Parmodalin.

What is Trimipramine?

Introduction

Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression.

It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. The drug is described as an atypical or “second-generation” TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor. Similarly to other TCAs however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.

Brief History

Trimipramine was developed by Rhône-Poulenc. It was patented in 1959 and first appeared in the literature in 1961. The drug was first introduced for medical use in 1966, in Europe. It was not introduced in the United States until later in 1979 or 1980.

Medical Uses

Trimipramine’s primary use in medicine is in the treatment of major depressive disorder, especially where sedation is helpful due to its prominent sedative effects. The drug is also an effective anxiolytic, and can be used in the treatment of anxiety. In addition to depression and anxiety, trimipramine is effective in the treatment of insomnia, and unlike most other hypnotics, does not alter the normal sleep architecture. In particular, it does not suppress REM sleep, and dreams are said to “brighten” during treatment. Trimipramine also has some weak antipsychotic effects with a profile of activity described as similar to that of clozapine, and may be useful in the treatment of psychotic symptoms such as in delusional depression or schizophrenia.

Contraindications

Contraindications include:

  • Recent myocardial infarction.
  • Any degree of heart block or other cardiac arrhythmias.
  • Mania.
  • Severe liver disease.
  • During breastfeeding.
  • Hypersensitivity to trimipramine or to any of the excipients.

Side Effects

The side effects of trimipramine have been said to be similar to those of other tertiary amine TCAs, with a preponderance of anticholinergic and sedative effects. However, trimipramine has also been said to be associated with a different side effect profile compared to other TCAs and in general with fewer side effects, chiefly due to its lack of norepinephrine reuptake inhibition and relatively lower anticholinergic effects (although it is still a potent anticholinergic). Somnolence is the most common side effect of the drug. Dry mouth is the most common anticholinergic side effect, but others like constipation, urinary retention, and blurred vision are also present.

It is described as being associated with minimal or no orthostatic hypotension, at least in comparison to clomipramine, in spite of its potent and comparable activity as an alpha-1 blocker. However, it has also been said to have a rate of orthostatic hypotension similar to that of other TCAs. Trimipramine is said to be less epileptogenic than other TCAs, although seizures have still been reported in association with it. It is also less cardiotoxic than other TCAs and cardiotoxicity is said to be minimal, with a “very favourable profile”.

List of Side Effects

Common adverse effects include:

  • Sedation:
    • Especially common with trimipramine compared to the other TCAs.
  • Anticholinergic effects including:
    • Dry mouth.
    • Blurred vision.
    • Mydriasis.
    • Decreased lacrimation.
    • Constipation.
    • Urinary hesitancy or retention.
    • Reduced GI motility.
    • Tachycardia (high heart rate).
    • Anticholinergic delirium (particularly in the elderly and in Parkinson’s disease).
  • Weight gain.
  • Orthostatic hypotension.
  • Sexual dysfunction including impotence, loss of libido and other sexual adverse effects.
  • Tremor.
  • Dizziness.
  • Sweating.
  • Anxiety.
  • Insomnia.
  • Agitation.
  • Rash.

Adverse effects with an unknown incidence includes:

  • Confusion.
  • Nausea.
  • Vomiting.
  • Extrapyramidal side effects (e.g. parkinsonism, dystonia, etc.).
  • Tinnitus.
  • Paraesthesia.
  • ECG changes.
  • Increased liver function tests.

Rare adverse effects include:

  • Seizures.
  • Syndrome of inappropriate secretion of antidiuretic hormone.
  • Blood dyscrasias including:
    • Agranulocytosis.
    • Thrombocytopenia.
    • Eosinophilia.
    • Leukopenia.
  • Myocardial infarction.
  • Heart block.
  • QTc interval prolongation.
  • Sudden cardiac death.
  • Depression worsening.
  • Suicidal ideation.

Overdose

Refer to Tricyclic Antidepressant Overdose.

Compared to other TCAs, trimipramine is relatively safe in overdose, although it is more dangerous than the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) but less dangerous than bupropion in cases of overdose.

Interactions

Trimipramine should not be given with sympathomimetic agents such as epinephrine (adrenaline), ephedrine, isoprenaline, norepinephrine (noradrenaline), phenylephrine and phenylpropanolamine.

Barbiturates may increase the rate of metabolism. Trimipramine should be administered with care in patients receiving therapy for hyperthyrodism.

Genotoxicity

Heavy exposure to any tricyclic antidepressants was associated with an elevated rate ratio for breast cancer 11–15 years later. However, on tests done on Drosophila melanogaster, nongenotoxic TCAs (amitriptyline, maprotiline, nortriptyline, and protriptyline), and genotoxic TCAs (amoxapine, clomipramine, desipramine, doxepin, imipramine, and trimipramine) were identified.

Pharmacology

Pharmacodynamics

The mechanism of action of trimipramine in terms of its antidepressant effects differs from that of other TCAs and is not fully clear. The mechanism of action of its anxiolytic effects is similarly unclear. Trimipramine is a very weak reuptake inhibitor of serotonin, norepinephrine, and dopamine (see below), and unlike most other TCAs, has been claimed to be devoid of clinically significant monoamine reuptake inhibition. The effects of the drug are thought to be mainly due to receptor antagonism as follows:

  • Very strong: H1.
  • Strong: 5-HT2A, α1-adrenergic.
  • Moderate: D2, mACh.
  • Weak: 5-HT2C, D1, α2-adrenergic.

In spite of its atypical nature and different profile of activity, trimipramine has been shown in head-to-head clinical studies to possess equivalent effectiveness to other antidepressants, including but not limited to other TCAs (e.g. amitriptyline, imipramine, doxepin, amineptine), tetracyclic antidepressants (TeCAs) (e.g. maprotiline), monoamine oxidase inhibitors (MAOIs) (e.g. phenelzine, isocarboxazid), and selective serotonin reuptake inhibitors (e.g. fluoxetine). In addition, trimipramine has been found to possess greater anxiolytic effects than other TCAs such as amitriptyline and doxepin in head-to-head comparisons. Indeed, its prominent anxiolytic effects have been said to distinguish it from most other TCAs. The atypicality of trimipramine in relation to its lack of monoamine reuptake inhibition is described as challenging the monoamine hypothesis of depression.

The major metabolite of trimipramine, desmethyltrimipramine, is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants.

Monoamine Reuptake Inhibition

Studies have generally found only very weak inhibition of serotonin and norepinephrine reuptake with trimipramine, and the drug has been described by various authors as devoid of monoamine reuptake inhibition. Richelson & Pfenning (1984) found a relatively high Ki for the NET of 510 nM in rat brain synaptosomes and Tatsumi et al. (1997) found a relatively high KD of 149 nM for the SERT in human HEK293 cells, but other authors and a more recent study with an improved design have not had the same findings. In the most recent study, by Haenisch et al. (2011), the researchers suggested that the discrepant findings from the Tatsumi et al. study were due to methodological differences, in particular the use of radioligand binding in isolated membranes (KD) to study interactions as opposed to actual functional reuptake inhibition (IC50).

Trimipramine is extensively metabolized, so its metabolites may contribute to its pharmacology, including potentially to monoamine reuptake inhibition. In what was the only study to date to have assessed the activity profiles of the metabolites of trimipramine, Haenisch et al. (2011) assayed desmethyltrimipramine, 2-hydroxytrimipramine, and trimipramine-N-oxide in addition to trimipramine and found that these metabolites showed IC50 values for the SERT, NET, and DAT similar to those of trimipramine (see table to the right). Like other secondary amine TCAs, desmethyltrimipramine was slightly more potent than trimipramine in its norepinephrine reuptake inhibition but less potent in its inhibition of serotonin reuptake. However, desmethyltrimipramine still showed only very weak inhibition of the NET.

Therapeutic concentrations of trimipramine are between 0.5 and 1.2 μM (150-350 ng/mL) and hence significant monoamine reuptake inhibition would not be expected with it or its metabolites. However, these concentrations are nearly 2-fold higher if the active metabolites of trimipramine are also considered, and studies of other TCAs have found that they cross the blood-brain barrier and accumulate in the brain to levels of up to 10-fold those in the periphery. As such, trimipramine and its metabolites might at least partially inhibit reuptake of serotonin and/or norepinephrine, though not of dopamine, at therapeutic concentrations, and this could be hypothesized to contribute at least in part to its antidepressant effects. This is relevant as Haenisch et al. has stated that these are the only actions known at present which could explain or at least contribute to the antidepressant effects of trimipramine. That said, blockade of the 5-HT2A, 5-HT2C, and α2-adrenergic receptors, as with mirtazapine, has also been implicated in antidepressant effects.

In any case, there is also clinical and animal evidence that trimipramine does not inhibit the reuptake of monoamines. Unlike other TCAs, it does not downregulate β3-adrenergic receptors, which is likely the reason that it does not cause orthostatic hypotension. It can be safely combined with MAOIs apparently without risk of serotonin syndrome or hypertensive crisis. Indeed, in rabbits, whereas hyperpyrexia (a symptom of serotonin syndrome) occurs with imipramine and an MAOI and to a lesser extent with amitriptyline and an MAOI, it does not occur at all with trimipramine and an MAOI, likely due to trimipramine’s lack of serotonin reuptake inhibition.

Antihistamine Activity

Trimipramine is a very potent antihistamine; it has the third highest affinity for the H1 receptor (Ki = 0.27 nM) after mirtazapine (Ki = 0.14 nM) and doxepin (Ki = 0.24 nM) among the TCAs and tetracyclic antidepressants (TeCAs). The TeCA mianserin (Ki = 0.40) and the TCA amitriptyline (Ki = 1.0) are also very potent H1 receptor antagonists, whereas other TCAs and TeCAs are less potent. These TCAs and TeCAs, including trimipramine, are far more potent than the standard antihistamine diphenhydramine (approximately 800 times for doxepin and 250 times for trimipramine), and are among the most potent antihistamines available.

Trimipramine is also an antagonist of the H2 receptor with lower potency and has been found to be effective in the treatment of duodenal ulcers.

As a Hypnotic

Blockade of the H1 receptor is responsible for the sedative effects of trimipramine and other TCAs and their effectiveness in the treatment of insomnia.

Most antidepressants suppress REM sleep, in parallel with their alleviation of depressive symptoms (although suppression of REM sleep is not required for antidepressant effects). This includes TCAs (e.g. amitriptyline, nortriptyline), TeCAs (e.g. mianserin, maprotiline), MAOIs (e.g. clorgiline, pargyline), and SSRIs (e.g. fluoxetine, zimelidine, indalpine). Trimipramine is unique in that it is an exception and produces antidepressant effects without compromising or otherwise affecting REM sleep. Even long-term treatment with trimipramine for up to 2 years has not been found to suppress REM sleep. In addition, trimipramine has been found to decrease nocturnal cortisol levels to normal and to normalize cortisol response in depressed patients; hence, it normalizes the hypothalamic-pituitary-adrenal axis, whereas imipramine and other antidepressants tend to increase nocturnal cortisol secretion.

In clinical studies, trimipramine has been found in doses of 50 to 200 mg/day to significantly increase sleep efficiency and total sleep time and to decrease waking time for up to 3 weeks in patients with insomnia. It also improved subjectively perceived sleep quality and well-being during daytime. Monitoring of patients upon discontinuation of trimipramine found that it did not cause rebound insomnia or worsening of sleep quality in subjective evaluations of sleep, although objective measurements found total sleep time below baseline in a subset of patients during trimipramine withdrawal.

