What is Tranylcypromine?

Introduction

Tranylcypromine (sold under the trade name Parnate among others) is a monoamine oxidase inhibitor (MAOI); more specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO).

It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.

Tranylcypromine is a propylamine formed from the cyclisation of amphetamine’s side chain; therefore, it is classified as a substituted amphetamine.

Brief History

Tranylcypromine was originally developed as an analogue of amphetamine. Although it was first synthesized in 1948, its MAOI action was not discovered until 1959. Precisely because tranylcypromine was not, like isoniazid and iproniazid, a hydrazine derivative, its clinical interest increased enormously, as it was thought it might have a more acceptable therapeutic index than previous MAOIs.

The drug was introduced by Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961. It was withdrawn from the market in February 1964 due to a number of patient deaths involving hypertensive crises with intracranial bleeding. However, it was reintroduced later that year with more limited indications and specific warnings of the risks.

Medical Uses

Tranylcypromine is used to treat major depressive disorder, including atypical depression, especially when there is an anxiety component, typically as a second-line treatment. It is also used in depression that is not responsive to reuptake inhibitor antidepressants, such as the SSRIs, TCAs, or bupropion.

Contraindications

Contraindications include:

  • Porphyria.
  • Cardiovascular or cerebrovascular disease.
  • Pheochromocytoma.
  • Tyramine, found in several foods, is metabolized by MAO. Ingestion and absorption of tyramine causes extensive release of norepinephrine, which can rapidly increase blood pressure to the point of causing hypertensive crisis.
  • Concomitant use of serotonin-enhancing drugs, including SSRIs, serotonergic TCAs, dextromethorphan, and meperidine may cause serotonin syndrome.
  • Concomitant use of MRAs, including fenfluramine, amphetamine, and pseudoephedrine may cause toxicity via serotonin syndrome or hypertensive crisis.
  • L-DOPA given without carbidopa may cause hypertensive crisis.

Dietary Restrictions

Tyramine is a common component in many foods, and is normally rapidly metabolised by MAO-A. Individuals not taking MAOIs may consume at least 2 grams of tyramine in a meal and not experience an increase in blood pressure, whereas those taking MAOIs such as tranylcypromine may experience a sharp increase in blood pressure following consumption of as little as 10 mg of tyramine, which can lead to hypertensive crisis.

Foods containing tyramine include aged cheeses, cured meats, tofu and certain red wines. Some, such as yeast extracts, contain enough tyramine to be potentially fatal in a single serving. Spoiled food is also likely to contain dangerous levels of tyramine.

Adverse Effects

Incidence of Adverse Effects

  • Very common (>10% incidence) adverse effects include:
    • Dizziness secondary to orthostatic hypotension (17%).
  • Common (1-10% incidence) adverse effects include:
    • Tachycardia (5-10%).
    • Hypomania (7%).
    • Paresthesia (5%).
    • Weight loss (2%).
    • Confusion (2%).
    • Dry mouth (2%).
    • Sexual function disorders (2%).
    • Hypertension (1-2 hours after ingestion) (2%).
    • Rash (2%).
    • Urinary retention (2%).
  • Other (unknown incidence) adverse effects include:
    • Increased/decreased appetite.
    • Blood dyscrasias.
    • Chest pain.
    • Diarrhoea.
    • Oedema.
    • Hallucinations.
    • Hyperreflexia.
    • Insomnia.
    • Jaundice.
    • Leg cramps.
    • Myalgia.
    • Palpitations.
    • Sensation of cold.
    • Suicidal ideation.
    • Tremor.

Of note, there has not been found to be a correlation between sex and age below 65 regarding incidence of adverse effects.

Tranylcypromine is not associated with weight gain and has a low risk for hepatotoxicity compared to the hydrazine MAOIs.

It is generally recommended that MAOIs be discontinued prior to anaesthesia; however, this creates a risk of recurrent depression. In a retrospective observational cohort study, patients on tranylcypromine undergoing general anaesthesia had a lower incidence of intraoperative hypotension, while there was no difference between patients not taking an MAOI regarding intraoperative incidence of bradycardia, tachycardia, or hypertension. The use of indirect sympathomimetic drugs or drugs affecting serotonin reuptake, such as meperidine or dextromethorphan poses a risk for hypertension and serotonin syndrome respectively; alternative agents are recommended. Other studies have come to similar conclusions. Pharmacokinetic interactions with anaesthetics are unlikely, given that tranylcypromine is a high-affinity substrate for CYP2A6 and does not inhibit CYP enzymes at therapeutic concentrations.

Tranylcypromine abuse has been reported at doses ranging from 120-600 mg per day. It is thought that higher doses have more amphetamine-like effects and abuse is promoted by the fast onset and short half-life of tranylcypromine.

Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation.

Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects.

Interactions

In addition to contraindicated concomitant medications, tranylcypromine inhibits CYP2A6, which may reduce the metabolism and increase the toxicity of substrates of this enzyme, such as:

  • Dexmedetomidine.
  • Nicotine.
  • TSNAs (found in cured tobacco products, including cigarettes).
  • Valproate.

Norepinephrine reuptake inhibitors prevent neuronal uptake of tyramine and may reduce its pressor effects.

Pharmacology

Pharmacodynamics

Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase. Regarding the isoforms of monoamine oxidase, it shows slight preference for the MAOB isoenzyme over MAOA. This leads to an increase in the availability of monoamines, such as serotonin, norepinephrine, and dopamine, as well as a marked increase in the availability of trace amines, such as tryptamine, octopamine, and phenethylamine. The clinical relevance of increased trace amine availability is unclear.

It may also act as a norepinephrine reuptake inhibitor at higher therapeutic doses. Compared to amphetamine, tranylcypromine shows low potency as a dopamine releasing agent, with even weaker potency for norepinephrine and serotonin release.

Tranylcypromine has also been shown to inhibit the histone demethylase, BHC110/LSD1. Tranylcypromine inhibits this enzyme with an IC50 < 2 μM, thus acting as a small molecule inhibitor of histone demethylation with an effect to de-repress the transcriptional activity of BHC110/LSD1 target genes. The clinical relevance of this effect is unknown.

Tranylcypromine has been found to inhibit CYP46A1 at nanomolar concentrations. The clinical relevance of this effect is unknown.

Pharmacokinetics

Tranylcypromine reaches its maximum concentration (tmax) within 1-2 hours. After a 20 mg dose, plasma concentrations reach at most 50-200 ng/mL. While its half-life is only about 2 hours, its pharmacodynamic effects last several days to weeks due to irreversible inhibition of MAO.

Metabolites of tranylcypromine include 4-hydroxytranylcypromine, N-acetyltranylcypromine, and N-acetyl-4-hydroxytranylcypromine, which are less potent MAO inhibitors than tranylcypromine itself. Amphetamine was once thought to be a metabolite of tranylcypromine, but has not been shown to be.

Tranylcypromine inhibits CYP2A6 at therapeutic concentrations.

Research

Tranylcypromine is known to inhibit LSD1, an enzyme that selectively demethylates two lysines found on histone H3. Genes promoted downstream of LSD1 are involved in cancer cell growth and metastasis, and several tumour cells express high levels of LSD1. Tranylcypromine analogues with more potent and selective LSD1 inhibitory activity are being researched in the potential treatment of cancers.

Tranylcypromine may have neuroprotective properties applicable to the treatment of Parkinson’s disease, similar to the MAO-B inhibitors selegiline and rasagiline. As of 2017, only one clinical trial in Parkinsonian patients has been conducted, which found some improvement initially and only slight worsening of symptoms after a 1.5 year follow-up.

What is an Atypical Antipsychotic?

Introduction

The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin-dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilisers and neuroleptics, although the latter is usually reserved for the typical antipsychotics) largely introduced after the 1970s and used to treat psychiatric conditions.

Some atypical antipsychotics have received regulatory approval (e.g. by the Food and Drug Administration (FDA) of the US, the Therapeutic Goods Administration (TGA) of Australia, the Medical and Healthcare Products Regulatory Agency (MHRA) of the UK) for schizophrenia, bipolar disorder, autism, and as an adjunct in major depressive disorder.

Both generations of medication tend to block receptors in the brain’s dopamine pathways. Atypicals are less likely than haloperidol – the most widely used typical antipsychotic – to cause extrapyramidal motor control disabilities in patients such as unsteady Parkinson’s disease-type movements, body rigidity, and involuntary tremors. However, only a few of the atypicals have been demonstrated to be superior to lesser-used, low-potency first-generation antipsychotics in this regard.

As experience with these agents has grown, several studies have questioned the utility of broadly characterising antipsychotic drugs as “atypical/second generation” as opposed to “first generation,” noting that each agent has its own efficacy and side-effect profile. It has been argued that a more nuanced view in which the needs of individual patients are matched to the properties of individual drugs is more appropriate. Although atypical antipsychotics are thought to be safer than typical antipsychotics, they still have severe side effects, including tardive dyskinesia (a serious movement disorder), neuroleptic malignant syndrome, and increased risk of stroke, sudden cardiac death, blood clots, and diabetes. Significant weight gain may occur. Critics have argued that “the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction.”

