Caproxamine is a drug which was patented as an antidepressant.
Caproxamine is 2-aminoethyl-oxime derivative patented by pharmaceutical company N. V. Philips’ Gloeilampenfabrieken as the compound with pronounced action on the central nervous system in doses of 10-500 mg/day for adults.
Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.
It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder, social anxiety disorder, posttraumatic stress disorder (PTSD), generalised anxiety disorder (GAD) and premenstrual dysphoric disorder. It has also been used in the treatment of premature ejaculation and hot flashes due to menopause. It is taken by mouth.
Common side effects include drowsiness, dry mouth, loss of appetite, sweating, trouble sleeping, and sexual dysfunction. Serious side effects may include suicidal thoughts in those under the age of 25, serotonin syndrome, and mania. While the rate of side effects appears similar compared to other SSRIs and SNRIs, antidepressant discontinuation syndromes may occur more often. Use in pregnancy is not recommended, while use during breastfeeding is relatively safe. It is believed to work by blocking the re-uptake of the chemical serotonin by neurons in the brain.
Paroxetine was approved for medical use in the United States in 1992 and initially sold by GlaxoSmithKline. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2019, it was the 78th most commonly prescribed medication in the United States, with more than 9 million prescriptions. In 2018, it was in the top 10 of most prescribed antidepressants in the United States. In 2012, the United States Department of Justice fined GlaxoSmithKline $3 billion for withholding data, unlawfully promoting use in those under 18, and preparing an article that misleadingly reported the effects of paroxetine in adolescents with depression following its clinical trial study 329.
Paroxetine is primarily used to treat major depressive disorder (MDD), obsessive-compulsive disorder (OCD), PTSD, social anxiety disorder, and panic disorder. It is also occasionally used for agoraphobia, GAD, premenstrual dysphoric disorder and menopausal hot flashes.
A variety of meta analyses have been conducted to evaluate the efficacy of paroxetine in depression. They have variously concluded that paroxetine is superior or equivalent to placebo and that it is equivalent or inferior to other antidepressants. Despite this, there was no clear evidence that paroxetine was better or worse compared with other antidepressants at increasing response to treatment at any point in time.
Paroxetine was the first antidepressant approved in the United States for the treatment of panic disorder. Several studies have concluded that paroxetine is superior to placebo in the treatment of panic disorder.
Paroxetine has demonstrated efficacy for the treatment of social anxiety disorder in adults and children. It is also beneficial for people with co-occurring social anxiety disorder and alcohol use disorder. It appears to be similar to a number of other SSRIs.
Paroxetine is used in the treatment of OCD. Comparative efficacy of paroxetine is equivalent to that of clomipramine and venlafaxine. Paroxetine is also effective for children with OCD.
Paroxetine is approved for treatment of PTSD in the United States, Japan and Europe. In the United States it is approved for short-term use.
Paroxetine is also Food and Drug Administration (FDA)-approved for GAD.
In 2013, low-dose paroxetine was approved in the US for the treatment of moderate-to-severe vasomotor symptoms such as hot flashes and night sweats associated with menopause. At the low dose used for menopausal hot flashes, side effects are similar to placebo and dose tapering is not required for discontinuation.
Studies have also shown paroxetine “appears to be well-tolerated and improve the overall symptomatology in patients with fibromyalgia” but is less robust in helping with the pain involved.
Common side effects include drowsiness, dry mouth, loss of appetite, sweating, trouble sleeping, and sexual dysfunction. Serious side effects may include suicide in those under the age of 25, serotonin syndrome, and mania. While the rate of side effects appears similar compared to other SSRIs and SNRIs, antidepressant discontinuation syndromes may occur more often. Use in pregnancy is not recommended while use during breastfeeding is relatively safe.
Paroxetine shares many of the common adverse effects of SSRIs, including (with the corresponding rates seen in people treated with placebo in parentheses):
Most of these adverse effects are transient and go away with continued treatment. Central and peripheral 5-HT3 receptor stimulation is believed to result in the gastrointestinal effects observed with SSRI treatment. Compared to other SSRIs, it has a lower incidence of diarrhoea, but a higher incidence of anticholinergic effects (e.g. dry mouth, constipation, blurred vision, etc.), sedation/somnolence/drowsiness, sexual side effects, and weight gain.