Antidopaminergic Activity

Trimipramine is a weak but significant antagonist of the dopamine D1 and D2 receptors, and also binds to the D4 receptor (Ki = 275 nM). Its affinities for various monoamine receptors including the D2 and 5-HT2A receptors closely resemble those of the atypical antipsychotic clozapine. In accordance, high doses of trimipramine have been found to have antipsychotic effects in schizophrenic patients, notably without causing extrapyramidal symptoms, and trimipramine has recently been found to be effective in reducing psychotic symptoms in patients with delusional depression. The lack of extrapyramidal symptoms with trimipramine may be related to its affinity for the D4 receptor, these both being properties it shares with clozapine. Unlike other TCAs, but reminiscent of antipsychotics, trimipramine has been found to markedly increase plasma prolactin levels (a marker of D2 receptor antagonism) at a dose of 75 mg/day and to increase nocturnal prolactin secretion at doses of 75 and 200 mg/day. These findings are suggestive of important antidopaminergic actions of trimipramine.

Unlike various other TCAs, trimipramine shows marked antagonism of presynaptic dopamine autoreceptors, potentially resulting in increased dopaminergic neurotransmission. This effect has also been observed with low-potency tricyclic antipsychotics like thioridazine and chlorprothixene. Notably, these two antipsychotics have been claimed many times to also possess antidepressant effects. As such, blockade of inhibitory dopamine autoreceptors and hence facilitation of dopaminergic signalling could be involved in the antidepressant effects of trimipramine. However, other authors have attributed the claimed antidepressant effects of antipsychotics like the two previously mentioned to α2-adrenergic receptor antagonism, although trimipramine specifically has only weak affinity for this receptor. Aside from antidepressant effects, low doses of antipsychotics have been found to increase REM sleep, and so dopamine autoreceptor antagonism could be involved in the unique effects of trimipramine in terms of REM sleep and sleep architecture.

Pharmacokinetics

The time to peak concentrations following a dose is 2 to 4 hours. The typical antidepressant therapeutic range of trimipramine concentrations is 150 to 300 ng/mL. The terminal half-life of trimipramine has been variously reported to be as little as 8 hours (in plasma) and as long as 24 hours. In any case, the terminal half-life of trimipramine is described as shorter than that of other TCAs, which makes it ideal for use in the treatment of insomnia.

Trimipramine is a racemic compound with two enantiomers. CYP2C19 is responsible for the demethylation of (D)- and (L)-trimipramine to (D)- (L)-desmethyltrimipramine, respectively, and CYP2D6 is responsible for the 2-hydroxylation of (D)- and (L)-desmethyltrimipramine to (D)- and (L)-2-hydroxydesmethyltrimipramine, respectively. CYP2D6 also metabolises (L)-trimipramine into (L)-2-hydroxytrimipramine.

Chemistry

Trimipramine 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 imipramine, desipramine, and clomipramine. Trimipramine is a derivative of imipramine with a methyl group added to its side chain and is also known as 2′-methylimipramine or β-methylimipramine. The tri- prefix in its name may allude to the fact that its side chain features three methyl groups. Trimipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desmethyltrimipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), and doxepin. The chemical name of trimipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine and its free base form has a chemical formula of C20H26N2 with a molecular weight of 294.434 g/mol. The drug is used commercially as the maleate salt. The CAS Registry Number of the free base is 739-71-9 and of the maleate is 521-78-8.

Society and Culture

Generic Names

Trimipramine is the generic name of the drug and its INN, USAN, BAN, and DCF, while trimipramine maleate is its USAN, USP, BANM, and JAN. Its generic name in Latin is trimipraminum, in German is trimipramin, and in Spanish is trimipramina.

Brand Names

Trimipramine is marketed throughout the world mainly under the brand name Surmontil. Other notable brand names of trimipramine have included Herphonal, Rhotrimine, Sapilent, Stangyl, and Tydamine.

Availability

Trimipramine is no longer marketed in Australia, though it was previously.

What is Venlafaxine?

Introduction

Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class.

It is used to treat major depressive disorder (MDD), generalised anxiety disorder (GAD), panic disorder, and social phobia. It may also be used for chronic pain. It is taken by mouth.

Common side effects include loss of appetite, constipation, dry mouth, dizziness, sweating, and sexual problems. Severe side effects include an increased risk of suicide, mania, and serotonin syndrome. Antidepressant withdrawal syndrome may occur if stopped. There are concerns that use during the later part of pregnancy can harm the baby. How it works is not entirely clear, but it seems to be related to the potentiation of the activity of some neurotransmitters in the brain.

Venlafaxine was approved for medical use in the United States in 1993. It is available as a generic medication. In 2018, it was the 50th most commonly prescribed medication in the United States with more than 16 million prescriptions.

Medical Uses

Venlafaxine is used primarily for the treatment of depression, general anxiety disorder, social phobia, panic disorder, and vasomotor symptoms.

Venlafaxine has been used off label for the treatment of diabetic neuropathy and migraine prevention (in some people, however, venlafaxine can exacerbate or cause migraines). It may work on pain via effects on the opioid receptor. It has also been found to reduce the severity of ‘hot flashes’ in menopausal women and men on hormonal therapy for the treatment of prostate cancer.

Due to its action on both the serotoninergic and adrenergic systems, venlafaxine is also used as a treatment to reduce episodes of cataplexy, a form of muscle weakness, in patients with the sleep disorder narcolepsy. Some open-label and three double-blind studies have suggested the efficacy of venlafaxine in the treatment of attention deficit-hyperactivity disorder (ADHD). Clinical trials have found possible efficacy in those with post-traumatic stress disorder (PTSD). Case reports, open trials and blinded comparisons with established medications have suggested the efficacy of venlafaxine in the treatment of obsessive-compulsive disorder (OCD).

Depression

A comparative meta-analysis of 21 major antidepressants found that venlafaxine, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, and vortioxetine were more effective than other antidepressants, although the quality of many comparisons was assessed as low or very low.

Venlafaxine was similar in efficacy to the atypical antidepressant bupropion; however, the remission rate was lower for venlafaxine. In a double-blind study, patients who did not respond to an SSRI were switched to either venlafaxine or another SSRI (citalopram); similar improvement was observed in both groups.

Studies of venlafaxine in children have not established its efficacy.

Studies have shown that the extended release is superior to the immediate release form of venlafaxine.

A meta-analysis shown that efficacity of venlafaxine is not correlated with baseline severity of depression.

Dosage

Venlafaxine has been shown to have an optimal efficacity and tolerability towards the lower end of their licensed dose range.

Contraindications

Venlafaxine is not recommended in patients hypersensitive to it, nor should it be taken by anyone who is allergic to the inactive ingredients, which include gelatin, cellulose, ethylcellulose, iron oxide, titanium dioxide and hypromellose. It should not be used in conjunction with a monoamine oxidase inhibitor (MAOI), as it can cause potentially fatal serotonin syndrome.

Adverse Effects

Refer to Adverse Effects of Venlafaxine.

Venlafaxine can increase eye pressure, so those with glaucoma may require more frequent eye checks.

A 2017 meta-analysis estimated venlafaxine discontinuation rate to 9.4%.

Suicide

The US Food and Drug Administration (FDA) requires all antidepressants, including venlafaxine, to carry a black box warning with a generic warning about a possible suicide risk.

A 2014 meta analysis of 21 clinical trials of venlafaxine for the treatment of depression in adults found that compared to placebo, venlafaxine reduced the risk of suicidal thoughts and behaviour.

A study conducted in Finland followed more than 15,000 patients for 3.4 years. Venlafaxine increased suicide risk by 60% (statistically significant), as compared to no treatment. At the same time, fluoxetine (Prozac) halved the suicide risk.

In another study, the data on more than 200,000 cases were obtained from the UK general practice research database. At baseline, patients prescribed venlafaxine had a greater number of risk factors for suicide (such as prior suicide attempts) than patients treated with other anti-depressants. The patients taking venlafaxine had significantly higher risk of completed suicide than the ones on fluoxetine or citalopram (Celexa). After adjusting for known risk factors, venlafaxine was associated with an increased risk of suicide relative to fluoxetine and dothiepin that was not statistically significant. A statistically significant greater risk for attempted suicide remained after adjustment, but the authors concluded that it could be due to residual confounding.[28]

An analysis of clinical trials by the FDA statisticians showed the incidence of suicidal behaviour among the adults on venlafaxine to be not significantly different from fluoxetine or placebo.

Venlafaxine is contraindicated in children, adolescents and young adults. According to the FDA analysis of clinical trials venlafaxine caused a statistically significant 5-fold increase in suicidal ideation and behaviour in persons younger than 25. In another analysis, venlafaxine was no better than placebo among children (7-11 years old), but improved depression in adolescents (12-17 years old). However, in both groups, hostility and suicidal behaviour increased in comparison to those receiving a placebo. In a study involving antidepressants that had failed to produce results in depressed teenagers, teens whose SSRI treatment had failed who were randomly switched to either another SSRI or to venlafaxine showed an increased rate of suicide on venlafaxine. Among teenagers who were suicidal at the beginning of the study, the rate of suicidal attempts and self-harm was significantly higher, by about 60%, after the switch to venlafaxine than after the switch to an SSRI.

Discontinuation Syndrome

Refer to Antidepressant Discontinuation Syndrome.

People stopping venlafaxine commonly experience discontinuation symptoms such as dysphoria, headaches, nausea, irritability, emotional lability, sensation of electric shocks, and sleep disturbance. Venlafaxine has a higher rate of moderate to severe discontinuation symptoms relative to other antidepressants (similar to the SSRI paroxetine).

The higher risk and increased severity of discontinuation syndrome symptoms relative to other antidepressants may be related to the short half-life of venlafaxine and its active metabolite. After discontinuing venlafaxine, the levels of both serotonin and norepinephrine decrease, leading to the hypothesis that the discontinuation symptoms could result from an overly rapid reduction of neurotransmitter levels.

Serotonin Syndrome

Refer to Serotonin Syndrome.

The development of a potentially life-threatening serotonin syndrome (also more recently classified as “serotonin toxicity”) may occur with venlafaxine treatment, particularly with concomitant use of serotonergic drugs, including but not limited to SSRIs and SNRIs, many hallucinogens such as tryptamines and phenethylamines (e.g. LSD/LSA, DMT, MDMA, mescaline), dextromethorphan (DXM), tramadol, tapentadol, pethidine (meperidine) and triptans and with drugs that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Venlafaxine-induced serotonin syndrome has also been reported when venlafaxine has been taken in isolation in overdose. An abortive serotonin syndrome state, in which some but not all of the symptoms of the full serotonin syndrome are present, has been reported with venlafaxine at mid-range dosages (150 mg per day). A case of a patient with serotonin syndrome induced by low-dose venlafaxine (37.5 mg per day) has also been reported.

Pregnancy

There are few well-controlled studies of venlafaxine in pregnant women. A study released in May 2010 by the Canadian Medical Association Journal suggests use of venlafaxine doubles the risk of miscarriage. Consequently, venlafaxine should only be used during pregnancy if clearly needed. A large case-control study done as part of the National Birth Defects Prevention Study and published in 2012 found a significant association of venlafaxine use during pregnancy and several birth defects including anencephaly, cleft palate, septal heart defects and coarctation of the aorta. Prospective studies have not shown any statistically significant congenital malformations. There have, however, been some reports of self-limiting effects on newborn infants. As with other serotonin reuptake inhibitors (SRIs), these effects are generally short-lived, lasting only 3 to 5 days, and rarely resulting in severe complications.

Drug Interactions

Venlafaxine should be taken with caution when using St John’s wort. Venlafaxine may lower the seizure threshold, and co-administration with other drugs that lower the seizure threshold such as bupropion and tramadol should be done with caution and at low doses.

Bipolar Disorder

Venlafaxine is neither recommended nor approved for the treatment of major depressive episodes in bipolar disorder, as it can induce mania or mixed episodes. Venlafaxine appears to be more likely than the SSRIs and bupropion to induce mania and mixed episodes in bipolar patients.

Liver Injury

A rare but serious side effect of venlafaxine is liver injury. It reaches man and female patients with a median age of 44 years. Cessation of venlafaxine is one of the appropriate measure of management. The mechanism of venlafaxine related-liver injury is unclear but may be related to a CYP2D6 polymorphism.