Brief History

The first major tranquiliser or antipsychotic medication, chlorpromazine (Thorazine), a typical antipsychotic, was discovered in 1951 and introduced into clinical practice shortly thereafter. Clozapine (Clozaril), an atypical antipsychotic, fell out of favour due to concerns over drug-induced agranulocytosis. Following research indicating its effectiveness in treatment-resistant schizophrenia and the development of an adverse event monitoring system, clozapine re-emerged as a viable antipsychotic. According to Barker (2003), the three most-accepted atypical drugs are clozapine, risperidone, and olanzapine. However, he goes on to explain that clozapine is usually the last resort when other drugs fail. Clozapine can cause agranulocytosis (a decreased number of white blood cells), requiring blood monitoring for the patient. Despite the effectiveness of clozapine for treatment-resistant schizophrenia, agents with a more favourable side-effect profile were sought-after for widespread use. During the 1990s, olanzapine, risperidone, and quetiapine were introduced, with ziprasidone and aripiprazole following in the early 2000s. The atypical anti-psychotic paliperidone was approved by the FDA in late 2006.

The atypical antipsychotics have found favour among clinicians and are now considered to be first-line treatments for schizophrenia and are gradually replacing the typical antipsychotics. In the past, most researchers have agreed that the defining characteristics of atypical antipsychotics are the decreased incidence of extrapyramidal side effects (EPS) and an absence of sustained prolactin elevation.

The terminology can still be imprecise. The definition of “atypicality” was based upon the absence of extrapyramidal side effects, but there is now a clear understanding that atypical antipsychotics can still induce these effects (though to a lesser degree than typical antipsychotics). Recent literature focuses more upon specific pharmacological actions and less upon categorization of an agent as “typical” or “atypical”. There is no clear dividing line between the typical and atypical antipsychotics therefore categorisation based on the action is difficult.

More recent research is questioning the notion that second-generation antipsychotics are superior to first generation typical anti-psychotics. Using a number of parameters to assess quality of life, Manchester University researchers found that typical antipsychotics were no worse than atypical antipsychotics. The research was funded by the National Health Service (NHS) of the UK. Because each medication (whether first or second generation) has its own profile of desirable and adverse effects, a neuropsychopharmacologist may recommend one of the older (“typical” or first generation) or newer (“atypical” or second generation) antipsychotics alone or in combination with other medications, based on the symptom profile, response pattern, and adverse effects history of the individual patient.

Medical Uses

Atypical antipsychotics are typically used to treat schizophrenia or bipolar disorder. They are also frequently used to treat agitation associated with dementia, anxiety disorder, autism spectrum disorder, and obsessive-compulsive disorder (an off-label use). In dementia, they should only be considered after other treatments have failed and if the patient is a risk to themselves and/or others.

Schizophrenia

The first-line psychiatric treatment for schizophrenia is antipsychotic medication, which can reduce the positive symptoms of schizophrenia in about 8-15 days. Antipsychotics only appear to improve secondary negative symptoms of schizophrenia in the short term and may worsen negative symptoms overall. Overall there is no good evidence that atypical antipsychotics have any therapeutic benefit for treating the negative symptoms of schizophrenia.

There is very little evidence on which to base a risk and benefit assessment of using antipsychotics for long-term treatment.

The choice of which antipsychotic to use for a specific patient is based on benefits, risks, and costs. It is debatable whether, as a class, typical or atypical antipsychotics are better. Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. There is a good response in 40-50% of patients, a partial response in 30-40%, and treatment resistance (failure of symptoms to respond satisfactorily after six weeks to two of three different antipsychotics) in the remaining 20%. Clozapine is considered a first choice treatment for treatment resistant schizophrenia, especially in the short term; in the longer-terms the risks of adverse effects complicate the choice. In turn, olanzapine, risperidone, and aripiprazole have been recommended for the treatment of first-episode psychosis.

Efficacy in the Treatment of Schizophrenia

The utility of broadly grouping the antipsychotics into first generation and atypical categories has been challenged. It has been argued that a more nuanced view, matching the properties of individual drugs to the needs of specific patients is preferable. While the atypical (second-generation) antipsychotics were marketed as offering greater efficacy in reducing psychotic symptoms while reducing side effects (and extrapyramidal symptoms in particular) than typical medications, the results showing these effects often lacked robustness, and the assumption was increasingly challenged even as atypical prescriptions were soaring. In 2005 the US government body NIMH (National Institute for Mental Health) published the results of a major independent (not funded by the pharmaceutical companies) multi-site, double-blind study (the CATIE project). This study compared several atypical antipsychotics to an older, mid-potency typical antipsychotic, perphenazine, among 1,493 persons with schizophrenia. The study found that only olanzapine outperformed perphenazine in discontinuation rate (the rate at which people stopped taking it due to its effects). The authors noted an apparent superior efficacy of olanzapine to the other drugs in terms of reduction in psychopathology and rate of hospitalizations, but olanzapine was associated with relatively severe metabolic effects such as a major weight gain problem (averaging 9.4 lbs over 18 months) and increases in glucose, cholesterol, and triglycerides. No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the typical perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine (a result supported by a meta-analysis by Leucht et al. published in The Lancet), although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%, P=0.002). A phase 2 part of this CATIE study roughly replicated these findings. Compliance has not been shown to be different between the two types. Overall evaluations of the CATIE and other studies have led many researchers to question the first-line prescribing of atypicals over typicals, or even to question the distinction between the two classes.

It has been suggested that there is no validity to the term “second-generation antipsychotic drugs” and that the drugs that currently occupy this category are not identical to each other in mechanism, efficacy, and side-effect profiles.

Bipolar Disorder

In bipolar disorder, SGAs are most commonly used to rapidly control acute mania and mixed episodes, often in conjunction with mood stabilizers (which tend to have a delayed onset of action in such cases) such as lithium and valproate. In milder cases of mania or mixed episodes, mood stabiliser monotherapy may be attempted first. SGAs are also used to treat other aspects of the disorder (such as acute bipolar depression or as a prophylactic treatment) as adjuncts or as a monotherapy, depending on the drug. Both quetiapine and olanzapine have demonstrated significant efficacy in all three treatment phases of bipolar disorder. Lurasidone (trade name Latuda) has demonstrated some efficacy in the acute depressive phase of bipolar disorder.

Major Depressive Disorder

In non-psychotic major depressive disorder (MDD), some SGAs have demonstrated significant efficacy as adjunctive agents; and, such agents include:

  • Aripiprazole.
  • Brexpiprazole.
  • Olanzapine.
  • Quetiapine.
  • Ziprasidone.

Whereas only quetiapine has demonstrated efficacy as a monotherapy in non-psychotic MDD. Olanzapine/fluoxetine is an efficacious treatment in both psychotic and non-psychotic MDD.

Aripiprazole, brexpiprazole, olanzapine, and quetiapine have been approved as adjunct treatment for MDD by the FDA in the United States. Quetiapine and lurasidone have been approved, as monotherapies, for bipolar depression, but as of present, lurasidone has not been approved for MDD.

Autism

Both risperidone and aripiprazole have received FDA labelling for autism.

Dementia and Alzheimer’s Disease

Between May 2007 and April 2008, Dementia and Alzheimer’s together accounted for 28% of atypical antipsychotic use in patients aged 65 or older. The FDA requires that all atypical antipsychotics carry a black box warning that the medication has been associated with an increased risk of mortality in elderly patients. In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia. In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%.

Adverse Effects

The side effects reportedly associated with the various atypical antipsychotics vary and are medication-specific. Generally speaking, atypical antipsychotics are widely believed to have a lower likelihood for the development of tardive dyskinesia than the typical antipsychotics. However, tardive dyskinesia typically develops after long-term (possibly decades) use of antipsychotics. It is not clear if atypical antipsychotics, having been in use for a relatively short time, produce a lower incidence of tardive dyskinesia.

Some of the other side effects that have been suggested is that atypical antipsychotics increase the risk of cardiovascular disease. The research that Kabinoff et al. found that the increase in cardiovascular disease is seen regardless of the treatment they receive, instead it is caused by many different factors such as lifestyle or diet.

Sexual side effects have also been reported when taking atypical antipsychotics. In males antipsychotics reduce sexual interest, impair sexual performance with the main difficulties being failure to ejaculate. In females there may be abnormal menstrual cycles and infertility. In both males and females the breasts may become enlarged and a fluid will sometimes ooze from the nipples. Sexual adverse effects caused by some anti-psychotics are a result of an increase of prolactin. Sulpiride and Amisulpiride, as well as Risperdone and paliperidone (to a lesser extent) cause a high increase of prolactin.