Due to reports of adverse withdrawal reactions upon terminating treatment, the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency recommends gradually reducing over several weeks or months if the decision to withdraw is made (Refer to discontinuation syndrome below).
Mania or hypomania may occur in 1% of patients with depression and up to 12% of patients with bipolar disorder. This side effect can occur in individuals with no history of mania but it may be more likely to occur in those with bipolar or with a family history of mania.
Like other antidepressants, paroxetine may increase the risk of suicidal thinking and behaviour in people under the age of 25. The FDA conducted a statistical analysis of paroxetine clinical trials in children and adolescents in 2004 and found an increase in suicidality and ideation as compared to placebo, which was observed in trials for both depression and anxiety disorders. In 2015 a paper published in The BMJ that reanalysed the original case notes argued that in Study 329, assessing paroxetine and imipramine against placebo in adolescents with depression, the incidence of suicidal behaviour had been under-reported and the efficacy exaggerated for paroxetine.
Sexual dysfunction, including loss of libido, anorgasmia, lack of vaginal lubrication, and erectile dysfunction, is one of the most commonly encountered adverse effects of treatment with paroxetine and other SSRIs. While early clinical trials suggested a relatively low rate of sexual dysfunction, more recent studies in which the investigator actively inquires about sexual problems suggest that the incidence is higher than 70%. Symptoms of sexual dysfunction have been reported to persist after discontinuing SSRIs, although this is thought to be occasional.
Antidepressant exposure (including paroxetine) is associated with shorter duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g or 2.6 oz), and lower Apgar scores (by <0.4 points). The American College of Obstetricians and Gynaecologists recommends that for pregnant women and women planning to become pregnant, paroxetine “be avoided, if possible”, as it may be associated with increased risk of birth defects.
Babies born to women who used paroxetine during the first trimester have an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs). Unless the benefits of paroxetine justify continuing treatment, consideration should be given to stopping or switching to another antidepressant. Paroxetine use during pregnancy is associated with about 1.5-1.7-fold increase in congenital birth defects, in particular, heart defects, cleft lip and palate, clubbed feet or any birth defects.
Refer to Antidepressant Discontinuation Syndrome.
Many psychoactive medications can cause withdrawal symptoms upon discontinuation from administration. Evidence has shown that paroxetine has among the highest incidence rates and severity of withdrawal syndrome of any medication of its class. Common withdrawal symptoms for paroxetine include nausea, dizziness, lightheadedness and vertigo; insomnia, nightmares and vivid dreams; feelings of electricity in the body, as well as rebound depression and anxiety. Liquid formulation of paroxetine is available and allows a very gradual decrease of the dose, which may prevent discontinuation syndrome. Another recommendation is to temporarily switch to fluoxetine, which has a longer half-life and thus decreases the severity of discontinuation syndrome.
In 2002, the FDA published a warning regarding “severe” discontinuation symptoms among those terminating paroxetine treatment, including paraesthesia, nightmares, and dizziness. The FDA also warned of case reports describing agitation, sweating, and nausea. In connection with a Glaxo spokesperson’s statement that withdrawal reactions occur only in 0.2% of patients and are “mild and short-lived”, the International Federation of Pharmaceutical Manufacturers Associations said GSK had breached two of the Federation’s codes of practice.
Paroxetine prescribing information posted at GlaxoSmithKline has been updated related to the occurrence of a discontinuation syndrome, including serious discontinuation symptoms.
Acute overdosage is often manifested by emesis, lethargy, ataxia, tachycardia, and seizures. Plasma, serum, or blood concentrations of paroxetine may be measured to monitor therapeutic administration, confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities. Plasma paroxetine concentrations are generally in a range of 40-400 μg/L in persons receiving daily therapeutic doses and 200-2,000 μg/L in poisoned patients. Postmortem blood levels have ranged from 1-4 mg/L in acute lethal overdose situations. Along with the other SSRIs, sertraline and fluoxetine, paroxetine is considered a low-risk drug in cases of overdose.
Interactions with other drugs acting on the serotonin system or impairing the metabolism of serotonin may increase the risk of serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reaction. Such reactions have been observed with SNRIs and SSRIs alone, but particularly with concurrent use of triptans, MAO inhibitors, antipsychotics, or other dopamine antagonists.