Other

In rare cases, drug-induced akathisia (movement disorder) can occur after use in some people.

Venlafaxine should be used with caution in hypertensive patients. Venlafaxine must be discontinued if significant hypertension persists. It can also have undesirable cardiovascular effects.

Overdose

Most patients overdosing with venlafaxine develop only mild symptoms. Plasma venlafaxine concentrations in overdose survivors have ranged from 6 to 24 mg/l, while postmortem blood levels in fatalities are often in the 10-90 mg/l range. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcome compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Healthcare professionals are advised to prescribe Effexor and Effexor XR in the smallest quantity of capsules consistent with good patient management to reduce the risk of overdose. It is usually reserved as a second-line treatment for depression due to a combination of its superior efficacy to the first-line treatments like fluoxetine, paroxetine and citalopram and greater frequency of side effects like nausea, headache, insomnia, drowsiness, dry mouth, constipation, sexual dysfunction, sweating and nervousness.

There is no specific antidote for venlafaxine, and management is generally supportive, providing treatment for the immediate symptoms. Administration of activated charcoal can prevent absorption of the drug. Monitoring of cardiac rhythm and vital signs is indicated. Seizures are managed with benzodiazepines or other anticonvulsants. Forced diuresis, hzemodialysis, exchange transfusion, or hemoperfusion are unlikely to be of benefit in hastening the removal of venlafaxine, due to the drug’s high volume of distribution.

Mechanism of Action

Pharmacology

Venlafaxine is usually categorised as a serotonin-norepinephrine reuptake inhibitor (SNRI), but it has also been referred to as a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It works by blocking the transporter “reuptake” proteins for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin and norepinephrine. Additionally, in high doses it weakly inhibits the reuptake of dopamine, since dopamine is inactivated by norepinephrine reuptake in the frontal cortex. The frontal cortex largely lacks dopamine transporters; therefore venlafaxine can increase dopamine neurotransmission in this part of the brain.

Venlafaxine indirectly affects opioid receptors as well as the alpha2-adrenergic receptor, and was shown to increase pain threshold in mice. These benefits with respect to pain were reversed with naloxone, an opioid antagonist, thus supporting an opioid mechanism.

Pharmacokinetics

Venlafaxine is well absorbed, with at least 92% of an oral dose being absorbed into systemic circulation. It is extensively metabolized in the liver via the CYP2D6 isoenzyme to desvenlafaxine (O-desmethylvenlafaxine, now marketed as a separate medication named Pristiq), which is just as potent an SNRI as the parent compound, meaning that the differences in metabolism between extensive and poor metabolisers are not clinically important in terms of efficacy. Side effects, however, are reported to be more severe in CYP2D6 poor metabolisers. Steady-state concentrations of venlafaxine and its metabolite are attained in the blood within 3 days. Therapeutic effects are usually achieved within 3 to 4 weeks. No accumulation of venlafaxine has been observed during chronic administration in healthy subjects. The primary route of excretion of venlafaxine and its metabolites is via the kidneys. The half-life of venlafaxine is relatively short, so patients are directed to adhere to a strict medication routine, avoiding missing a dose. Even a single missed dose can result in withdrawal symptoms.

Venlafaxine is a substrate of P-glycoprotein (P-gp), which pumps it out of the brain. The gene encoding P-gp, ABCB1, has the SNP rs2032583, with alleles C and T. The majority of people (about 70% of Europeans and 90% of East Asians) have the TT variant. A 2007 study found that carriers of at least one C allele (variant CC or CT) are 7.72 times more likely than non-carriers to achieve remission after 4 weeks of treatment with amitriptyline, citalopram, paroxetine or venlafaxine (all P-gp substrates). The study included patients with mood disorders other than major depression, such as bipolar II; the ratio is 9.4 if these other disorders are excluded. At the 6-week mark, 75% of C-carriers had remitted, compared to only 38% of non-carriers.

Chemistry

The IUPAC name of venlafaxine is 1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl]cyclohexanol, though it is sometimes referred to as (±)-1-[a-[a-(dimethylamino)methyl]-p-methoxybenzyl]cyclohexanol. It consists of two enantiomers present in equal quantities (termed a racemic mixture), both of which have the empirical formula of C17H27NO2. It is usually sold as a mixture of the respective hydrochloride salts, (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl]cyclohexanol hydrochloride, C17H28ClNO2, which is a white to off-white crystalline solid. Venlafaxine is structurally and pharmacologically related to the atypical opioid analgesic tramadol, and more distantly to the newly released opioid tapentadol, but not to any of the conventional antidepressant drugs, including tricyclic antidepressants, SSRIs, MAOIs, or RIMAs.

Venlafaxine extended release is chemically the same as normal venlafaxine. The extended release (controlled release) version distributes the release of the drug into the gastrointestinal tract over a longer period than normal venlafaxine. This results in a lower peak plasma concentration. Studies have shown that the extended release formula has a lower incidence of nausea as a side effect, resulting in better compliance.

Society and Culture

Venlafaxine was originally marketed as Effexor in most of the world; generic venlafaxine has been available since around 2008 and extended release venlaxafine has been available since around 2010.

As of January 2020 venlafaxine is marketed under many brand names worldwide, many with alternative extended release forms (not shown): Adefaxin, Alenthus, Altven, Alventa, Amfax, Anapresin, Ansifix, Arafaxina, Argofan, Arrow Venlafaxine, Axone, Axyven, Benolaxe, Blossom, Calmdown, Dalium, Defaxine, Depefex, Depretaxer, Deprevix, Deprexor, Deprixol, Depurol, Desinax, Dislaven, Dobupal, Duofaxin, Easyfor, Ectien, Eduxon, Efastad, Efaxin, Efaxine, Efectin, Efegen, Efevelon, Efevelone, Efexiva, Efexor, Effegad, Effexine, Effexor, Elafax, Elaxine, Elify, Enpress, Enlafax, Envelaf, Falven, Faxigen, Faxine, Faxiprol, Faxiven, Faxolet, Flavix, Flaxen, Fobiless, Ganavax, Idixor, Idoxen, Intefred, Illovex, Lafactin, Lafaxin, Lanvexin, Laroxin, Levest, Limbic, Linexel, Maxibral, Mazda, Melocin, Memomax, Mezine, Neoxacina, Neoxacina, Nervix, Norafexine, Norezor, Norpilen, Noviser, Nulev, Odiven, Olwexya, Oriven, Paxifar, Politid, Pracet, Prefaxine, Psiseven, Quilarex, Rafax, Senexon, Sentidol, Sentosa, Serosmine, Seroxine, Sesaren, Subelan, Sulinex, Sunveniz, Sunvex, Symfaxin, Tedema, Tifaxin, Tonpular, Trevilor, Tudor, Vafexin, Valosine, Vandral, Velaf, Velafax, Velahibin, Velaxin, Velept, Velpine, Venax, Venaxin, Venaxx, Vencarm, Vencontrol, Vendep, Venegis, Venex, Venexor, Venfalex, Venfax, Ven-Fax, Venfaxine, Venforin, Venforspine, Veniba, Veniz, Venjoy, Venla, Venlabax, Venlablue, Venlabrain, Venladep, Venladex, Venladoz, Venlaf, Venlafab, Venlafaxin, Venlafaxina, Venlafaxine, Venlagamma, Venlalic, Venlamax, Venlamylan, Venlaneo, Venlapine, Venla-Q, Venlasand, Venlatrin, Venlavitae, Venlax, Venlaxin, Venlaxine, Venlaxor, Venlazid, Venlectine, Venlifax, Venlift, Venlix, Venlobax, Venlofex, Venlor, Venorion, Venozap, Vensate, Ventab, Venxin, Venxor, Venzip, Vexamode, Vfax, Viepax, ViePax, Voxafen, Zacalen, Zanfexa, Zaredrop, Zarelis, Zarelix, and Zenexor.

What is Bupropion?

Introduction

Bupropion, sold under the brand names Wellbutrin and Zyban among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. Bupropion is an effective antidepressant on its own, but it is also popular as an add-on medication in the cases of incomplete response to the first-line selective serotonin reuptake inhibitor (SSRI) antidepressant. Bupropion has several features that distinguish it from other antidepressants: it does not usually cause sexual dysfunction; it is not associated with weight gain and sleepiness, and it is more effective than SSRIs at improving symptoms of hypersomnia and fatigue.

Common adverse effects of bupropion with the greatest difference from placebo are dry mouth, nausea, constipation, insomnia, anxiety, tremor, and excessive sweating. Raised blood pressure is notable. Rare but serious side effects include seizure, liver toxicity, psychosis, and risk of overdose. Bupropion use during pregnancy may be associated with increased odds of congenital heart defects.

Bupropion acts as a norepinephrine-dopamine reuptake inhibitor and a nicotinic receptor antagonist. Chemically, it is an aminoketone that belongs to the class of substituted cathinones and more generally that of substituted amphetamines and substituted phenethylamines.

Bupropion was invented by Nariman Mehta, who worked at Burroughs Wellcome, in 1969. It was first approved for medical use in the United States in 1985. Bupropion was originally called by the generic name amfebutamone, before being renamed in 2000. In 2018, it was the 27th most commonly prescribed medication in the United States, with more than 24 million prescriptions.

Brief History

Bupropion was invented by Nariman Mehta of Burroughs Wellcome (now GlaxoSmithKline) in 1969, and the US patent for it was granted in 1974. It was approved by the US Food and Drug Administration (FDA) as an antidepressant on 30 December 1985, and marketed under the name Wellbutrin.[19][95] However, a significant incidence of seizures at the originally recommended dosage (400-600 mg/day) caused the withdrawal of the drug in 1986. Subsequently, the risk of seizures was found to be highly dose-dependent, and bupropion was re-introduced to the market in 1989 with a lower maximum recommended daily dose of 450 mg/day.

In 1996, the FDA approved a sustained-release formulation of alcohol-resistant bupropion called Wellbutrin SR, intended to be taken twice a day (as compared with three times a day for immediate-release Wellbutrin). In 2003, the FDA approved another sustained-release formulation called Wellbutrin XL, intended for once-daily dosing. Wellbutrin SR and XL are available in generic form in the United States and Canada. In 1997, bupropion was approved by the FDA for use as a smoking cessation aid under the name Zyban. In 2006, Wellbutrin XL was similarly approved as a treatment for seasonal affective disorder.

In France, marketing authorisation was granted for Zyban on 03 August 2001, with a maximum daily dose of 300 mg; only sustained-release bupropion is available, and only as a smoking cessation aid.

On 11 October 2007, two providers of consumer information on nutritional products and supplements, ConsumerLab.com and The People’s Pharmacy, released the results of comparative tests of different brands of bupropion. The People’s Pharmacy received multiple reports of increased side effects and decreased efficacy of generic bupropion, which prompted it to ask ConsumerLab.com to test the products in question. The tests showed that “one of a few generic versions of Wellbutrin XL 300 mg, sold as Budeprion XL 300 mg, didn’t perform the same as the brand-name pill in the lab.” The FDA investigated these complaints and concluded that Budeprion XL is equivalent to Wellbutrin XL in regard to bioavailability of bupropion and its main active metabolite hydroxybupropion. The FDA also said that coincidental natural mood variation is the most likely explanation for the apparent worsening of depression after the switch from Wellbutrin XL to Budeprion XL. On 03 October 2012, however, the FDA reversed this opinion, announcing that “Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg.” The FDA did not test the bioequivalence of any of the other generic versions of Wellbutrin XL 300 mg, but requested that the four manufacturers submit data on this question to the FDA by March 2013. As of October 2013 the FDA has made determinations on the formulations from some manufacturers not being bioequivalent.

In April 2008, the FDA approved a formulation of bupropion as a hydrobromide salt instead of a hydrochloride salt, to be sold under the name Aplenzin by Sanofi-Aventis.