In April 2005, the FDA issued an advisory and subsequent black box warning regarding the risks of atypical anti psychotic use among elderly patients with dementia. The FDA advisory was associated with decreases in the use of atypical antipsychotics, especially among elderly patients with dementia. Subsequent research reports confirmed the mortality risks associated with the use of both conventional and atypical antipsychotics to treat patients with dementia. Consequently, in 2008 the FDA issued although a black box warning for classical neuroleptics. Data on treatment efficacies are strongest for atypical antipsychotics. Adverse effects in patients with dementia include an increased risk of mortality and cerebrovascular events, as well as metabolic effects, extrapyramidal symptoms, falls, cognitive worsening, cardiac arrhythmia, and pneumonia. Conventional antipsychotics may pose an even greater safety risk. No clear efficacy evidence exists to support the use of alternative psychotropic classes (e.g. antidepressants, anticonvulsants).

Atypical antipsychotics may also cause anhedonia.

Drug-Induced OCD

Many different types of medication can create/induce pure OCD in patients that have never had symptoms before. A new chapter about OCD in the DSM-5 (2013) now specifically includes drug-induced OCD.

Atypical antipsychotics (second generation antipsychotics), such as olanzapine (Zyprexa), have been proven to induce de-novo OCD in patients.

Tardive Dyskinesia

All of the atypical antipsychotics warn about the possibility of tardive dyskinesia in their package inserts and in the PDR. It is not possible to truly know the risks of tardive dyskinesia when taking atypicals, because tardive dyskinesia can take many decades to develop and the atypical antipsychotics are not old enough to have been tested over a long enough period of time to determine all of the long-term risks. One hypothesis as to why atypicals have a lower risk of tardive dyskinesia is because they are much less fat-soluble than the typical antipsychotics and because they are readily released from D2 receptor and brain tissue. The typical antipsychotics remain attached to the D2 receptors and accumulate in the brain tissue which may lead to TD.

Both typical and atypical antipsychotics can cause tardive dyskinesia. According to one study, rates are lower with the atypicals at 3.9% per year as opposed to the typicals at 5.5% per year.

Metabolism

Recently, metabolic concerns have been of grave concern to clinicians, patients and the FDA. In 2003, the FDA required all manufacturers of atypical antipsychotics to change their labelling to include a warning about the risks of hyperglycaemia and diabetes with atypical antipsychotics. It must also be pointed out that although all atypicals must carry the warning on their labelling, some evidence shows that atypicals are not equal in their effects on weight and insulin sensitivity. The general consensus is that clozapine and olanzapine are associated with the greatest effects on weight gain and decreased insulin sensitivity, followed by risperidone and quetiapine. Ziprasidone and aripiprazole are thought to have the smallest effects on weight and insulin resistance, but clinical experience with these newer agents is not as developed as that with the older agents. The mechanism of these adverse effects is not completely understood but it is believed to result from a complex interaction between a number of pharmacologic actions of these drugs. Their effects on weight are believed to mostly derive from their actions on the H1 and 5-HT2C receptors, while their effects on insulin sensitivity are believed to be the result of a combination of their effects on body weight (as increased body mass is known to be a risk factor for insulin resistance) and their antagonistic effects on the M3receptor. Some of the newer agents, however, such as risperidone and its metabolite paliperidone, ziprasidone, lurasidone, aripiprazole, asenapine and iloperidone have clinically-insignificant effects on the M3 receptor and appear to carry a lower risk of insulin resistance. Whereas clozapine, olanzapine and quetiapine (indirectly via its active metabolite, norquetiapine) all antagonise the M3 receptor at therapeutic-relevant concentrations.

Recent evidence suggests a role of the α1 adrenoceptor and 5-HT2A receptor in the metabolic effects of atypical antipsychotics. The 5-HT2A receptor, however, is also believed to play a crucial role in the therapeutic advantages of atypical antipsychotics over their predecessors, the typical antipsychotics.

A study by Sernyak and colleagues found that the prevalence of diabetes in atypical antipsychotic treatments was statistically significantly higher than that of conventional treatment. The authors of this study suggest that it is a causal relationship the Kabinoff et al. suggest the findings only suggest a temporal association. Kabinoff et al. suggest that there is insufficient data from large studies to demonstrate a consistent or significant difference in the risk of insulin resistance during treatment with various atypical antipsychotics.

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.

Pharmacology

Pharmacodynamics

The atypical antipsychotics integrate with the serotonin (5-HT), norepinephrine (α, β), and dopamine (D) receptors in order to effectively treat schizophrenia.

D2 Receptor: Hyperactive dopaminergic activity on D2 receptors in the mesolimbic pathway is responsible for the positive symptoms of schizophrenia (hallucinations, delusions, paranoia). After taking an antipsychotic, antagonism of D2 receptors occurs throughout the entire brain, leading to a number of deleterious side effects from D2 receptor antagonism throughout the entire dopamine pathway system. Unfortunately, it’s not possible to affect D2 receptors only in the mesolimbic pathway. Fortunately, 5-HT2A receptor antagonism reverses these side effects to some extent. Reducing D2 dopaminergic activity in the mesolimbic pathway also results in an anhedonic effect, reducing pleasure, motivation, and the salience of one’s life experience. In the mesocortical pathway to the DLPFC and VMPFC, endogenous D2 receptor dopamine activity is sometimes low in schizophrenia, resulting in cognitive, affective, and, broadly, the negative symptoms of schizophrenia. D2 receptor antagonism here further compounds these problems. In the nigrostriatal pathway, D2 receptor antagonism results in extrapyramidal symptoms. If this antagonism occurs long enough, symptoms of EPS may become permanent, even if antipsychotic use is discontinued. In the tuberoinfundibular pathway, D2 receptor antagonism results in elevated prolactin. If prolactin levels become high enough, hyperprolactinaemia may occur, resulting in sexual dysfunction, weight gain, more rapid demineralisation of bones, and possibly galactorrhea and amenorrhea.

5-HT2A Receptor: When serotonin is released on to postsynaptic 5-HT2A receptors, the dopamine neuron is inhibited, thus acting as a brake on dopamine release. This brake is disrupted through action of a 5-HT2A antagonist, which disinhibits the dopamine neuron, stimulating dopamine release. The result of this is that dopamine competes with antipsychotic D2 antagonistic action at D2 receptors, thereby reducing antagonistic binding there and eliminating or lowering D2 antagonistic effects in several pathways of the dopamine system. In the nigrostratial pathway, it reduces EPS. In the tuberoinfundibular pathway, it reduces or eliminates prolactin elevation. Dopamine release in the mesolimbic pathway from 5-HT2A antagonism does not appear to be as robust as in the other pathways of the dopamine system, thereby accounting for why atypical antipsychotics still retain part of their efficacy against the positive symptoms of schizophrenia through their D2 antagonism. When 5-HT2A antagonistic agent particles occupy 5-HT2A receptors in the mesocortical pathway and in the prefrontal cortex, the negative symptoms of schizophrenia, affective symptoms, and cognitive deficits and abnormalities are treated and reduced. Furthermore, 5-HT2A receptor antagonism blocks the serotonergic excitation of cortical pyramidal cells, reducing glutamate release, which in turn lowers hyperactive dopaminergic D2 receptor activity in the mesolimbic pathway, reducing or eliminating the positive symptoms of schizophrenia.

Some effects of 5-HT1A receptor activation include decreased aggressive behaviour/ideation, increased sociability, and decreased anxiety and depression. 5-HT2C activation blocks dopamine and inhibits norepinephrine release. Blockade of the 5-HT2C receptor increases serotonin, releasing norepinephrine and dopamine within the brain. But neuronal reuptake of norepinephrine is limited sharply by some antipsychotics, for example ziprasidone. Increased norepinephrine can cause increased glucose levels, which is to say blood sugar levels. Increased blood sugar levels by increased norepinephrine causes hunger in many humans, which is why weight gain occurs with some antipsychotics if the norepinephrine is not inhibited. Inhibition of norepinephrine stabilises mood in humans. 5-HT6 receptor antagonists improve cognition, learning, and memory. The 5-HT7 receptor is very potent for the mitigation of bipolar conditions and also yields an antidepressant effect. The antipsychotics asenapine, lurasidone, risperidone, and aripiprazole are very potent at the 5-HT7 receptor. Antagonistic affinity for the H1 receptor also has an antidepressant effect. H1 antagonism blocks serotonin and norepinephrine reuptake. Patients with increased histamine levels have been observed to have lower serotonin levels. However, the H1 receptor is linked to weight gain. To have partial agonism at the 5-HT1A receptor can yield absence of weight gain in an antipsychotic. This is very relevant for ziprasidone, but it creates a risk for a prolonged QTc interval. On the other hand, blockade of the 5-HT3 receptor removes the risk for a prolonged QTc interval, but then creates a larger risk for weight gain. Relation to the 5-HT3 receptor increases caloric uptake and glucose, which is seen in clozapine and olanzapine. Other ways for dopamine to resolve is to have agonism at both the D2 receptor and 5-HT1A receptor, which normalises the dopamine level in the brain. This occurs with haloperidol and aripiprazole.