The prescribing information states that paroxetine should “not be used in combination with an MAOI (including linezolid, an antibiotic which is a reversible non-selective MAOI), or within 14 days of discontinuing treatment with an MAOI”, and should not be used in combination with pimozide, thioridazine, tryptophan, or warfarin.
Paroxetine interacts with the following cytochrome P450 enzymes:
Paroxetine has been shown to be an inhibitor of G protein-coupled receptor kinase 2 (GRK2).
Paroxetine is the most potent and one of the most specific selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs). It also binds to the allosteric site of the serotonin transporter, similarly, but less potently, than escitalopram. Paroxetine also inhibits the reuptake of norepinephrine to a lesser extent (<50 nmol/L). Based on evidence from four weeks of administration in rats, the equivalent of 20 mg paroxetine taken once daily occupies approximately 88% of serotonin transporters in the prefrontal cortex.
Paroxetine is well-absorbed following oral administration. It has an absolute bioavailability of about 50%, with evidence of a saturable first pass effect. When taken orally, it achieves maximum concentration in about 6-10 hours and reaches steady-state in 7-14 days. Paroxetine exhibits significant interindividual variations in volume of distribution and clearance. Less than 2% of an oral dose is excreted in urine unchanged.
Paroxetine is a mechanism-based inhibitor of CYP2D6.
GlaxoSmithKline has paid substantial fines, paid settlements in class-action lawsuits, and become the subject of several highly critical books about its marketing of paroxetine, in particular the off-label marketing of paroxetine for children, the suppression of negative research results relating to its use in children, and allegations that it failed to warn consumers of substantial withdrawal effects associated with use of the drug. Paroxetine was approved for medical use in the United States in 1992 and initially sold by GlaxoSmithKline. It is currently available as a generic medication. In 2017, it was the 68th most commonly prescribed medication in the United States, with more than eleven million prescriptions. The United States Department of Justice fined GlaxoSmithKline $3 billion in 2012, for withholding data, unlawfully promoting use in those under 18, and preparing an article that misleadingly reported the effects of paroxetine in adolescents with depression following its clinical trial study 329.
In early 2004, GSK agreed to settle charges of consumer fraud for $2.5 million. The legal discovery process also uncovered evidence of deliberate, systematic suppression of unfavourable Paxil research results. One of GSK’s internal documents read, “It would be commercially unacceptable to include a statement that efficacy [in children] had not been demonstrated, as this would undermine the profile of paroxetine”.
In 2012 the US Justice Department announced that GSK agreed to plead guilty and pay a $3 billion fine, in part for promoting the use of Paxil for children.
On 12 February 2016, the UK Competition and Markets Authority imposed record fines of £45 million on companies which were found to have infringed European Union and UK Competition law by entering into agreements to delay the market entry of generic versions of the drug in the UK. GlaxoSmithKline received the bulk of the fines, being fined £37,600,757. Other companies, which produce generics, were issued fines which collectively total £7,384,146. UK public health services are likely to claim damages for being overcharged in the period where the generic versions of the drug were illegally blocked from the market, as the generics are over 70% less expensive. GlaxoSmithKline may also face actions from other generics manufacturers who incurred loss as a result of the anticompetitive conduct. On 18 April 2016, appeals were lodged with the Competition Appeal Tribunal by the companies which were fined.
GSK marketed paroxetine through television advertisements throughout the late 1990s and early 2000s. Commercials also aired for the CR version of the drug beginning in 2003.
In 2007, paroxetine was ranked 94th on the list of bestselling drugs, with over $1 billion in sales. In 2006, paroxetine was the fifth-most prescribed antidepressant in the US retail market, with more than 19.7 million prescriptions. In 2007, sales had dropped slightly to 18.1 million but paroxetine remained the fifth-most prescribed antidepressant in the US.
Trade names include Aropax, Brisdelle, Deroxat, Paxil, Pexeva, Paxtine, Paxetin, Paroxat, Paraxyl, Sereupin, Daparox and Seroxat.
Several studies have suggested that paroxetine can be used in the treatment of premature ejaculation. In particular, intravaginal ejaculation latency time (IELT) was found to increase with 6- to 13-fold, which was somewhat longer than the delay achieved by the treatment with other SSRIs (fluvoxamine, fluoxetine, sertraline, and citalopram). However, paroxetine taken acutely (“on demand”) 3-10 hours before coitus resulted only in a “clinically irrelevant and sexually unsatisfactory” 1.5-fold delay of ejaculation and was inferior to clomipramine, which induced a fourfold delay.