In 2009, the FDA issued a health advisory warning that the prescription of bupropion for smoking cessation has been associated with reports about unusual behaviour changes, agitation and hostility. Some people, according to the advisory, have become depressed or have had their depression worsen, have had thoughts about suicide or dying, or have attempted suicide. This advisory was based on a review of anti-smoking products that identified 75 reports of “suicidal adverse events” for bupropion over ten years. Based on the results of follow-up trials this warning was removed in 2016.

In 2012, the US Justice Department announced that GlaxoSmithKline had agreed to plead guilty and pay a $3-billion fine, in part for promoting the unapproved use of Wellbutrin for weight loss and sexual dysfunction.

In 2017, the European Medicines Agency recommended suspending a number of nationally approved medicines due to misrepresentation of bioequivalence study data by Micro Therapeutic Research Labs in India. The products recommended for suspension included several 300 mg modified-release Bupropion tablets.

Medical Uses

Depression

A majority of controlled clinical trials support efficacy of bupropion for the treatment of depression. However, the overall quality of the evidence is low, with one meta-analysis, for example, finding a small effect size of bupropion in depression and another finding a large effect size. Comparative head-to-head clinical trials indicate that bupropion is similar in response rate against depression to fluoxetine, sertraline, paroxetine, and venlafaxine; meanwhile remission rate tends to favour buproprion.

Given over the fall and winter months, bupropion prevents development of depression in those who suffer from recurring seasonal affective disorder: 15% of participants on bupropion experienced a major depressive episode vs 27% of those on placebo. Bupropion also improves depression in bipolar disorder, with the efficacy and risk of affective switch being similar to other antidepressants.

Bupropion has several features that distinguish it from other antidepressants: for instance, unlike the majority of antidepressants, it does not usually cause sexual dysfunction, and the occurrence of sexual side effects is not different from placebo. Bupropion treatment is not associated with weight gain; on the contrary, the majority of studies observed significant weight loss in bupropion-treated participants. Bupropion treatment also is not associated with the sleepiness that may be produced by other antidepressants. Bupropion is more effective than selective serotonin reuptake inhibitors (SSRIs) at improving symptoms of hypersomnia and fatigue in depressed patients. There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of depression with high anxiety; they are equivalent for the depression with moderate or low anxiety.

The addition of bupropion to a prescribed SSRI is a common strategy when people do not respond to the SSRI, and it is supported by clinical trials; however, it appears to be inferior to the addition of atypical antipsychotic aripiprazole.

Smoking Cessation

Prescribed as an aid for smoking cessation bupropion reduces the severity of craving for tobacco and withdrawal symptoms such as depressed mood, irritability, difficulty concentrating, and increased appetite. Initially, bupropion slows the weight gain that often occurs in the first weeks after quitting smoking. With time, however, this effect becomes negligible.

The bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco about ten days into the course. After the course, the effectiveness of bupropion for maintaining abstinence from smoking declines over time, from 37% of tobacco abstinence at 3 months to 20% at one year. It is unclear whether extending bupropion treatment helps to prevent relapse of smoking.

Overall, six months after the therapy, bupropion increases the likelihood of quitting smoking by approximately 1.6 fold as compared to placebo. In this respect, bupropion is as effective as nicotine replacement therapy but inferior to varenicline. Combining bupropion and nicotine replacement therapy does not improve the quitting rate.

In children and adolescents, the use of bupropion for smoking cessation does not appear to offer any significant benefits. The evidence for its use to aid smoking cessation in pregnant women is insufficient.

Attention Deficit Hyperactivity Disorder

The treatment of ADHD is not an approved indication of bupropion, and it is not mentioned in the current (2019) guideline on the ADHD treatment from the American Academy of Paediatrics. Systematic reviews of bupropion for the treatment of ADHD in both adults and children note that bupropion may be effective for ADHD but warn that this conclusion has to be interpreted with caution, because clinical trials were of low quality due to small sizes and risk of bias.

Sexual Dysfunction

Bupropion is less likely than other antidepressants to cause sexual dysfunction. A range of studies indicate that bupropion not only produces fewer sexual side effects than other antidepressants but can actually help to alleviate sexual dysfunction including sexual dysfunction induced by SSRI antidepressants. There have also been small studies suggesting that bupropion or a bupropion/trazodone combination may improve some measures of sexual function in women who have hypoactive sexual desire disorder (HSDD) and are not depressed. According to an expert consensus recommendation from the International Society for the Study of Women’s Sexual Health, bupropion can be considered as an off-label treatment for HSDD despite limited safety and efficacy data.

Obesity

Bupropion, when used for treating obesity over a period of 6 to 12 months, results in an average weight loss of 2.7 kg (5.9 lbs) over placebo. This is not much different from the weight loss produced by several other weight-loss medications such as sibutramine or orlistat. The combination drug naltrexone/bupropion has been approved by the US Food and Drug Administration (FDA) for the treatment of obesity.

Other Uses

Bupropion is not effective in the treatment of cocaine dependence, but it is showing promise in reducing drug use in light methamphetamine users. Based on studies indicating that bupropion lowers the level of the inflammatory mediator TNF-alpha, there have been suggestions that it might be useful in treating inflammatory bowel disease, psoriasis, and other autoimmune conditions, but very little clinical evidence is available. Bupropion is not effective in treating chronic low back pain.

Contraindications

The drug label advises that bupropion should not be prescribed to individuals with epilepsy or other conditions that lower the seizure threshold, such as anorexia nervosa, bulimia nervosa, benzodiazepine or alcohol withdrawal. It should be avoided in individuals who are taking monoamine oxidase inhibitors (MAOIs). When switching from MAOIs to bupropion, it is important to include a washout period of about two weeks between the medications. The label recommends that caution should be exercised when treating people with liver damage, severe kidney disease, and severe hypertension, and in children, adolescents and young adults due to the increased risk of suicidal ideation.

Side Effects

The common adverse effects of bupropion with the greatest difference from placebo are dry mouth, nausea, constipation, insomnia, anxiety, tremor, and excessive sweating. Bupropion has highest incidence of insomnia of all second-generation antidepressants, bar desvenlafaxine. It is also associated with about 20% increased risk of headache.

Bupropion raises systolic blood pressure by 6 mm Hg and the heart rate by 7 beats per minute. The prescribing information notes that hypertension, sometimes severe, is observed in some people taking bupropion, both with and without pre-existing hypertension. Safety of bupropion in people with cardiovascular conditions and its general cardiovascular safety profile remain unclear due to the lack of data.

Seizure is a rare but serious adverse effect of bupropion. It is strongly dose-dependent: for the immediate release preparation, the seizure incidence is 0.4% at the dose 300-450 mg per day; the incidence climbs almost ten-fold for the higher than recommended dose of 600 mg. For comparison, the incidence of unprovoked seizure in the general population is 0.07 to 0.09%, and the risk of seizure for a variety of other antidepressants is generally between 0 and 0.5% at the recommended doses.

Cases of liver toxicity leading to death or liver transplantation have been reported for bupropion. It is considered to be one of several antidepressants with greater risk of hepatotoxicity.

The prescribing information warns about bupropion triggering an angle-closure glaucoma attack. On the other hand, bupropion may decrease the risk of development of open angle glaucoma.

Bupropion use by mothers in the first trimester of pregnancy is associated with 23% increase of the odds in congenital heart defects in their children.

Psychiatric

The FDA requires all antidepressants, including bupropion, to carry a boxed warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on a statistical analysis conducted by the FDA which found a 2-fold increase in suicidal thought and behaviour in children and adolescents, and 1.5-fold increase in the 18-24 age group. For this analysis the FDA combined the results of 295 trials of 11 antidepressants in order to obtain statistically significant results. Considered in isolation, bupropion was not statistically different from placebo.

Bupropion prescribed for smoking cessation results in 25% increase of the risk of psychiatric side effects, in particular, anxiety (about 40% increase) and insomnia (about 80% increase). The evidence is insufficient to determine whether bupropion is associated with suicides or suicidal behaviour.

In rare cases, bupropion-induced psychosis may develop. It is associated with higher doses of bupropion; many cases described are at higher than recommended doses. Concurrent antipsychotic medication appears to be protective. In most cases the psychotic symptoms are eliminated by reducing the dose, ceasing treatment or adding antipsychotic medication.

Although studies are lacking, a handful of case reports suggest that abrupt discontinuation of bupropion may cause antidepressant discontinuation syndrome.

Overdose

Bupropion is considered moderately dangerous in overdose. According to an analysis of US National Poison Data System, adjusted for the number of prescriptions, bupropion and venlafaxine are the two new generation antidepressants (that is excluding tricyclic antidepressants) that result in the highest mortality and morbidity. For significant overdoses, seizures have been reported in about a third of all cases; other serious effects include hallucinations, loss of consciousness, and abnormal heart rhythms. When bupropion was one of several kinds of pills taken in an overdose, fever, muscle rigidity, muscle damage, hypertension or hypotension, stupor, coma, and respiratory failure have been reported. While most people recover, some people have died, and before they died suffered multiple uncontrolled seizures and heart attacks.

Interactions

Since bupropion is metabolised to hydroxybupropion by the enzyme CYP2B6, drug interactions with CYP2B6 inhibitors are possible: this includes such medications as paroxetine, sertraline, norfluoxetine (active metabolite of fluoxetine), diazepam, clopidogrel, and orphenadrine. The expected result is the increase of bupropion and decrease of hydroxybupropion blood concentration. The reverse effect (decrease of bupropion and increase of hydroxybupropion) can be expected with CYP2B6 inducers such as carbamazepine, clotrimazole, rifampicin, ritonavir, St John’s wort, and phenobarbital. Indeed, carbamazepine decreases exposure to bupropion by 90% and increases exposure to hydroxybupropion by 94%. Ritonavir, lopinavir/ritonavir, and efavirenz have been shown to decrease levels of bupropion and/or its metabolites. Ticlopidine and clopidogrel, both potent CYP2B6 inhibitors, have been found to considerably increase bupropion levels as well as decrease levels of its metabolite hydroxybupropion.

Bupropion and its metabolites are inhibitors of CYP2D6, with hydroxybupropion responsible for most of the inhibition. Additionally, bupropion and its metabolites may decrease expression of CYP2D6 in the liver. The end effect is a significant slowing of the clearance of other drugs metabolised by this enzyme. For instance, bupropion has been found to increase area-under-the-curve of desipramine, a CYP2D6 substrate, by 5-fold. Bupropion has also been found to increase levels of atomoxetine by 5.1-fold, while decreasing the exposure to its main metabolite by 1.5-fold. As another example, the ratio of dextromethorphan (a drug that is mainly metabolized by CYP2D6) to its major metabolite dextrorphan increased approximately 35-fold when it was administered to people being treated with 300 mg/day bupropion. When people on bupropion are given MDMA, about 30% increase of exposure to both drugs is observed, with enhanced mood but decreased heart rate effects of MDMA. Interactions with other CYP2D6 substrates, such as metoprolol, imipramine, nortriptyline, venlafaxine, and nebivolol have also been reported. However, in a notable exception, bupropion does not affect the concentrations of CYP2D6 substrates fluoxetine and paroxetine.

Bupropion lowers the seizure threshold, and therefore can potentially interact with other medications that also lower it, such as antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids. The prescribing information recommends minimising the use of alcohol, since in rare cases bupropion reduces alcohol tolerance.

Caution should be observed when combining bupropion with a monoamine oxidase inhibitor (MAOI), as it may result in hypertensive crisis.

Pharmacology

Pharmacodynamics and Mechanism of Action

The mechanism of action of bupropion is unclear but believed to be related to the fact that bupropion is a norepinephrine-dopamine reuptake inhibitor and antagonist of several nicotinic receptors. It is uncertain if it is a norepinephrine-dopamine releasing agent. Pharmacological actions of bupropion, to a significant degree, are due to its active metabolites hydroxybupropion, threo-hydrobupropion, and erythro-hydrobupropion that are present in the blood plasma at comparable or higher levels. Overall action of these metabolites, and particularly one enantiomer S,S-hydroxybupropion, is also characterised by inhibition of norepinephrine and dopamine reuptake and nicotinic antagonism. The occupancy of dopamine transporter (DAT) by bupropion and its metabolites in the human brain as measured by positron emission tomography is 6-35%.