Whether the anhedonic, loss of pleasure and motivation effect resulting from dopamine insufficiency or blockade at D2 receptors in the mesolimbic pathway, which is mediated in some part by antipsychotics (and despite dopamine release in the mesocortical pathway from 5-HT2A antagonism, which is seen in atypical antipsychotics), or the positive mood, mood stabilisation, and cognitive improvement effect resulting from atypical antipsychotic serotonergic activity is greater for the overall quality of life effect of an atypical antipsychotic is a question that is variable between individual experience and the atypical antipsychotic(s) being used.

Terms

Inhibition. Disinhibition: The opposite process of inhibition, the turning on of a biological function. Release: Causes the appropriate neurotransmitters to be discharged in vesicles into the synapse where they attempt to bind to and activate a receptor. Downregulation and Upregulation.

Pharmacokinetics

Atypical antipsychotics are most commonly administered orally. Antipsychotics can also be injected, but this method is not as common. They are lipid-soluble, are readily absorbed from the digestive tract, and can easily pass the blood-brain barrier and placental barriers. Once in the brain, the antipsychotics work at the synapse by binding to the receptor. Antipsychotics are completely metabolised in the body and the metabolites are excreted in urine. These drugs have relatively long half-lives. Each drug has a different half-life, but the occupancy of the D2 receptor falls off within 24 hours with atypical antipsychotics, while lasting over 24 hours for the typical antipsychotics. This may explain why relapse into psychosis happens quicker with atypical antipsychotics than with typical antipsychotics, as the drug is excreted faster and is no longer working in the brain. Physical dependence with these drugs is very rare. However, if the drug is abruptly discontinued, psychotic symptoms, movement disorders, and sleep difficulty may be observed. It is possible that withdrawal is rarely seen because the AAP are stored in body fat tissues and slowly released.

Society and Culture

Between May 2007 and April 2008, 5.5 million Americans filled at least one prescription for an atypical antipsychotic. In patients under the age of 65, 71% of patients were prescribed an atypical antipsychotic to treat Schizophrenia or Bipolar Disorder where this dropped to 38% in patients aged 65 or above.

What is Antidepressant Discontinuation Syndrome?

Introduction

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

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

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

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

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

Signs and Symptoms

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

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

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

Duration

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

Mechanism

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

Prevention and Treatment

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

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

Pregnancy and Newborns

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

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

Culture and History

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

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

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

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

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

2013 Class Action Lawsuit

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

Research

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

What is Triazolam?

Introduction

Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives.

It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia. In addition to the hypnotic properties, triazolam’s amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced, as well. Due to its short half-life, triazolam is not effective for patients who experience frequent awakenings or early wakening.

Triazolam was initially patented in 1970 and went on sale in the United States in 1982. In 2017, it was the 280th most commonly prescribed medication in the United States, with more than one million prescriptions.

Medical Uses

Triazolam is usually used for short-term treatment of acute insomnia and circadian rhythm sleep disorders, including jet lag. It is an ideal benzodiazepine for this use because of its fast onset of action and short half-life. It puts a person to sleep for about 1.5 hours, allowing its user to avoid morning drowsiness. Triazolam is also sometimes used as an adjuvant in medical procedures requiring anaesthesia or to reduce anxiety during brief events, such as MRI scans and nonsurgical dental procedures. Triazolam is ineffective in maintaining sleep, however, due to its short half-life, with quazepam showing superiority.

Triazolam is frequently prescribed as a sleep aid for passengers travelling on short- to medium-duration flights. If this use is contemplated, the user avoiding the consumption of alcoholic beverages is especially important, as is trying a ground-based “rehearsal” of the medication to ensure that the side effects and potency of this medication are understood by the user prior to using it in a relatively more public environment (as disinhibition can be a common side effect, with potentially severe consequences). Triazolam causes anterograde amnesia, which is why so many dentists administer it to patients undergoing even minor dental procedures. This practice is known as sedation dentistry.

Side Effects

Adverse drug reactions associated with the use of triazolam include:

  • Relatively common (>1% of patients): somnolence, dizziness, feeling of lightness, coordination problems.
  • Less common (0.9% to 0.5% of patients): euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, visual disturbances.
  • Rare (<0.5% of patients): constipation, taste alteration, diarrhoea, dry mouth, dermatitis/allergy, dreams/nightmares, insomnia, paraesthesia, tinnitus, dysesthesia, weakness, congestion.

Triazolam, although a short-acting benzodiazepine, may cause residual impairment into the next day, especially the next morning. A meta-analysis demonstrated that residual “hangover” effects after night-time administration of triazolam such as sleepiness, psychomotor impairment, and diminished cognitive functions may persist into the next day, which may impair the ability of users to drive safely and increase risks of falls and hip fractures. Confusion and amnesia have been reported.

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Tolerance, Dependence, and Withdrawal

Refer to Benzodiazepine Withdrawal Syndrome.

A review of the literature found that long-term use of benzodiazepines, including triazolam, is associated with drug tolerance, drug dependence, rebound insomnia, and CNS-related adverse effects. Benzodiazepine hypnotics should be used at their lowest possible dose and for a short period of time. Nonpharmacological treatment options were found to yield sustained improvements in sleep quality. A worsening of insomnia (rebound insomnia) compared to baseline may occur after discontinuation of triazolam, even following short-term, single-dose therapy.

Other withdrawal symptoms can range from mild unpleasant feelings to a major withdrawal syndrome, including stomach cramps, vomiting, muscle cramps, sweating, tremor, and in rare cases, convulsions.

Contraindications

Benzodiazepines require special precautions if used in the elderly, during pregnancy, in children, in alcoholics, or in other drug-dependent individuals and individuals with comorbid psychiatric disorders. Triazolam belongs to the Pregnancy Category X of the FDA. It is known to have the potential to cause birth defects.

Elderly

Triazolam, similar to other benzodiazepines and nonbenzodiazepines, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments. Daytime withdrawal effects can occur.

An extensive review of the medical literature regarding the management of insomnia and the elderly found considerable evidence of the effectiveness and durability of nondrug treatments for insomnia in adults of all ages and that these interventions are underused. Compared with the benzodiazepines including triazolam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. Newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment, anterograde amnesia, daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. One study found no evidence of sustained hypnotic efficacy throughout the 9 weeks of treatment for triazolam.

In addition, the effectiveness and safety of long-term use of these agents remain to be determined. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

Interactions

Ketoconazole and itraconazole have a profound effect on the pharmacokinetics of triazolam, leading to greatly enhanced effects. Anxiety, tremor, and depression have been documented in a case report following administration of nitrazepam and triazolam. Following administration of erythromycin, repetitive hallucinations and abnormal bodily sensations developed. The patient had, however, acute pneumonia, and kidney failure. Co-administration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms, especially in those with other physical complications. Caffeine reduces the effectiveness of triazolam. Other important interactions include cimetidine, diltiazem, fluconazole, grapefruit juice, isoniazid, itraconazole, nefazodone, rifampicin, ritonavir, and troleandomycin. Triazolam should not be administered to patients on Atripla.

Overdose

Refer to Benzodiazepine Overdose.

Symptoms of an overdose include:

  • Coma.
  • Hypoventilation (respiratory depression).
  • Somnolence (drowsiness).
  • Slurred speech.
  • Seizures.

Death can occur from triazolam overdose, but is more likely to occur in combination with other depressant drugs such as opioids, alcohol, or tricyclic antidepressants.

Pharmacology

The pharmacological effects of triazolam are similar to those of most other benzodiazepines. It does not generate active metabolites. Triazolam is a short-acting benzodiazepine, is lipophilic, and is metabolised hepatically via oxidative pathways. The main pharmacological effects of triazolam are the enhancement of the neurotransmitter GABA at the GABAA receptor. The half-life of triazolam is only 2 hours making it a very short acting benzodiazepine drug. It has anticonvulsant effects on brain function.

Society and Culture

Recreational Use

Refer to Benzodiazepine Drug Misuse.

Triazolam issued nonmedically: recreational use wherein the drug is taken to achieve a high or continued long-term dosing against medical advice.

Legal Status

Triazolam is a Schedule IV drug under the Convention on Psychotropic Substances and the US Controlled Substances Act.

Brandnames

The drug is marketed in English-speaking countries under the brand names Apo-Triazo, Halcion, Hypam, and Trilam. Other (designer) names include 2′-chloroxanax, chloroxanax, triclazolam, and chlorotriazolam.

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 Zimelidine?

Introduction

Zimelidine (INN, BAN) (brand names Zimeldine, Normud, Zelmid) was one of the first selective serotonin reuptake inhibitor (SSRI) antidepressants to be marketed.

It is a pyridylallylamine, and is structurally different from other antidepressants.

Zimelidine was developed in the late 1970s and early 1980s by Arvid Carlsson, who was then working for the Swedish company Astra AB. It was discovered following a search for drugs with structures similar to brompheniramine (it is a derivative of brompheniramine), an antihistamine with antidepressant activity. Zimelidine was first sold in 1982.

While zimelidine had a very favourable safety profile, within a year and a half of its introduction, rare case reports of Guillain–Barré syndrome emerged that appeared to be caused by the drug, prompting its manufacturer to withdraw it from the market. After its withdrawal, it was succeeded by fluvoxamine and fluoxetine (derived from the antihistamine diphenhydramine) in that order, and the other SSRIs.