There is also evidence that paroxetine may be effective in the treatment of compulsive gambling and hot flashes.
Benefits of paroxetine prescription for diabetic neuropathy or chronic tension headache are uncertain.
Although the evidence is conflicting, paroxetine may be effective for the treatment of dysthymia, a chronic disorder involving depressive symptoms for most days of the year.
There is evidence to support that paroxetine selectively binds to and inhibits G protein-coupled receptor kinase 2 (GRK2). Since GRK2 regulates the activity of the beta adrenergic receptor, which becomes desensitised in cases of heart failure, paroxetine (or a paroxetine derivative) could be used as a heart failure treatment in the future.
Paroxetine has been deemed to have dmoad activity.
Reboxetine, sold under the brand name Edronax among others, is a drug of the norepinephrine reuptake inhibitor (NRI) class, marketed as an antidepressant by Pfizer for use in the treatment of major depression, although it has also been used off-label for panic disorder and attention deficit hyperactivity disorder (ADHD).
It is approved for use in many countries worldwide, but has not been approved for use in the United States. Although its effectiveness as an antidepressant has been challenged in multiple published reports, its popularity has continued to increase.
Reboxetine was discovered at Farmitalia-Carlo Erba and was first published in 1984; Farmitalia did the first clinical studies. Farmitalia was acquired by Pharmacia in 1993, and Pharmacia in turn was acquired by Pfizer in 2003.
It was first approved in Europe in 1997 and was provisionally approved by the US Food and Drug Administration (FDA) in 1999. In 2001 the FDA issued Pfizer a “not approvable” letter based on clinical trials the FDA had required when it issued the preliminary approval letter.
In 2010, the German Institute for Quality and Efficiency in Health Care (IQEHC) published results of a meta-analysis of clinical trial data for reboxetine in acute depression, which included data on about 3,000 subjects that Pfizer had never published but had mentioned; IQEHC had combed through Pfizer’s publications and reboxetine approvals and had determined this data was missing from the publication record. The analysis of the complete data set yielded a result that reboxetine was not more effective than placebo but had more side effects than placebo and more than fluoxetine; the paper led to widespread and sharp criticism of Pfizer, and stronger calls for publication of all clinical trial data.
There has been much debate as to whether reboxetine is more efficacious than placebo in the treatment of depression. According to a 2009 meta-analysis of 12 second-generation antidepressants, reboxetine was no more effective than placebo, and was “significantly less” effective, and less acceptable, than the other drugs in treating the acute-phase of adults with unipolar major depression.
The UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) said in September 2011 that the study had several limitations, and that “Overall the balance of benefits and risks for reboxetine remains positive in its authorised indication.” A UK and Europe-wide review of available efficacy and safety data has confirmed that reboxetine has benefit over placebo in its authorised indication. Efficacy was clearly shown in patients with severe or very severe depression.
According to a systematic review and meta-analysis by IQWiG, including unpublished data, published data on reboxetine overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm, concluding that reboxetine was an ineffective and potentially harmful antidepressant. The study also showed that nearly three quarters of the data on patients who took part in trials of reboxetine had not been published by Pfizer.
A 2018 systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs concluded that reboxetine was significantly less efficacious than other antidepressants tested.
In a randomised double-blind placebo-controlled trial reboxetine significantly improved the symptoms of panic disorder. Another randomised controlled trial that compared paroxetine to reboxetine found that paroxetine significantly outperformed reboxetine as a treatment for panic disorder. Despite this discouraging finding an open-label trial examining the efficacy of reboxetine in SSRI-resistant panic disorder demonstrated significant benefit from reboxetine treatment.
Numerous clinical trials have provided support for the efficacy of reboxetine in the treatment of attention deficit hyperactivity disorder (ADHD) in both the short and long-term and in both children/adolescents and adults.
A case series and open-label pilot study demonstrated the efficacy of reboxetine in treating bulimia nervosa. Reboxetine may also have efficacy in treating therapy-resistant paediatric nocturnal enuresis. A pilot study demonstrated the efficacy of reboxetine in the treatment of narcolepsy. Individual trials and meta-analysis suggest that reboxetine can attenuate antipsychotic-induced weight gain and there is some evidence of a benefit on depressive, and possibly other symptoms of schizophrenia when added to antipsychotic treatment.