Bupropion also weakly inhibits the α1 adrenergic receptor, with IC50 of 16μM.

Pharmacokinetics

After oral administration, bupropion is rapidly and completely absorbed reaching the peak blood plasma concentration after 1.5 hours (tmax). Sustained release (SR) and extended release (XL) formulations have been designed to slow down absorption resulting in tmax of 3 hours and 5 hours, respectively. Absolute bioavailability of bupropion is unknown but is presumed to be low, at 5-20%, due to the first-pass metabolism. As for the relative biovailability of the formulations, XL formulation has lower bioavailability (68%) compared to SR formulation and immediate release bupropion.

Bupropion is metabolized in the body by a variety of pathways. The oxidative pathways are by cytochrome P450 isoenzymes CYP2B6 leading to R,R- and S,S-hydroxybupropion and, to a lesser degree, CYP2C19 leading to 4′-hydroxybupropion. The reductive pathways are by 11β-hydroxysteroid dehydrogenase type 1 in the liver and AKR7A2/AKR7A3 in the intestine leading to threo-hydrobupropion and by yet unknown enzyme leading to erythro-hydrobupropion.

The metabolism of bupropion is highly variable: the effective doses of bupropion received by persons who ingest the same amount of the drug may differ by as much as 5.5 times (with a half-life of 12-30 hours), while the effective doses of hydroxybupropion may differ by as much as 7.5 times (with a half-life of 15-25 hours). Based on this, some researchers have advocated monitoring of the blood level of bupropion and hydroxybupropion.

Chemistry

Bupropion is an aminoketone that belongs to the class of substituted cathinones and the more general class of substituted phenethylamines. The clinically used bupropion is racemic, that is a mixture of two enantiomers: S-bupropion and R-bupropion. Although the optical isomers on bupropion can be separated, they rapidly racemize under physiological conditions.

There have been reported cases of false-positive urine amphetamine tests in persons taking bupropion.

Synthesis

It is synthesized in two chemical steps starting from 3′-chloro-propiophenone. The alpha position adjacent to the ketone is first brominated followed by nucleophilic displacement of the resulting alpha-bromoketone with t-butylamine and treated with hydrochloric acid to give bupropion as the hydrochloride salt in 75-85% overall yield.

Society and Culture

Recreational Use

While bupropion demonstrates some potential for misuse, this potential is less than of other commonly used stimulants, being limited by features of bupropion’s pharmacology. Bupropion misuse is uncommon. There have been a number of anecdotal and case-study reports of bupropion abuse, but the bulk of evidence indicates that the subjective effects of bupropion via the oral route are markedly different from those of addictive stimulants such as cocaine or amphetamine. That said, bupropion, via non-conventional routes of administration (e.g. injection, insufflation), is reported to be abused in the United States and Canada, notably in prisons.

Legal Status

In Russia bupropion is banned as a narcotic drug, yet not per se but rather as a derivative of methcathinone. In Australia and the UK, smoking cessation is the only licensed use of bupropion.

What is Escitalopram?

Introduction

Escitalopram, sold under the brand names Cipralex and Lexapro, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Escitalopram is mainly used to treat major depressive disorder (MDD) or generalised anxiety disorder (GAD). It is taken by mouth.

Common side effects include trouble sleeping, nausea, sexual problems, and feeling tired. More serious side effects may include suicide in people under the age of 25. It is unclear if use during pregnancy or breastfeeding is safe. Escitalopram is the (S)-stereoisomer (left-handed version) of citalopram (which exists as a racemate), hence the name escitalopram. In other words, escitalopram is a chiral switch of citalopram.

Escitalopram was approved for medical use in the United States in 2002. Escitalopram is sometimes replaced by twice the dose of citalopram. In 2018, it was the 22nd most commonly prescribed medication in the United States with more than 25 million prescriptions.

Brief History

Escitalopram was developed in close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.

The FDA issued the approval of escitalopram for major depression in August 2002 and for GAD in December 2003. On 23 May 2006, the FDA approved a generic version of escitalopram by Teva. On 14 July of that year, however, the US District Court of Delaware decided in favour of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.

In 2006, Forest Laboratories was granted an 828-day (2 years and 3 months) extension on its US patent for escitalopram. This pushed the patent expiration date from 07 December 2009, to 14 September 2011. Together with the 6-month paediatric exclusivity, the final expiration date was 14 March 2012.

Medical Uses

Escitalopram has FDA approval for the treatment of major depressive disorder in adolescents and adults, and generalized anxiety disorder in adults. In European countries and the United Kingdom, it is approved for depression (MDD) and anxiety disorders, these include: GAD, social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder with or without agoraphobia. In Australia it is approved for major depressive disorder.

Depression

Escitalopram was approved by regulatory authorities for the treatment of major depressive disorder on the basis of four placebo-controlled, double-blind trials, three of which demonstrated a statistical superiority over placebo.

Controversy existed regarding the effectiveness of escitalopram compared with its predecessor, citalopram. The importance of this issue followed from the greater cost of escitalopram relative to the generic mixture of isomers of citalopram, prior to the expiration of the escitalopram patent in 2012, which led to charges of evergreening. Accordingly, this issue has been examined in at least 10 different systematic reviews and meta analyses. As of 2012, reviews had concluded (with caveats in some cases) that escitalopram is modestly superior to citalopram in efficacy and tolerability.

A 2011 review concluded that second-generation antidepressants appear equally effective, although they may differ in onset and side effects. Treatment guidelines issued by the National Institute of Health and Clinical Excellence and by the American Psychiatric Association generally reflect this viewpoint.

In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed escitalopram to be one of the most effective.

Anxiety Disorder

Escitalopram appears to be effective in treating general anxiety disorder, with relapse on escitalopram at 20% rather than placebo at 50%.

Escitalopram appears effective in treating social anxiety disorder.

Other

Escitalopram is effective in reducing the symptoms of premenstrual syndrome, whether taken continuously or in the luteal phase only. There are no good data available for escitalopram as treatment for seasonal affective disorder as of 2021.

Side Effects

Escitalopram, like other SSRIs, has been shown to affect sexual functions causing side effects such as decreased libido, delayed ejaculation, and anorgasmia.

There is also evidence that SSRIs may cause an increase in suicidal ideation. An analysis conducted by the FDA found a statistically insignificant 1.5 to 2.4-fold (depending on the statistical technique used) increase of suicidality among the adults treated with escitalopram for psychiatric indications. The authors of a related study note the general problem with statistical approaches: due to the rarity of suicidal events in clinical trials, it is hard to draw firm conclusions with a sample smaller than two million patients.

Citalopram and escitalopram are associated with dose-dependent QT interval prolongation and should not be used in those with congenital long QT syndrome or known pre-existing QT interval prolongation, or in combination with other medicines that prolong the QT interval. ECG measurements should be considered for patients with cardiac disease, and electrolyte disturbances should be corrected before starting treatment. In December 2011, the UK implemented new restrictions on the maximum daily doses at 20 mg for adults and 10 mg for those older than 65 years or with liver impairment. There are concerns of higher rates of QT prolongation and torsades de pointes compared with other SSRIs. The US Food and Drug Administration (FDA) and Health Canada did not similarly order restrictions on escitalopram dosage, only on its predecessor citalopram.

Very Common Effects

Very common effects (>10% incidence) include:

  • Headache (24%).
  • Nausea (18%).
  • Ejaculation disorder (9-14%).
  • Somnolence (4-13%).
  • Insomnia (7-12%).

Common Effects

Common effects (1-10% incidence) include:

  • Insomnia.
  • Somnolence (sleepiness).
  • Dizziness.
  • Paraesthesia.
  • Tremor.
  • Decreased or increased appetite.
  • Anxiety.
  • Restlessness.
  • Abnormal dreams.
  • Libido decreased.
  • Anorgasmia.
  • Sinusitis (nasal congestion).
  • Yawning.
  • Diarrhoea.
  • Constipation.
  • Vomiting.
  • Dry mouth.
  • Excessive sweating.
  • Arthralgia (joint pain).
  • Myalgia (muscular aches and pains).
  • Fatigue.
  • Pyrexia (fever).
  • Impotence (erectile dysfunction).

Psychomotor Effects

The most common effect is fatigue or somnolence, particularly in older adults, although patients with pre-existing daytime sleepiness and fatigue may experience paradoxical improvement of these symptoms. Escitalopram has not been shown to affect serial reaction time, logical reasoning, serial subtraction, multitask, or MacWorth clock task performance.

Discontinuation Symptoms

Refer to Antidepressant Discontinuation Syndrome.

Escitalopram discontinuation, particularly abruptly, may cause certain withdrawal symptoms such as anhedonia (83%), “electric shock” sensations, colloquially called “brain shivers” or “brain zaps” by sufferers. Frequent symptoms in one study were dizziness (44%), muscle tension (44%), chills (44%), confusion or trouble concentrating (40%), amnesia (28%), and crying (28%). Very slow tapering was recommended. There have been spontaneous reports of discontinuation of Lexapro and other SSRIs and SNRIs, especially when abrupt, leading to dysphoric mood, irritability, agitation, anxiety, headache, lethargy, emotional lability, insomnia, and hypomania. Other symptoms such as panic attacks, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), mania, worsening of depression, and suicidal ideation can emerge when the dose is adjusted down.

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 include genital anaesthesia, erectile dysfunction, anhedonia, decreased libido, premature ejaculation, vaginal lubrication issues, and nipple insensitivity in women. Rates are unknown, and there is no established treatment.

Pregnancy

Antidepressant exposure (including escitalopram) is associated with shorter duration of pregnancy (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. There is a tentative association of SSRI use during pregnancy with heart problems in the baby. The advantages of their use during pregnancy may thus outweigh the possible negative effects on the baby.

Overdose

Excessive doses of escitalopram usually cause relatively minor untoward effects, such as agitation and tachycardia. However, dyskinesia, hypertonia, and clonus may occur in some cases. Therapeutic blood levels of escitalopram are usually in the range of 20-80 μg/L but may reach 80-200 μg/L in the elderly, patients with hepatic dysfunction, those who are poor CYP2C19 metabolisers or following acute overdose. Monitoring of the drug in plasma or serum is generally accomplished using chromatographic methods. Chiral techniques are available to distinguish escitalopram from its racemate, citalopram.

Pharmacology

Mechanism of Action

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently available, escitalopram has the highest selectivity for the serotonin transporter (SERT) compared to the norepinephrine transporter (NET), making the side-effect profile relatively mild in comparison to less-selective SSRIs.

Escitalopram is a substrate of P-glycoprotein and hence P-glycoprotein inhibitors such as verapamil and quinidine may improve its blood brain barrier penetrability. In a preclinical study in rats combining escitalopram with a P-glycoprotein inhibitor, its antidepressant-like effects were enhanced.

Interactions

Escitalopram, similarly to other SSRIs, inhibits CYP2D6 and hence may increase plasma levels of a number of CYP2D6 substrates such as aripiprazole, risperidone, tramadol, codeine, etc. As escitalopram is only a weak inhibitor of CYP2D6, analgesia from tramadol may not be affected. Escitalopram should be taken with caution when using St. John’s wort. Exposure to escitalopram is increased moderately, by about 50%, when it is taken with omeprazole. The authors of this study suggested that this increase is unlikely to be of clinical concern. Caution should be used when taking cough medicine containing dextromethorphan (DXM) as serotonin syndrome has been reported.

Bupropion has been found to significantly increase citalopram plasma concentration and systemic exposure; as of April 2018 the interaction with escitalopram had not been studied, but some monographs warned of the potential interaction.