Mechanism of Action

The mode of action is a strong reuptake inhibition of serotonin from the synaptic cleft. Postsynaptic receptors are not acted upon.

Other Uses

Zimelidine was reported by Montplaisir and Godbout to be very effective for cataplexy in 1986, back when this was usually controlled by tricyclic antidepressants, which often had anticholinergic effects. Zimelidine was able to improve cataplexy without causing daytime sleepiness.

Side Effects

Most often reported were:

  • Dry mouth, dryness of pharyngeal and nasal membranes.
  • Increased sweating (hyperhidrosis).
  • Vertigo.
  • Nausea.

Interactions

MAO inhibitors – severe or life-threatening reactions possible.

What is a Serotonin-Norepinephrine Reuptake Inhibitor?

Introduction

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs that treat major depressive disorder (MDD), anxiety disorders, obsessive-compulsive disorder (OCD), social phobia, attention-deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the more widely used selective serotonin reuptake inhibitors (SSRIs), which act upon serotonin only.

The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane transport proteins that are responsible for the reuptake of serotonin and norepinephrine from the synaptic cleft back into the presynaptic nerve terminal. Dual inhibition of serotonin and norepinephrine reuptake can offer advantages over other antidepressant drugs by treating a wider range of symptoms. They can be especially useful in concomitant chronic or neuropathic pain.

SNRIs, along with SSRIs and norepinephrine reuptake inhibitors (NRIs), are second-generation antidepressants. Over the past two decades, second-generation antidepressants have simply replaced first-generation antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), as the drugs of choice for the treatment of MDD due to their improved tolerability and safety profile.

Medications

There are eight FDA approved SNRIs in the United States, with venlafaxine being the first drug to be developed in 1993 and levomilnacipran being the latest drug to be developed in 2013. The drugs vary by their other medical uses, chemical structure, adverse effects, and efficacy.

  • Atomoxetine.
  • Desvenlafaxine.
  • Duloxetine.
  • Levomilnacipran.
  • Milnacipran.
  • Sibutramine.
  • Tramadol.
  • Venlafaxine.

Brief History

Refer to Development and Discovery of SSRI Drugs.

In 1952, iproniazid, an antimycobacterial agent, was discovered to have psychoactive properties while researched as a possible treatment for tuberculosis. Researchers noted that patients given iproniazid became cheerful, more optimistic, and more physically active. Soon after its development, iproniazid and related substances were shown to slow enzymatic breakdown of serotonin, dopamine, and norepinephrine via inhibition of the enzyme monoamine oxidase. For this reason, this class of drugs became known as monoamine oxidase inhibitors, or MAOIs. During this time development of distinctively different antidepressant agents was also researched. Imipramine became the first clinically useful tricyclic antidepressant (TCA). Imipramine was found to affect numerous neurotransmitter systems and to block the reuptake of norepinephrine and serotonin from the synapse, therefore increasing the levels of these neurotransmitters. Use of MAOIs and TCAs gave major advances in treatment of depression but their use was limited by unpleasant side effects and significant safety and toxicity issues.

Throughout the 1960s and 1970s, the catecholamine hypothesis of emotion and its relation to depression was of wide interest and that the decreased levels of certain neurotransmitters, such as norepinephrine, serotonin, and dopamine might play a role in the pathogenesis of depression. This led to the development of fluoxetine, the first SSRI. The improved safety and tolerability profile of the SSRIs in patients with MDD, compared with TCAs and MAOIs, represented yet another important advance in the treatment of depression.

Since the late 1980s, SSRIs have dominated the antidepressant drug market. Today, there is increased interest in antidepressant drugs with broader mechanisms of action that may offer improvements in efficacy and tolerability. In 1993, a new drug was introduced to the US market called venlafaxine, a SNRI. Venlafaxine was the first compound described in a new class of antidepressive substances called phenylethylamines. These substances are unrelated to TCA and other SSRIs. Venlafaxine blocks the neuronal reuptake of serotonin, noradrenaline, and, to a lesser extent, dopamine in the central nervous system. In contrast with several other antidepressant drugs, venlafaxine can induce a rapid onset of action mainly due to a subsequent norepinephrine reuptake inhibition.

Mechanism of Action

Monoamines are connected to the pathophysiology of depression. Symptoms may occur because concentrations of neurotransmitters, such as norepinephrine and serotonin, are insufficient, leading to downstream changes. Medications for depression affect the transmission of serotonin, norepinephrine, and dopamine. Older and more unselective antidepressants like TCAs and MAOIs inhibit the reuptake or metabolism of norepinephrine and serotonin in the brain, which results in higher concentrations of neurotransmitters. Antidepressants that have dual mechanisms of action inhibit the reuptake of both serotonin and norepinephrine and, in some cases, inhibit with weak effect the reuptake of dopamine. Antidepressants affect variable neuronal receptors like muscarinic-cholinergic, α1- and α2-adrenergic, and H1-histaminergic receptors, and sodium channels in the cardiac muscle, leading to decreased cardiac conduction and cardiotoxicity {source needed}. Selectivity of antidepressant agents are based on the neurotransmitters that are thought to influence symptoms of depression. Drugs that selectively block the reuptake of serotonin and norepinephrine effectively treat depression and are better tolerated than TCAs. TCAs have comprehensive effects on various neurotransmitters receptors, which leads to lack of tolerability and increased risk of toxicity.

Tricyclic Antidepressants

TCAs were the first medications that had dual mechanism of action. The mechanism of action of tricyclic secondary amine antidepressants is only partly understood. TCAs have dual inhibition effects on norepinephrine reuptake transporters and serotonin reuptake transporters. Increased norepinephrine and serotonin concentrations are obtained by inhibiting both of these transporter proteins. TCAs have substantially more affinity for norepinephrine reuptake proteins than the SSRIs. This is because of a formation of secondary amine TCA metabolites.

In addition, the TCAs interact with adrenergic receptors. This interaction seems to be critical for increased availability of norepinephrine in or near the synaptic clefts. Actions of imipramine-like tricyclic antidepressants have complex, secondary adaptions to their initial and sustained actions as inhibitors of norepinephrine transport and variable blockade of serotonin transport.

Norepinephrine interacts with postsynaptic α and β adrenergic receptor subtypes and presynaptic α2 autoreceptors. The α2 receptors include presynaptic autoreceptors which limit the neurophysiological activity of noradrenergic neurons in the central nervous system. Formation of norepinephrine is reduced by autoreceptors through the rate-limiting enzyme tyrosine hydroxylase, an effect mediated by decreased cyclic AMP-mediated phosphorylation-activation of the enzyme. α2 receptors also cause decreased intracellular cyclic AMP expression which results in smooth muscle relaxation or decreased secretion.

TCAs activate a negative feedback mechanism through their effects on presynaptic receptors. One probable explanation for the effects on decreased neurotransmitter release is that, as the receptors activate, inhibition of neurotransmitter release occurs (including suppression of voltage-gated Ca2+ currents and activation of G protein-coupled receptor-operated K+ currents). Repeated exposure of agents with this type of mechanism leads to inhibition of neurotransmitter release, but repeated administration of TCAs finally leads to decreased responses by α2 receptors. The desensitization of these responses may be due to increased exposure to endogenous norepinephrine or from the prolonged occupation of the norepinephrine transport mechanisms (via an allosteric effect). The adaptation allows the presynaptic synthesis and secretion of norepinephrine to return to, or even exceed, normal levels of norepinephrine in the synaptic clefts. Overall, inhibition of norepinephrine reuptake induced by TCAs leads to decreased rates of neuron firing (mediated through α2 autoreceptors), metabolic activity, and release of neurotransmitters.

TCAs do not block dopamine transport directly but might facilitate dopaminergic effects indirectly by inhibiting dopamine transport into noradrenergic terminals of the cerebral cortex. Because they affect so many different receptors, TCAs have adverse effects, poor tolerability, and an increased risk of toxicity.

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) selectively inhibit the reuptake of serotonin and are a widely used group of antidepressants. With increased receptor selectivity compared to TCAs, undesired effects such as poor tolerability are avoided. Serotonin is synthesized from an amino acid called L-tryptophan. Active transport system regulates the uptake of tryptophan across the blood-brain barrier. Serotonergic pathways are classified into two main ways in the brain: the ascending projections from the medial and dorsal raphe and the descending projections from the caudal raphe into the spinal cord.

Selective Norepinephrine Reuptake Inhibitors

Noradrenergic neurons are located in two major regions in the brain. These regions are locus coeruleus and lateral tegmental. With administration of SNRIs, neuronal activity in locus coeruleus region is induced because of increased concentration of norepinephrine in the synaptic cleft. This results in activation of α2 adrenergic receptors, as discussed previously.

Assays have shown that SNRIs have insignificant penchant for mACh, α1 and α2 adrenergic, or H1 receptors.

Dual Serotonin and Norepinephrine Reuptake Inhibitors

Agents with dual serotonin and norepinephrine reuptake inhibition (SNRIs) are sometimes called non-tricyclic serotonin and norepinephrine reuptake inhibitors. Clinical studies suggest that compounds that increase the concentration in the synaptic cleft of both norepinephrine and serotonin are more successful than single acting agents in the treatment of depression, but the data is not conclusive whether SNRIs are a more effective treatment option over SSRIs for depression. Dual reuptake inhibitors have low affinity at neuronal receptors of the other neurotransmitters, which have low adverse effects compared with the TCAs. Nontricyclic antidepressants have improved potency and onset action acceleration in antidepressant response than SSRIs alone, which give the impression that synergism is an efficient property in mediating antidepressant activity.

The non-tricyclic SNRIs have several important differences that are based on pharmacokinetics, metabolism to active metabolites, inhibition of CYP isoforms, effect of drug-drug interactions, and the half-life of the nontricyclic SNRIs.

Combination of mechanisms of action in a single active agent is an important development in psychopharmacology.

Structure Activity Relationship (SAR)

Aryloxypropanamine Scaffold

Several reuptake inhibitors contain an aryloxypropanamine scaffold. This structural motif has potential for high affinity binding to biogenic amine transports. Drugs containing an aryloxypropanamine scaffold have selectivity profile for norepinephrine and serotonin transporters that depends on the substitution pattern of the aryloxy ring. Selective NRIs contain a substituent in 2′ position of the aryloxy ring but SSRIs contain a substituent in 4′ position of the aryloxy ring. Atomoxetine, nisoxetine and reboxetine all have a substitution group in the 2′ position and are selective NRIs while compounds that have a substitution group in the 4′ position (like fluoxetine and paroxetine) are SSRIs. Duloxetine contains a phenyl group fused at the 2′ and 3′ positions, therefore it has dual selective norepinephrine and serotonin reuptake inhibitory effects and has similar potencies for the both transporters. The nature of the aromatic substituent also has a significant influence on the activity and selectivity of the compounds as inhibitors of the serotonin or the norepinephrine transporters.

Cycloalkanol Ethylamine Scaffold

Venlafaxine and desvenlafaxine contain a cycloalkanol ethylamine scaffold. Increasing the electron-withdrawing nature of the aromatic ring provides a more potent inhibitory effect of norepinephrine uptake and improves the selectivity for norepinephrine over the serotonin transporter. Effects of chloro, methoxy and trifluoromethyl substituents in the aromatic ring of cycloalkanol ethylamine scaffold were tested. The results showed that the strongest electron-withdrawing m-trifluoromethyl analogue exhibited the most potent inhibitory effect of norepinephrine and the most selectivity over serotonin uptake. WY-46824, a piperazine-containing derivative, has shown norepinephrine and dopamine reuptake inhibition. Further synthesis and testing identified WAY-256805, a potent norepinephrine reuptake inhibitor that exhibited excellent selectivity and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.

Milnacipran

Milnacipran is structurally different from other SNRIs. The SAR of milnacipran derivatives at transporter level is still largely unclear and is based on in vivo efficacy that was reported in 1987. N-methylation of milnacipran in substituent group R4 and R5 reduces the norepinephrine and serotonin activity. Researches on different secondary amides in substitution groups R6 and R7 showed that π electrons play an important role in the interaction between transporters and ligands. A phenyl group in substituent R6 showed effect on norepinephrine transporters. Substituent groups in R6 and R7 with allylic double bond showed significant improved effect on both norepinephrine and serotonin transporters. Studies show that introducing a 2-methyl group in substituent R3, the potency at norepinephrine and serotonin transporters are almost abolished. Methyl groups in substituent groups R1 and R2 also abolish the potency at norepinephrine and serotonin transporters. Researchers found that replacing one of the ethyl groups of milnacipran with an allyl moiety increases the norepinephrine potency. The pharmacophore of milnacipran derivatives is still largely unclear.

The conformation of milnacipran is an important part of its pharmacophore. Changing the SAR in milnacipran changes the stereochemistry of the compound and affects the norepinephrine and serotonin concentration. Milnacipran is marketed as a racemic mixture. Effects of milnacipran reside in the (1S,2R)-isomer and substitution of the phenyl group in the (1S,2R)-isomer has negative impact on norepinephrine concentration. Milnacipran has low molecular weight and low lipophilicity. Because of these properties, milnacipran exhibits almost ideal pharmacokinetics in humans such as high bioavailability, low inter-subject variability, limited liver enzyme interaction, moderate tissue distribution and a reasonably long elimination half-life. Milnacipran’s lack of drug-drug interactions via cytochrome P450 enzymes is thought to be an attractive feature because many of the central nervous system drugs are highly lipophilic and are mainly eliminated by liver enzymes.

Future Development of SAR

The application of an aryloxypropanamine scaffold has generated a number of potent MAOIs. Before the development of duloxetine, the exploration of aryloxypropanamine SAR resulted in the identification of fluoxetine and atomoxetine. The same motif can be found in reboxetine where it is constrained in a morpholine ring system. Some studies have been made where the oxygen in reboxetine is replaced by sulfur to give arylthiomethyl morpholine. Some of the arylthiomethyl morpholine derivatives maintain potent levels of serotonin and norepinephrine reuptake inhibition. Dual serotonin and norepinephrine reuptake inhibition resides in different enantiomers for arylthiomethyl morpholine scaffold. Possible drug candidates with dual serotonin and norepinephrine reuptake inhibitory activity have also been derived from piperazine, 3-amino-pyrrolidine and benzylamine templates.

Clinical Trials

Depression

Several studies have shown that antidepressant drugs which have combined serotonergic and noradrenergic activity are generally more effective than SSRIs, which act upon serotonin reuptake by itself. Serotonergic-noradrenergic antidepressant drugs may have a modest efficacy advantage compared to SSRIs in treating major depressive disorder (MDD), but are slightly less well tolerated. Further research is needed to examine the possible differences of efficacy in specific MDD sub-populations or for specific MDD symptoms, between these classes of antidepressant drugs.

Analgesic

Data from clinical trials have indicated that SNRIs might have pain relieving properties. Although the perception and transmission of pain stimuli in the central nervous system have not been fully elucidated, extensive data support a role for serotonin and norepinephrine in the modulation of pain. Findings from clinical trials in humans have shown these antidepressants can to reduce pain and functional impairment in central and neuropathic pain conditions. This property of SNRIs might be used to reduce doses of other pain relieving medication and lower the frequency of safety, limited efficacy and tolerability issues. Clinical research data have shown in patients with GAD that the SNRI duloxetine is significantly more effective than placebo in reducing pain-related symptoms of GAD, after short-term and long-term treatment. However, findings suggested that such symptoms of physical pain reoccur in relapse situations, which indicates a need for ongoing treatment in patients with GAD and concurrent painful physical symptoms.

Indications

SNRIs have been tested for treatment of the following conditions:

Pharmacology

Route of Administration

SNRIs are delivered orally, usually in the form of capsules or tablets. It is recommended to take SNRIs in the morning with breakfast, which does not affect drug levels, but may help with certain side effects. Norepinephrine has activating effects in the body and therefore can cause insomnia in some patients if taken at bedtime. SNRIs can also cause nausea, which is usually mild and goes away within a few weeks of treatment, but taking the medication with food can help alleviate this. The drugs themselves are usually a fine crystalline powder that diffuses into the body during digestion.

Dosage

Dosages vary depending on the SNRI used due to varying potencies of the drug in question as well as multiple strengths for each drug.

Mode of Action

The condition for which SNRIs are mostly indicated, major depressive disorder, is thought to be mainly caused by decreased levels of serotonin and norepinephrine in the synaptic cleft, causing erratic signalling. Based on the monoamine hypothesis of depression, which asserts that decreased concentrations of monoamine neurotransmitters leads to depressive symptoms, the following relations were determined: “Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life.” SNRIs work by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in increased extracellular concentrations of serotonin and norepinephrine and, consequently, an increase in neurotransmission. Most SNRIs including venlafaxine, desvenlafaxine, and duloxetine, are several fold more selective for serotonin over norepinephrine, while milnacipran is three times more selective for norepinephrine than serotonin. Elevation of norepinephrine levels is thought to be necessary for an antidepressant to be effective against neuropathic pain, a property shared with the older tricyclic antidepressants (TCAs), but not with the SSRIs.

Recent studies have shown that depression may be linked to increased inflammatory response, thus attempts at finding an additional mechanism for SNRIs have been made. Studies have shown that SNRIs as well as SSRIs have significant anti-inflammatory action on microglia in addition to their effect on serotonin and norepinephrine levels. As such, it is possible that an additional mechanism of these drugs that acts in combination with the previously understood mechanism exist. The implication behind these findings suggests use of SNRIs as potential anti-inflammatories following brain injury or any other disease where swelling of the brain is an issue. However, regardless of the mechanism, the efficacy of these drugs in treating the diseases for which they have been indicated has been proven, both clinically and in practice.