Escitalopram can also prolong the QT interval and hence it is not recommended in patients that are concurrently on other medications that also have the ability to prolong the QT interval. These drugs include antiarrhythmics, antipsychotics, tricyclic antidepressants, some antihistamines (astemizole, mizolastine) and some antiretrovirals (ritonavir, saquinavir, lopinavir). As an SSRI, escitalopram should generally not be given concurrently with MAOIs.

Chemistry

Escitalopram is the (S)-stereoisomer (left-handed version) of the racemate citalopram, which is responsible for its name: escitalopram. The (R)-stereoisomer (R-citalopram, the right-handed version) is not thought to have useful effects for treating depression.

Society and Culture

Allegations of Illegal Marketing

In 2004, separate civil suits alleging illegal marketing of citalopram and escitalopram for use by children and teenagers by Forest were initiated by two whistleblowers: a physician named Joseph Piacentile and a Forest salesman named Christopher Gobble. In February 2009, the suits were joined. Eleven states and the District of Columbia filed notices of intent to intervene as plaintiffs in the action.

The suits alleged that Forest illegally engaged in off-label promotion of Lexapro for use in children; hid the results of a study showing lack of effectiveness in children; paid kickbacks to physicians to induce them to prescribe Lexapro to children; and conducted so-called “seeding studies” that were, in reality, marketing efforts to promote the drug’s use by doctors. Forest denied the allegations but ultimately agreed to settle with the plaintiffs for over $313 million.

Brand Names

Escitalopram is sold under many brand names worldwide such as Cipralex, Lexapro, Mozarin, Aciprex, Depralin, Ecytara, Elicea, Nexpram, Pramatis, and Betesda.

What is Fluoxetine?

Introduction

Fluoxetine, sold under the brand names Prozac and Sarafem among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorder (OCD), bulimia nervosa, panic disorder, and premenstrual dysphoric disorder. It is also approved for treatment of major depressive disorder in adolescents and children 8 years of age and over. It has also been used to treat premature ejaculation. Fluoxetine is taken by mouth.

Common side effects include indigestion, trouble sleeping, sexual dysfunction, loss of appetite, dry mouth, and rash. Serious side effects include serotonin syndrome, mania, seizures, an increased risk of suicidal behaviour in people under 25 years old, and an increased risk of bleeding. Discontinuation syndrome is less likely to occur with fluoxetine than with other antidepressants, but it still happens in many cases. Fluoxetine taken during pregnancy is associated with significant increase in congenital heart defects in the newborns. It has been suggested that fluoxetine therapy may be continued during breastfeeding if it was used during pregnancy or if other antidepressants were ineffective. Its mechanism of action is unknown, but some hypothesize that it is related to serotonin activity in the brain.

Fluoxetine was discovered by Eli Lilly and Company in 1972, and entered medical use in 1986. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2018, it was the 23rd most commonly prescribed medication in the United States, with more than 25 million prescriptions. Lilly also markets fluoxetine in a fixed-dose combination with olanzapine as olanzapine/fluoxetine (Symbyax).

Brief History

The work which eventually led to the discovery of fluoxetine began at Eli Lilly and Company in 1970 as a collaboration between Bryan Molloy and Robert Rathbun. It was known at that time that the antihistamine diphenhydramine shows some antidepressant-like properties. 3-Phenoxy-3-phenylpropylamine, a compound structurally similar to diphenhydramine, was taken as a starting point, and Molloy synthesized a series of dozens of its derivatives. Hoping to find a derivative inhibiting only serotonin reuptake, an Eli Lilly scientist, David T. Wong, proposed to retest the series for the in vitro reuptake of serotonin, norepinephrine and dopamine. This test, carried out by Jong-Sir Horng in May 1972, showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series. Wong published the first article about fluoxetine in 1974. A year later, it was given the official chemical name fluoxetine and the Eli Lilly and Company gave it the trade name Prozac. In February 1977, Dista Products Company, a division of Eli Lilly & Company, filed an Investigational New Drug application to the US Food and Drug Administration (FDA) for fluoxetine.

Fluoxetine appeared on the Belgian market in 1986. In the US, the FDA gave its final approval in December 1987, and a month later Eli Lilly began marketing Prozac; annual sales in the US reached $350 million within a year. Worldwide sales eventually reached a peak of $2.6 billion a year.

Lilly tried several product line extension strategies, including extended release formulations and paying for clinical trials to test the efficacy and safety of fluoxetine in premenstrual dysphoric disorder and rebranding fluoxetine for that indication as “Sarafem” after it was approved by the FDA in 2000, following the recommendation of an advisory committee in 1999. The invention of using fluoxetine to treat PMDD was made by Richard Wurtman at MIT; the patent was licensed to his startup, Interneuron, which in turn sold it to Lilly.

To defend its Prozac revenue from generic competition, Lilly also fought a five-year, multimillion-dollar battle in court with the generic company Barr Pharmaceuticals to protect its patents on fluoxetine, and lost the cases for its line-extension patents, other than those for Sarafem, opening fluoxetine to generic manufacturers starting in 2001. When Lilly’s patent expired in August 2001, generic drug competition decreased Lilly’s sales of fluoxetine by 70% within two months.

In 2000 an investment bank had projected that annual sales of Sarafem could reach $250M/year. Sales of Sarafem reached about $85M/year in 2002, and in that year Lilly sold its assets connected with the drug for $295M to Galen Holdings, a small Irish pharmaceutical company specializing in dermatology and women’s health that had a sales force tasked to gynaecologists’ offices; analysts found the deal sensible since the annual sales of Sarafem made a material financial difference to Galen, but not to Lilly.

Bringing Sarafem to market harmed Lilly’s reputation in some quarters. The diagnostic category of PMDD was controversial since it was first proposed in 1987, and Lilly’s role in retaining it in the appendix of the DSM-IV-TR, the discussions for which got under way in 1998, has been criticised. Lilly was criticised for inventing a disease in order to make money, and for not innovating but rather just seeking ways to continue making money from existing drugs. It was also criticised by the FDA and groups concerned with women’s health for marketing Sarafem too aggressively when it was first launched; the campaign included a television commercial featuring a harried woman at the grocery store who asks herself if she has PMDD.

Medical Uses

Fluoxetine is frequently used to treat major depressive disorder, OCD, post-traumatic stress disorder (PTSD), bulimia nervosa, panic disorder, premenstrual dysphoric disorder, and trichotillomania. It has also been used for cataplexy, obesity, and alcohol dependence, as well as binge eating disorder. Fluoxetine seems to be ineffective for social anxiety disorder. Studies do not support a benefit in children with autism, though there is but tentative evidence for its benefit in adult autism.

Depression

Efficacy of fluoxetine for acute and maintenance treatment of major depressive disorder in adults as well as children and adolescents (8 to 18 years) was established in multiple clinical trials. In addition to being effective for depression in 6-week long double-blind controlled trials, fluoxetine was better than placebo for the prevention of depression recurrence, when the patients, who originally responded to fluoxetine, were treated for a further 38 weeks. Efficacy of fluoxetine for geriatric as well as paediatric depression was also demonstrated in placebo-controlled trials.

Fluoxetine is as effective as tricyclic antidepressants but is better tolerated. It is less effective than sertraline, mirtazapine, and venlafaxine. According to a network analysis of clinical trials, fluoxetine may belong to the group of less effective antidepressants; however, its acceptability is higher than any other antidepressant, except agomelatine.

Obsessive-Compulsive Disorder

The efficacy of fluoxetine in the treatment of OCD was demonstrated in two randomised multicentre phase III clinical trials. The pooled results of these trials demonstrated that 47% of completers treated with the highest dose were “much improved” or “very much improved” after 13 weeks of treatment, compared to 11% in the placebo arm of the trial. The American Academy of Child and Adolescent Psychiatry state that SSRIs, including fluoxetine, should be used as first-line therapy in children, along with cognitive behavioural therapy (CBT), for the treatment of moderate to severe OCD.

Panic Disorder

The efficacy of fluoxetine in the treatment of panic disorder was demonstrated in two 12-week randomised multicentre phase III clinical trials that enrolled patients diagnosed with panic disorder, with or without agoraphobia. In the first trial, 42% of subjects in the fluoxetine-treated arm were free of panic attacks at the end of the study, vs. 28% in the placebo arm. In the second trial, 62% of fluoxetine treated patients were free of panic attacks at the end of the study, vs. 44% in the placebo arm.

Bulimia Nervosa

A 2011 systematic review discussed seven trials which compared fluoxetine to a placebo in the treatment of bulimia nervosa, six of which found a statistically significant reduction in symptoms such as vomiting and binge eating. However, no difference was observed between treatment arms when fluoxetine and psychotherapy were compared to psychotherapy alone.

Premenstrual Dysphoric Disorder

Fluoxetine is used to treat premenstrual dysphoric disorder, a condition where individuals have affective and somatic symptoms monthly during the luteal phase of menstruation. Taking fluoxetine 20 mg/d can be effective in treating PMDD, though doses of 10mg/d have also been prescribed effectively.

Impulsive Aggression

Fluoxetine is considered a first-line medication for the treatment of impulsive aggression of low intensity. Fluoxetine reduced low intensity aggressive behaviour in patients in intermittent aggressive disorder and borderline personality disorder. Fluoxetine also reduced acts of domestic violence in alcoholics with a history of such behaviour.

Special Populations

In children and adolescents, fluoxetine is the antidepressant of choice due to tentative evidence favouring its efficacy and tolerability. In pregnancy, fluoxetine is considered a category C drug by the US Food and Drug Administration (FDA). Evidence supporting an increased risk of major foetal malformations resulting from fluoxetine exposure is limited, although the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK has warned prescribers and patients of the potential for fluoxetine exposure in the first trimester (during organogenesis, formation of the foetal organs) to cause a slight increase in the risk of congenital cardiac malformations in the newborn. Furthermore, an association between fluoxetine use during the first trimester and an increased risk of minor foetal malformations was observed in one study.

However, a systematic review and meta-analysis of 21 studies – published in the Journal of Obstetrics and Gynaecology Canada – concluded:

“the apparent increased risk of fetal cardiac malformations associated with maternal use of fluoxetine has recently been shown also in depressed women who deferred SSRI therapy in pregnancy, and therefore most probably reflects an ascertainment bias. Overall, women who are treated with fluoxetine during the first trimester of pregnancy do not appear to have an increased risk of major fetal malformations.”

Per the FDA, infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn. Limited data support this risk, but the FDA recommends physicians consider tapering SSRIs such as fluoxetine during the third trimester. A 2009 review recommended against fluoxetine as a first-line SSRI during lactation, stating, “Fluoxetine should be viewed as a less-preferred SSRI for breastfeeding mothers, particularly with newborn infants, and in those mothers who consumed fluoxetine during gestation.” Sertraline is often the preferred SSRI during pregnancy due to the relatively minimal foetal exposure observed and its safety profile while breastfeeding.

Adverse Effects

Side effects observed in fluoxetine-treated persons in clinical trials with an incidence >5% and at least twice as common in fluoxetine-treated persons compared to those who received a placebo pill include abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhoea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, decreased libido, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilation, and yawning. Fluoxetine is considered the most stimulating of the SSRIs (that is, it is most prone to causing insomnia and agitation). It also appears to be the most prone of the SSRIs for producing dermatologic reactions (e.g. urticaria (hives), rash, itchiness, etc.).

Sexual Dysfunction

Sexual dysfunction, including loss of libido, anorgasmia, lack of vaginal lubrication, and erectile dysfunction, are some of the most commonly encountered adverse effects of treatment with fluoxetine 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 >70%. On the 11th of June 2019 the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency concluded that there is a possible causal association between SSRI use and long-lasting sexual dysfunction that persists despite discontinuation of SSRI, including fluoxetine, and that the labels of these drugs should be updated to include a warning.