Pharmacodynamics

Most SNRIs function alongside primary metabolites and secondary metabolites in order to inhibit reuptake of serotonin, norepinepherine, and marginal amounts of dopamine. For example, venlafaxine works alongside its primary metabolite O-desmethylvenlafaxine to strongly inhibit serotonin and norepinephrine reuptake in the brain. The evidence also suggests that dopamine and norepinepherine behave in a co-transportational manner, due to the inactivation of dopamine by norepinephrine reuptake in the frontal cortex, an area of the brain largely lacking in dopamine transporters. This effect of SNRIs results in increased dopamine neurotransmission, in addition to the increases in serotonin and norepinephrine activity. Furthermore, because SNRIs are extremely selective, they have no measurable effects on other, unintended receptors, in contrast to monoamine oxidase inhibition. Pharmaceutical tests have determined that use of both SNRIs or SSRIs can generate significant anti-inflammatory action on microglia, as well.

Pharmacokinetics

The half-life of venlafaxine is about 5 hours, and with once-daily dosing, steady-state concentration is achieved after about 3 days, though its active metabolite desvenlafaxine lasts longer. The half-life of desvenlafaxine is about 11 hours, and steady-state concentrations are achieved after 4 to 5 days. The half-life of duloxetine is about 12 hours (range: 8-17 hours), and steady-state is achieved after about 3 days. Milnacipran has a half-life of about 6 to 8 hours, and steady-state levels are reached within 36 to 48 hours.

Contraindications

SNRIs are contraindicated in patients taking MAOIs within the last two weeks due to the increased risk of serotonin syndrome, which can be life-threatening.[65] Other drugs and substances that should be avoided due to increased risk of serotonin syndrome when combined with an SNRI include: other anti-depressants, anti-convulsants, analgesics, antiemetic agents, anti-migraine medications, methylene blue, linezolid, Lithium, St. John’s worts, ecstasy, and LSD. Signs and symptoms of serotonin syndrome include: hyperthermia, rigidity, myoclonus, autonomic instability with fluctuating vital signs, and mental status changes that include extreme agitation progressing to delirium and coma.

Due to the effects of increased norepinephrine levels and, therefore, higher noradrenergic activity, pre-existing hypertension should be controlled before treatment with SNRIs and blood pressure periodically monitored throughout treatment. Duloxetine has also been associated with cases of liver failure and should not be prescribed to patients with chronic alcohol use or liver disease. Studies have found that Duloxetine can increase liver function tests three times above their upper normal limit. Patients suffering from coronary artery disease should caution the use of SNRIs. Furthermore, due to some SNRIs’ actions on obesity, patients with major eating disorders such as anorexia nervosa or bulimia should not be prescribed SNRIs. Duloxetine and milnacipran are also contraindicated in patients with uncontrolled narrow-angle glaucoma, as they have been shown to increase incidence of mydriasis.

Side Effects

Because the SNRIs and SSRIs act in similar ways to elevate serotonin levels, they share many side effects, though to varying degrees. The most common side effects include nausea/vomiting, sweating, loss of appetite, dizziness, headache, increase in suicidal thoughts, and sexual dysfunction. Elevation of norepinephrine levels can sometimes cause anxiety, mildly elevated pulse, and elevated blood pressure. However, norepinephrine-selective antidepressants, such as reboxetine and desipramine, have successfully treated anxiety disorders. People at risk for hypertension and heart disease should monitor their blood pressure. The side effects of upset stomach may be decreased by taking SNRIs with food.

Sexual Dysfunction

SNRIs, similarly to SSRIs, can cause several types of sexual dysfunction, such as erectile dysfunction, decreased libido, sexual anhedonia, and anorgasmia. The two common sexual side effects are diminished interest in sex (libido) and difficulty reaching climax (anorgasmia), which are usually somewhat milder with SNRIs compared to SSRIs. To manage sexual dysfunction, studies have shown that switching to or augmenting with bupropion or adding a PDE5 Inhibitor have decreased symptoms of sexual dysfunction. Studies have shown that PDE5 Inhibitors, such as sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra), have sometimes been helpful to decrease the sexual dysfunction, including erectile dysfunction, although they have been shown to be more effective in men than women.

Serotonin Syndrome

A serious, but rare, side effect of SNRIs is serotonin syndrome, which is caused by an excess of serotonin in the body. Serotonin syndrome can be caused by taking multiple serotonergic drugs, such as SSRIs or SNRIs. Other drugs that contribute to serotonin syndrome include MAO inhibitors, linezolid, tedizolid, methylene blue, procarbazine, amphetamines, clomipramine, and more. Early symptoms of serotonin syndrome may include nausea, vomiting, diarrhoea, sweating, agitation, confusion, muscle rigidity, dilated pupils, hyperthermia, rigidity, and goose bumps. More severe symptoms include fever, seizures, irregular heartbeat, delirium, and coma. If signs or symptoms arise, discontinue treatment with serotonergic agents immediately. It is recommended to washout 4 to 5 half-lives of the serotonergic agent before using an MAO inhibitor.

Bleeding

Some studies suggest there are risks of upper gastrointestinal bleeding, especially venlafaxine, due to impairment of platelet aggregation and depletion of platelet serotonin levels. Similarly to SSRIs, SNRIs may interact with anticoagulants, like warfarin. Currently, there is more evidence of SSRIs having higher risk of bleeding than SNRIs. Studies have suggested caution when using SNRIs or SSRIs with high doses of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or naproxen due to an increased risk of upper GI bleeding.

Precautions

Starting an SNRI Regimen

Due to the extreme changes in noradrenergic activity produced from norepinephrine and serotonin reuptake inhibition, patients that are just starting an SNRI regimen are usually given lower doses than their expected final dosing to allow the body to acclimate to the drug’s effects. As the patient continues along at low doses without any side-effects, the dose is incrementally increased until the patient sees improvement in symptoms without detrimental side-effects.

Discontinuation Syndrome

As with SSRIs, the abrupt discontinuation of an SNRI usually leads to withdrawal, or “discontinuation syndrome“, which could include states of anxiety and other symptoms. Therefore, it is recommended that users seeking to discontinue an SNRI slowly taper the dose under the supervision of a professional. Discontinuation syndrome has been reported to be markedly worse for venlafaxine when compared to other SNRIs. As such, as tramadol is related to venlafaxine, the same conditions apply. This is likely due to venlafaxine’s relatively short half-life and therefore rapid clearance upon discontinuation. In some cases, switching from venlafaxine to fluoxetine, a long-acting SSRI, and then tapering off fluoxetine, may be recommended to reduce discontinuation symptoms. Signs and symptoms of withdrawal from abrupt cessation of an SNRI include dizziness, anxiety, insomnia, nausea, sweating, and flu-like symptoms, such as lethargy and malaise.

Overdose

Causes

Overdosing on SNRIs can be caused by either drug combinations or excessive amounts of the drug itself. Venlafaxine is marginally more toxic in overdose than duloxetine or the SSRIs. Risk of overdose is increased in patients taking multiple serotonergic agents or interacting agents.

Symptoms

Symptoms of SNRI overdose, whether it be a mixed drug interaction or the drug alone, vary in intensity and incidence based on the amount of medicine taken and the individuals sensitivity to SNRI treatment. Possible symptoms may include:

  • Somnolence.
  • Coma.
  • Serotonin syndrome.
  • Seizures.
  • Syncope.
  • Tachycardia.
  • Hypotension.
  • Hypertension.
  • Hyperthermia.
  • Vomiting.

Management

Overdose is usually treated symptomatically, especially in the case of serotonin syndrome, which requires treatment with cyproheptadine and temperature control based on the progression of the serotonin toxicity. Patients are often monitored for vitals and airways cleared to ensure that they are receiving adequate levels of oxygen. Another option is to use activated carbon in the GI tract in order to absorb excess neurotransmitter. It is important to consider drug interactions when dealing with overdose patients, as separate symptoms can arise.

Comparison to SSRIs

Because SNRIs were developed more recently than SSRIs, there are relatively few of them. However, the SNRIs are among the most widely used antidepressants today. In 2009, Cymbalta and Effexor were the 11th- and 12th-most-prescribed branded drugs in the United States, respectively. This translates to the 2nd- and 3rd-most-common antidepressants, behind Lexapro (escitalopram), an SSRI. In some studies, SNRIs demonstrated slightly higher antidepressant efficacy than the SSRIs (response rates 63.6% versus 59.3%). However, in one study escitalopram had a superior efficacy profile to venlafaxine.

Special Populations

Pregnancy

Currently, no antidepressants are FDA approved during pregnancy. All SSRIs and SNRIs are Category C, except paroxetine, which is Category D since it has shown association with congenital heart disorders. Use of antidepressants during pregnancy may result in foetus abnormalities affecting functional development of the brain and behaviour. Untreated depression may also affect birth outcomes, so it is recommended to discuss options with a provider to weigh the risks and benefits.

Paediatrics

SSRIs and SNRIs have been shown to be effective in treating major depressive disorder and anxiety in paediatric populations. However, there is a risk of increased suicidality in paediatric populations for treatment of major depressive disorder, especially with venlafaxine. Fluoxetine is the only antidepressant that is approved for child/adolescent major depressive disorder.