Discontinuation Syndrome

Fluoxetine’s longer half-life makes it less common to develop discontinuation syndrome following cessation of therapy, especially when compared to antidepressants with shorter half-lives such as paroxetine. Although gradual dose reductions are recommended with antidepressants with shorter half-lives, tapering may not be necessary with fluoxetine.

Pregnancy

Antidepressant exposure (including fluoxetine) is associated with shorter average duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). There is 30-36% increase in congenital heart defects among children whose mothers were prescribed fluoxetine during pregnancy, with fluoxetine use in the first trimester associated with 38-65% increase in septal heart defects.

Suicide

In 2007 the FDA required all antidepressants to carry a black box warning stating that antidepressants increase the risk of suicide in people younger than 25. This warning is based on statistical analyses conducted by two independent groups of FDA experts that found a 2-fold increase of the suicidal ideation and behaviour in children and adolescents, and 1.5-fold increase of suicidality in the 18-24 age group. The suicidality was slightly decreased for those older than 24, and statistically significantly lower in the 65 and older group. This analysis was criticized by Donald Klein, who noted that suicidality, that is suicidal ideation and behaviour, is not necessarily a good surrogate marker for completed suicide, and it is still possible, while unproven, that antidepressants may prevent actual suicide while increasing suicidality.

There is less data on fluoxetine than on antidepressants as a whole. For the above analysis on the antidepressant level, the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications to obtain statistically significant results. Considered separately, fluoxetine use in children increased the odds of suicidality by 50%, and in adults decreased the odds of suicidality by approximately 30%. Similarly, the analysis conducted by the UK MHRA found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the children and adolescents on fluoxetine as compared to the ones on placebo. According to the MHRA data, for adults fluoxetine did not change the rate of self-harm and statistically significantly decreased suicidal ideation by 50%.

QT Prolongation

Fluoxetine can affect the electrical currents that heart muscle cells use to coordinate their contraction, specifically the potassium currents Ito and IKs that repolarise the cardiac action potential. Under certain circumstances, this can lead to prolongation of the QT interval, a measurement made on an electrocardiogram reflecting how long it takes for the heart to electrically recharge after each heartbeat. When fluoxetine is taken alongside other drugs that prolong the QT interval, or by those with a susceptibility to long QT syndrome, there is a small risk of potentially lethal abnormal heart rhythms such as Torsades de Pointes. As of 2019, the drug reference site CredibleMeds lists Fluoxetine as leading to a conditional risk of arrhythmias.

Overdose

In overdose, most frequent adverse effects include:

  • Nervous system effects:
    • Anxiety.
    • Nervousness.
    • Insomnia.
    • Drowsiness.
    • Fatigue or asthenia.
    • Tremor.
    • Dizziness or lightheadedness.
  • Gastrointestinal effects:
    • Anorexia (symptom).
    • Nausea.
    • Diarrhoea.
    • Vasodilation.
    • Dry mouth.
    • Abnormal vision.
  • Other effects:
    • Abnormal ejaculation.
    • Rash.
    • Sweating.
    • Decreased libido.

Interactions

Contraindications include prior treatment (within the past 5-6 weeks, depending on the dose) with MAOIs such as phenelzine and tranylcypromine, due to the potential for serotonin syndrome. Its use should also be avoided in those with known hypersensitivities to fluoxetine or any of the other ingredients in the formulation used. Its use in those concurrently receiving pimozide or thioridazine is also advised against.

In some cases, use of dextromethorphan-containing cold and cough medications with fluoxetine is advised against, due to fluoxetine increasing serotonin levels, as well as the fact that fluoxetine is a cytochrome P450 2D6 inhibitor, which causes dextromethorphan to not be metabolized at a normal rate, thus increasing the risk of serotonin syndrome and other potential side effects of dextromethorphan.

Patients who are taking anticoagulants or NSAIDS must be careful when taking fluoxetine or other SSRIs, as they can sometimes increase the blood-thinning effects of these medications.

Fluoxetine and norfluoxetine inhibit many isozymes of the cytochrome P450 system that are involved in drug metabolism. Both are potent inhibitors of CYP2D6 (which is also the chief enzyme responsible for their metabolism) and CYP2C19, and mild to moderate inhibitors of CYP2B6 and CYP2C9. In vivo, fluoxetine and norfluoxetine do not significantly affect the activity of CYP1A2 and CYP3A4. They also inhibit the activity of P-glycoprotein, a type of membrane transport protein that plays an important role in drug transport and metabolism and hence P-glycoprotein substrates such as loperamide may have their central effects potentiated. This extensive effect on the body’s pathways for drug metabolism creates the potential for interactions with many commonly used drugs.

Its use should also be avoided in those receiving other serotonergic drugs such as monoamine oxidase inhibitors, tricyclic antidepressants, methamphetamine, amphetamine, MDMA, triptans, buspirone, serotonin–norepinephrine reuptake inhibitors and other SSRIs due to the potential for serotonin syndrome to develop as a result.

There is also the potential for interaction with highly protein-bound drugs due to the potential for fluoxetine to displace said drugs from the plasma or vice versa hence increasing serum concentrations of either fluoxetine or the offending agent.

Pharmacology

Pharmacodynamics

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and does not appreciably inhibit norepinephrine and dopamine reuptake at therapeutic doses. It does, however, delay the reuptake of serotonin, resulting in serotonin persisting longer when it is released. Large doses in rats have been shown to induce a significant increase in synaptic norepinephrine and dopamine. Thus, dopamine and norepinephrine may contribute to the antidepressant action of fluoxetine in humans at supratherapeutic doses (60-80 mg). This effect may be mediated by 5HT2C receptors, which are inhibited by higher concentrations of fluoxetine.

Fluoxetine increases the concentration of circulating allopregnanolone, a potent GABAA receptor positive allosteric modulator, in the brain. Norfluoxetine, a primary active metabolite of fluoxetine, produces a similar effect on allopregnanolone levels in the brains of mice. Additionally, both fluoxetine and norfluoxetine are such modulators themselves, actions which may be clinically-relevant.

In addition, fluoxetine has been found to act as an agonist of the σ1-receptor, with a potency greater than that of citalopram but less than that of fluvoxamine. However, the significance of this property is not fully clear. Fluoxetine also functions as a channel blocker of anoctamin 1, a calcium-activated chloride channel. A number of other ion channels, including nicotinic acetylcholine receptors and 5-HT3 receptors, are also known to be inhibited at similar concentrations.

Fluoxetine has been shown to inhibit acid sphingomyelinase, a key regulator of ceramide levels which derives ceramide from sphingomyelin.

Mechanism of Action

Fluoxetine elicits antidepressant effect by inhibiting serotonin re-uptake in the synapse by binding to the re-uptake pump on the neuronal membrane to increase serotonin availability and enhance neurotransmission. Norfluoxetine and desmethylfluoxetine are metabolites of fluoxetine and also act as serotonin re-uptake inhibitors, increasing the duration of action of the drug.

Pharmacokinetics

The bioavailability of fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6-8 hours. It is highly bound to plasma proteins, mostly albumin and α1-glycoprotein. Fluoxetine is metabolised in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6. The role of CYP2D6 in the metabolism of fluoxetine may be clinically important, as there is great genetic variability in the function of this enzyme among people. CYP2D6 is responsible for converting fluoxetine to its only active metabolite, norfluoxetine. Both drugs are also potent inhibitors of CYP2D6.

The extremely slow elimination of fluoxetine and its active metabolite norfluoxetine from the body distinguishes it from other antidepressants. With time, fluoxetine and norfluoxetine inhibit their own metabolism, so fluoxetine elimination half-life increases from 1 to 3 days, after a single dose, to 4 to 6 days, after long-term use. Similarly, the half-life of norfluoxetine is longer (16 days) after long-term use. Therefore, the concentration of the drug and its active metabolite in the blood continues to grow through the first few weeks of treatment, and their steady concentration in the blood is achieved only after four weeks. Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment. The full benefit of the current dose a patient receives is not realised for at least a month following ingestion. For example, in one 6-week study, the median time to achieving consistent response was 29 days. Likewise, complete excretion of the drug may take several weeks. During the first week after treatment discontinuation, the brain concentration of fluoxetine decreases by only 50%, The blood level of norfluoxetine four weeks after treatment discontinuation is about 80% of the level registered by the end of the first treatment week, and, seven weeks after discontinuation, norfluoxetine is still detectable in the blood.

Measurement in Body Fluids

Fluoxetine and norfluoxetine may be quantitated in blood, plasma or serum to monitor therapy, confirm a diagnosis of poisoning in a hospitalised person or assist in a medicolegal death investigation. Blood or plasma fluoxetine concentrations are usually in a range of 50-500 μg/L in persons taking the drug for its antidepressant effects, 900-3000 μg/L in survivors of acute overdosage and 1000-7000 μg/L in victims of fatal overdosage. Norfluoxetine concentrations are approximately equal to those of the parent drug during chronic therapy, but may be substantially less following acute overdosage, since it requires at least 1-2 weeks for the metabolite to achieve equilibrium.

Usage

In 2010, over 24.4 million prescriptions for generic fluoxetine were filled in the United States, making it the third-most prescribed antidepressant after sertraline and citalopram. In 2011, 6 million prescriptions for fluoxetine were filled in the United Kingdom.

Society and Culture

American Airline Pilots

Beginning 05 April 2010, fluoxetine became one of four antidepressant drugs that the US Federal Aviation Authority (FAA) permitted for pilots with authorisation from an aviation medical examiner. The other permitted antidepressants are sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro). These four remain the only antidepressants permitted by FAA as of 02 December 2016.

Sertraline, citalopram and escitalopram are the only antidepressants permitted for EASA medical certification, as of January 2019.

Environmental Effects

Fluoxetine has been detected in aquatic ecosystems, especially in North America. There is a growing body of research addressing the effects of fluoxetine (among other SSRIs) exposure on non-target aquatic species.

In 2003, one of the first studies addressed in detail the potential effects of fluoxetine on aquatic wildlife; this research concluded that exposure at environmental concentrations was of little risk to aquatic systems if a hazard quotient approach was applied to risk assessment. However, they also stated the need for further research addressing sub-lethal consequences of fluoxetine, specifically focusing on study species’ sensitivity, behavioural responses, and endpoints modulated by the serotonin system.

Since 2003, a number of studies have reported fluoxetine-induced impacts on a number of behavioural and physiological endpoints, inducing antipredator behaviour, reproduction, and foraging at or below field-detected concentrations. However, a 2014 review on the ecotoxicology of fluoxetine concluded that, at that time, a consensus on the ability of environmentally realistic dosages to affect the behaviour of wildlife could not be reached.

Politics

During the 1990 campaign for Governor of Florida, it was disclosed that one of the candidates, Lawton Chiles, had depression and had resumed taking fluoxetine, leading his political opponents to question his fitness to serve as Governor.

What is Dysthymia?

Introduction

Dysthymia, also known as persistent depressive disorder (PDD), is a mental and behavioural disorder, specifically a disorder primarily of mood, consisting of the same cognitive and physical problems as depression, but with longer-lasting symptoms.

The concept was coined by Robert Spitzer as a replacement for the term “depressive personality” in the late 1970s.

In the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), dysthymia is a serious state of chronic depression, which persists for at least two years (one year for children and adolescents). Dysthymia is less acute than major depressive disorder, but not necessarily less severe.

As dysthymia is a chronic disorder, sufferers may experience symptoms for many years before it is diagnosed, if diagnosis occurs at all. As a result, they may believe that depression is a part of their character, so they may not even discuss their symptoms with doctors, family members or friends. In the DSM-5, dysthymia is replaced by persistent depressive disorder. This new condition includes both chronic major depressive disorder and the previous dysthymic disorder. The reason for this change is that there was no evidence for meaningful differences between these two conditions.

Epidemiology

Globally dysthymia occurs in about 105 million people a year (1.5% of the population). It is 38% more common in women (1.8% of women) than in men (1.3% of men). The lifetime prevalence rate of dysthymia in community settings appears to range from 3 to 6% in the United States. However, in primary care settings the rate is higher ranging from 5 to 15 percent. United States prevalence rates tend to be somewhat higher than rates in other countries.

Signs and Symptoms

Dysthymia characteristics include an extended period of depressed mood combined with at least two other symptoms which may include insomnia or hypersomnia, fatigue or low energy, eating changes (more or less), low self-esteem, or feelings of hopelessness. Poor concentration or difficulty making decisions are treated as another possible symptom. Irritability is one of the more common symptoms in children and adolescents.

Mild degrees of dysthymia may result in people withdrawing from stress and avoiding opportunities for failure. In more severe cases of dysthymia, people may withdraw from daily activities. They will usually find little pleasure in usual activities and pastimes.

Diagnosis of dysthymia can be difficult because of the subtle nature of the symptoms and patients can often hide them in social situations, making it challenging for others to detect symptoms. Additionally, dysthymia often occurs at the same time as other psychological disorders, which adds a level of complexity in determining the presence of dysthymia, particularly because there is often an overlap in the symptoms of disorders.

There is a high incidence of comorbid illness in those with dysthymia. Suicidal behaviour is also a particular problem with those with dysthymia. It is vital to look for signs of major depression, panic disorder, generalised anxiety disorder, alcohol and substance use disorders, and personality disorder.

Causes

There are no known biological causes that apply consistently to all cases of dysthymia, which suggests diverse origin of the disorder. However, there are some indications that there is a genetic predisposition to dysthymia: “The rate of depression in the families of people with dysthymia is as high as fifty percent for the early-onset form of the disorder”. Other factors linked with dysthymia include stress, social isolation, and lack of social support.

In a study using identical and fraternal twins, results indicated that there is a stronger likelihood of identical twins both having depression than fraternal twins. This provides support for the idea that dysthymia is in part caused by heredity.

Co-Occurring Conditions

Dysthymia often co-occurs with other mental disorders. A “double depression” is the occurrence of episodes of major depression in addition to dysthymia. Switching between periods of dysthymic moods and periods of hypomanic moods is indicative of cyclothymia, which is a mild variant of bipolar disorder.

“At least three-quarters of patients with dysthymia also have a chronic physical illness or another psychiatric disorder such as one of the anxiety disorders, cyclothymia, drug addiction, or alcoholism”. Common co-occurring conditions include major depression (up to 75%), anxiety disorders (up to 50%), personality disorders (up to 40%), somatoform disorders (up to 45%) and substance use disorders (up to 50%). People with dysthymia have a higher-than-average chance of developing major depression. A 10-year follow-up study found that 95% of dysthymia patients had an episode of major depression. When an intense episode of depression occurs on top of dysthymia, the state is called “double depression.”

Double Depression

Double depression occurs when a person experiences a major depressive episode on top of the already-existing condition of dysthymia. It is difficult to treat, as sufferers accept these major depressive symptoms as a natural part of their personality or as a part of their life that is outside of their control. The fact that people with dysthymia may accept these worsening symptoms as inevitable can delay treatment. When and if such people seek out treatment, the treatment may not be very effective if only the symptoms of the major depression are addressed, but not the dysthymic symptoms. Patients with double depression tend to report significantly higher levels of hopelessness than is normal. This can be a useful symptom for mental health services providers to focus on when working with patients to treat the condition. Additionally, cognitive therapies can be effective for working with people with double depression in order to help change negative thinking patterns and give individuals a new way of seeing themselves and their environment.

It has been suggested that the best way to prevent double depression is by treating the dysthymia. A combination of antidepressants and cognitive therapies can be helpful in preventing major depressive symptoms from occurring. Additionally, exercise and good sleep hygiene (e.g. improving sleep patterns) are thought to have an additive effect on treating dysthymic symptoms and preventing them from worsening.

Pathophysiology

There is evidence that there may be neurological indicators of early onset dysthymia. There are several brain structures (corpus callosum and frontal lobe) that are different in women with dysthymia than in those without dysthymia. This may indicate that there is a developmental difference between these two groups.

Another study, which used fMRI techniques to assess the differences between individuals with dysthymia and other people, found additional support for neurological indicators of the disorder. This study found several areas of the brain that function differently. The amygdala (associated with processing emotions such as fear) was more activated in dysthymia patients. The study also observed increased activity in the insula (which is associated with sad emotions). Finally, there was increased activity in the cingulate gyrus (which serves as the bridge between attention and emotion).

A study comparing healthy individuals to people with dysthymia indicates there are other biological indicators of the disorder. An anticipated result appeared as healthy individuals expected fewer negative adjectives to apply to them, whereas people with dysthymia expected fewer positive adjectives to apply to them in the future. Biologically these groups are also differentiated in that healthy individuals showed greater neurological anticipation for all types of events (positive, neutral, or negative) than those with dysthymia. This provides neurological evidence of the dulling of emotion that individuals with dysthymia have learned to use to protect themselves from overly strong negative feelings, compared to healthy people.

There is some evidence of a genetic basis for all types of depression, including dysthymia. A study using identical and fraternal twins indicated that there is a stronger likelihood of identical twins both having depression than fraternal twins. This provides support for the idea that dysthymia is caused in part by heredity.

A new model has recently surfaced in the literature regarding the HPA axis (structures in the brain that get activated in response to stress) and its involvement with dysthymia (e.g. phenotypic variations of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP), and down-regulation of adrenal functioning) as well as forebrain serotonergic mechanisms. Since this model is highly provisional, further research is still needed.

Diagnosis

The Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV), published by the American Psychiatric Association, characterises dysthymic disorder. The essential symptom involves the individual feeling depressed for the majority of days, and parts of the day, for at least two years. Low energy, disturbances in sleep or in appetite, and low self-esteem typically contribute to the clinical picture as well. Sufferers have often experienced dysthymia for many years before it is diagnosed. People around them often describe the sufferer in words similar to “just a moody person”. Note the following diagnostic criteria:

  1. During a majority of days for two years or more, the adult patient reports depressed mood, or appears depressed to others for most of the day.
  2. When depressed, the patient has two or more of:
    1. decreased or increased appetite
    2. decreased or increased sleep (insomnia or hypersomnia)
    3. Fatigue or low energy
    4. Reduced self-esteem
    5. Decreased concentration or problems making decisions
    6. Feelings of hopelessness or pessimism
  3. During this two-year period, the above symptoms are never absent longer than two consecutive months.
  4. During the duration of the two-year period, the patient may have had a perpetual major depressive episode.
  5. The patient has not had any manic, hypomanic, or mixed episodes.
  6. The patient has never fulfilled criteria for cyclothymic disorder.
  7. The depression does not exist only as part of a chronic psychosis (such as schizophrenia or delusional disorder).
  8. The symptoms are often not directly caused by a medical illness or by substances, including substance use or other medications.
  9. The symptoms may cause significant problems or distress in social, work, academic, or other major areas of life functioning.

In children and adolescents, mood can be irritable, and duration must be at least one year, in contrast to two years needed for diagnosis in adults.

Early onset (diagnosis before age 21) is associated with more frequent relapses, psychiatric hospitalisations, and more co-occurring conditions. For younger adults with dysthymia, there is a higher co-occurrence in personality abnormalities and the symptoms are likely chronic. However, in older adults suffering from dysthymia, the psychological symptoms are associated with medical conditions and/or stressful life events and losses.

Dysthymia can be contrasted with major depressive disorder by assessing the acute nature of the symptoms. Dysthymia is far more chronic (long lasting) than major depressive disorder, in which symptoms may be present for as little as 2 weeks. Also Dysthymia often presents itself at an earlier age than Major Depressive Disorder.

Prevention

Though there is no clear-cut way to prevent dysthymia from occurring, some suggestions have been made. Since dysthymia will often first occur in childhood, it is important to identify children who may be at risk. It may be beneficial to work with children in helping to control their stress, increase resilience, boost self-esteem, and provide strong networks of social support. These tactics may be helpful in warding off or delaying dysthymic symptoms.

Treatment

Persistent depressive disorder can be treated with psychotherapy and pharmacotherapy. The overall rate and degree of treatment success is somewhat lower than for non-chronic depression, and a combination of psychotherapy and pharmacotherapy shows best results.

Therapy

Psychotherapy can be effective in treating dysthymia. In a meta-analytic study from 2010, psychotherapy had a small but significant effect when compared to control groups. However, psychotherapy is significantly less effective than pharmacotherapy in direct comparisons.

There are many different types of therapy, and some are more effective than others.

  • The empirically most studied type of treatment is cognitive-behavioural therapy.
    • This type of therapy is very effective for non-chronic depression, and it appears to be also effective for chronic depression.
  • Cognitive behavioural analysis system of psychotherapy (CBASP) has been designed specifically to treat PDD.
    • Empirical results on this form of therapy are inconclusive: While one study showed remarkably high treatment success rates, a later, even larger study showed no significant benefit of adding CBASP to treatment with antidepressants.
  • Schema therapy and psychodynamic psychotherapy have been used for PDD, though good empirical results are lacking.
  • Interpersonal psychotherapy has also been said to be effective in treating the disorder, though it only shows marginal benefit when added to treatment with antidepressants.

Medications

In a 2010 meta-analysis, the benefit of pharmacotherapy was limited to selective serotonin reuptake inhibitors (SSRIs) rather than tricyclic antidepressants (TCA).

According to a 2014 meta-analysis, antidepressants are at least as effective for persistent depressive disorder as for major depressive disorder. The first line of pharmacotherapy is usually SSRIs due to their purported more tolerable nature and reduced side effects compared to the irreversible monoamine oxidase inhibitors or tricyclic antidepressants. Studies have found that the mean response to antidepressant medications for people with dysthymia is 55%, compared with a 31% response rate to a placebo. The most commonly prescribed antidepressants/SSRIs for dysthymia are escitalopram, citalopram, sertraline, fluoxetine, paroxetine, and fluvoxamine. It often takes an average of 6-8 weeks before the patient begins to feel these medications’ therapeutic effects. Additionally, STAR*D, a multi-clinic governmental study, found that people with overall depression will generally need to try different brands of medication before finding one that works specifically for them. Research shows that 1 in 4 of those who switch medications get better results regardless of whether the second medication is an SSRI or some other type of antidepressant.

In a meta-analytic study from 2005, it was found that SSRIs and TCAs are equally effective in treating dysthymia. They also found that MAOIs have a slight advantage over the use of other medication in treating this disorder. However, the author of this study cautions that MAOIs should not necessarily be the first line of defence in the treatment of dysthymia, as they are often less tolerable than their counterparts, such as SSRIs.

Tentative evidence supports the use of amisulpride to treat dysthymia but with increased side effects.

Combination Treatment

When pharmacotherapy alone is compared with combined treatment with pharmacotherapy plus psychotherapy, there is a strong trend in favour of combined treatment. Working with a psychotherapist to address the causes and effects of the disorder, in addition to taking antidepressants to help eliminate the symptoms, can be extremely beneficial. This combination is often the preferred method of treatment for those who have dysthymia. Looking at various studies involving treatment for dysthymia, 75% of people responded positively to a combination of cognitive behavioural therapy and pharmacotherapy, whereas only 48% of people responded positively to just CBT or medication alone.

A 2019 Cochrane review of 10 studies involving 840 participants could not conclude with certainty that continued pharmacotherapy with antidepressants (those used in the studies) was effective in preventing relapse or recurrence of persistent depressive disorder. The body of evidence was too small for any greater certainty although the study acknowledges that continued psychotherapy may be beneficial when compared to no treatment.

Resistance

Because of dysthymia’s chronic nature, treatment resistance is somewhat common. In such a case, augmentation is often recommended. Such treatment augmentations can include lithium pharmacology, thyroid hormone augmentation, amisulpride, buspirone, bupropion, stimulants, and mirtazapine. Additionally, if the person also suffers from seasonal affective disorder, light therapy can be useful in helping augment therapeutic effects.