Geriatrics

Most antidepressants, including SNRIs, are safe and effective in the geriatric population. Decisions are often based on co-morbid conditions, drug interactions, and patient tolerance. Due to differences in body composition and metabolism, starting doses are often half that of the recommended dose for younger adults.

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 Fluvoxamine?

Introduction

Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class which is used primarily for the treatment of depression disorder and obsessive-compulsive disorder (OCD). It is also used to treat anxiety disorders, such as panic disorder, social anxiety disorder, and post-traumatic stress disorder.

Fluvoxamine’s side-effect profile is very similar to other SSRIs: constipation, gastrointestinal problems, headache, anxiety, irritation, sexual problems, dry mouth, sleep problems and a risk of suicide at the start of treatment by lifting the psychomotor inhibition, but these effects appear to be significantly weaker than with other SSRIs (except gastrointestinal side-effects). The tolerance profile also appears to be quite superior than other SSRIs, despite its age.

Anti-inflammatory effects of fluvoxamine are being researched to determine if it can be used to treat COVID-19. It is not approved by the US Federal Drug Administration (FDA) for treatment of any infection.

Brief History

Fluvoxamine was developed by Kali-Duphar, part of Solvay Pharmaceuticals, Belgium, now Abbott Laboratories, and introduced as Floxyfral in Switzerland in 1983. It was approved by the FDA in 1994, and introduced as Luvox in the US. In India, it is available, among several other brands, as Uvox by Abbott. It was one of the first SSRI antidepressants to be launched, and is prescribed in many countries to patients with major depression. It was the first SSRI, a non-TCA drug, approved by the FDA specifically for the treatment of OCD. At the end of 1995, more than ten million patients worldwide had been treated with fluvoxamine. Fluvoxamine was the first SSRI to be registered for the treatment of obsessive compulsive disorder in children by the FDA in 1997. In Japan, fluvoxamine was the first SSRI to be approved for the treatment of depression in 1999 and was later in 2005 the first drug to be approved for the treatment of social anxiety disorder. Fluvoxamine was the first SSRI approved for clinical use in the United Kingdom.

Medical Uses

In many countries (e.g. Australia, the UK, and Russia) it is commonly used for major depressive disorder. Fluvoxamine is also approved in the United States for OCD, and social anxiety disorder. In Japan it is also approved to treat OCD, social anxiety disorder (SAD) and major depressive disorder (MDD). Fluvoxamine is indicated for children and adolescents with OCD. The drug works long-term, and retains its therapeutic efficacy for at least one year. It has also been found to possess some analgesic properties in line with other SSRIs and tricyclic antidepressants.

There is tentative evidence that fluvoxamine is effective for social phobia in adults. Fluvoxamine is also effective for generalised anxiety disorder (GAD), SAD, panic disorder and separation anxiety disorder in children and adolescents. There is tentative evidence that fluvoxamine may help some people with negative symptoms of chronic schizophrenia.

Adverse Effects

Gastrointestinal side effects are more common in those receiving fluvoxamine than with other SSRIs. Otherwise, fluvoxamine’s side-effect profile is very similar to other SSRIs.

Common (1-10% Incidence) Adverse Effects

  • Nausea.
  • Vomiting.
  • Weight loss.
  • Yawning.
  • Loss of appetite.
  • Agitation.
  • Nervousness.
  • Anxiety.
  • Insomnia.
  • Somnolence (drowsiness).
  • Tremor.
  • Restlessness.
  • Headache.
  • Dizziness.
  • Palpitations.
  • Tachycardia (high heart rate).
  • Abdominal pain.
  • Dyspepsia (indigestion).
  • Diarrhoea.
  • Constipation.
  • Hyperhidrosis (excess sweating).
  • Asthenia (weakness).
  • Malaise.
  • Sexual dysfunction (including delayed ejaculation, erectile dysfunction, decreased libido, etc.).
  • Xerostomia (dry mouth).

Uncommon (0.1-1% Incidence) Adverse Effects

  • Arthralgia.
  • Hallucination.
  • Confusional state.
  • Extrapyramidal side effects (e.g. dystonia, parkinsonism, tremor, etc.).
  • Orthostatic hypotension.
  • Cutaneous hypersensitivity reactions (e.g. oedema [buildup of fluid in the tissues], rash, pruritus).

Rare (0.01-0.1% Incidence) Adverse Effects

  • Mania.
  • Seizures.
  • Abnormal hepatic (liver) function.
  • Photosensitivity (being abnormally sensitive to light).
  • Galactorrhoea (expulsion of breast milk unrelated to pregnancy or breastfeeding).

Unknown Frequency Adverse Effects

  • Hyperprolactinaemia (elevated plasma prolactin levels leading to galactorrhoea, amenorrhoea [cessation of menstrual cycles], etc.).
  • Bone fractures.
  • Glaucoma.
  • Mydriasis.
  • Urinary incontinence.
  • Urinary retention.
  • Bed-wetting.
  • Serotonin syndrome: A potentially fatal condition characterised by abrupt onset muscle rigidity, hyperthermia (elevated body temperature), rhabdomyolysis, mental status changes (e.g. coma, hallucinations, agitation), etc.
  • Neuroleptic malignant syndrome – practically identical presentation to serotonin syndrome except with a more prolonged onset.
  • Akathisia – a sense of inner restlessness that presents itself with the inability to stay still.
  • Paraesthesia.
  • Dysgeusia.
  • Haemorrhage.
  • Withdrawal symptoms.
  • Weight changes.
  • Suicidal ideation and behaviour.
  • Violence towards others.
  • Hyponatraemia.
  • Syndrome of inappropriate antidiuretic hormone secretion.
  • Ecchymoses.

Interactions

Fluvoxamine inhibits the following cytochrome P450 enzymes:

  • CYP1A2 (strongly) which metabolises agomelatine, amitriptyline, caffeine, clomipramine, clozapine, duloxetine, haloperidol, imipramine, phenacetin, tacrine, tamoxifen, theophylline, olanzapine, etc.
  • CYP3A4 (moderately) which metabolises alprazolam, aripiprazole, clozapine, haloperidol, quetiapine, pimozide, ziprasidone, etc.
  • CYP2D6 (weakly) which metabolises aripiprazole, chlorpromazine, clozapine, codeine, fluoxetine, haloperidol, olanzapine, oxycodone, paroxetine, perphenazine, pethidine, risperidone, sertraline, thioridazine, zuclopenthixol, etc.[43]
  • CYP2C9 (moderately) which metabolises nonsteroidal anti-inflammatory drugs, phenytoin, sulfonylureas, etc.
  • CYP2C19 (strongly) which metabolises clonazepam, diazepam, phenytoin, etc.
  • CYP2B6 (weakly) which metabolises bupropion, cyclophosphamide, sertraline, tamoxifen, valproate, etc.

By so doing, fluvoxamine can increase serum concentration of the substrates of these enzymes.

The plasma levels of oxidatively metabolised benzodiazepines (e.g. triazolam, midazolam, alprazolam and diazepam) are likely to be increased when co-administered with fluvoxamine. However the clearance of benzodiazepines metabolised by glucuronidation (e.g. lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine. It appears that benzodiazepines metabolised by nitro-reduction (clonazepam, nitrazepam) are unlikely to be affected by fluvoxamine. Using fluvoxamine and alprazolam together can increase alprazolam plasma concentrations. If alprazolam is co-administered with fluvoxamine, the initial alprazolam dose should be reduced to the lowest effective dose.

Fluvoxamine and ramelteon co-administration is not indicated.

Fluvoxamine has been observed to increase serum concentrations of mirtazapine, which is mainly metabolised by CYP1A2, CYP2D6, and CYP3A4, by three- to four-fold in humans. Caution and adjustment of dosage as necessary are warranted when combining fluvoxamine and mirtazapine.

Fluvoxamine seriously affects the pharmacokinetics of tizanidine and increases the intensity and duration of its effects. Because of the potentially hazardous consequences, the concomitant use of tizanidine with fluvoxamine, or other potent inhibitors of CYP1A2, should be avoided.

Fluvoxamine’s interaction with St John’s wort can lead to increased serotonin levels and potentially lead to serotonin syndrome.

Pharmacology

Fluvoxamine is a potent selective serotonin reuptake inhibitor with around 100-fold affinity for the serotonin transporter over the norepinephrine transporter. It has negligible affinity for the dopamine transporter or any other site, with the sole exception of the σ1 receptor. It behaves as a potent agonist at this receptor and has the highest affinity (36 nM) of any SSRI for doing so. This may contribute to its antidepressant and anxiolytic effects and may also afford it some efficacy in treating the cognitive symptoms of depression. Unlike some other SSRI, fluvoxamine’s metabolites are pharmacologically neutral.

Society and Culture

Manufacturers include BayPharma, Synthon, and Teva, among others. Luvox was notably used by Eric Harris, one of the Columbine shooters.

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.