Reboxetine is contraindicated in narrow-angle glaucoma, cardiovascular disease, epilepsy, bipolar disorder, urinary retention, prostatic hypertrophy, patients concomitantly on MAOIs and those hypersensitive to reboxetine or any of its excipients.
Very common (>10% incidence) adverse effects include insomnia, dizziness, dry mouth, constipation, nausea, and excessive sweating.
Common (1-10%) adverse effects include loss of appetite, agitation, anxiety, headache, restlessness, tingling sensations, distorted sense of taste, difficulty with seeing near or far (problems with accommodation), fast heart beat, heart palpitations, relaxing of blood vessels leading to low blood pressure, high blood pressure, vomiting, rash, sensation of incomplete bladder emptying, urinary tract infection, painful or difficult urination, urinary retention, erectile dysfunction, ejaculatory pain or delay, and chills.
A 2009 meta-analysis found that reboxetine was significantly less well tolerated than the other 11 second-generation antidepressants compared in the analysis
Reboxetine is considered a relatively low-risk antidepressant in overdose.[26] The symptoms are as follows:
Because of its reliance on CYP3A4, reboxetine O-desethylation is markedly inhibited by papaverine and ketoconazole. It weakly inhibits CYP2D6 and CYP3A4.[25] Reboxetine is an intermediate-level inhibitor of P-glycoprotein, which gives it the potential to interact with ciclosporin, tacrolimus, paroxetine, sertraline, quinidine, fluoxetine, fluvoxamine.
Reboxetine is a fairly selective norepinephrine reuptake inhibitor (NRI), with approximately 20-fold selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Despite this selectivity, reboxetine does slightly inhibit the reuptake of serotonin at therapeutic doses. It does not interact with or inhibit the dopamine transporter (DAT).
Reboxetine has been found to inhibit both brain and cardiac GIRKs, a characteristic it shares with the NRI atomoxetine.
Both the (R,R)-(–) and (S,S)-(+)-enantiomers of reboxetine are predominantly metabolised by the CYP3A4 isoenzyme. The primary metabolite of reboxetine is O-desethylreboxetine, and there are also three minor metabolites – Phenol A, Phenol B, and UK1, Phenol B being the most minor
Reboxetine has two chiral centres. Thus, four stereoisomers may exist, the (R,R)-, (S,S)-, (R,S)-, and (S,R)-isomers. The active ingredient of reboxetine is a racemic mixture of two enantiomers, the (R,R)-(–)- and (S,S)-(+)-isomer.
Edronax is the brand name of reboxetine in every English-speaking country that has approved it for clinical use. Brand names include (where † denotes a product that is no longer marketed):
Flupentixol (INN), also known as flupenthixol (former BAN), marketed under brand names such as Depixol and Fluanxol is a typical antipsychotic drug of the thioxanthene class.
It was introduced in 1965 by Lundbeck. In addition to single drug preparations, it is also available as flupentixol/melitracen – a combination product containing both melitracen (a tricyclic antidepressant) and flupentixol. Flupentixol is not approved for use in the United States. It is, however, approved for use in the UK, Australia, Canada, Russian Federation, South Africa, New Zealand, Philippines and various other countries.
In March 1963 the Danish pharmaceutical company Lundbeck began research into further agents for schizophrenia, having already developed the thioxanthene derivatives clopenthixol and chlorprothixene. By 1965 the promising agent flupenthixol had been developed and trialled in two hospitals in Vienna by Austrian psychiatrist Heinrich Gross. The long-acting decanoate preparation was synthesised in 1967 and introduced into hospital practice in Sweden in 1968, with a reduction in relapses among patients who were put on the depot.
Flupentixol’s main use is as a long-acting injection given once in every two or three weeks to individuals with schizophrenia who have poor compliance with medication and suffer frequent relapses of illness, though it is also commonly given as a tablet. There is little formal evidence to support its use for this indication but it has been in use for over fifty years.
Flupentixol is also used in low doses as an antidepressant. There is tentative evidence that it reduces the rate of deliberate self-harm, among those who self-harm repeatedly.
Common (>1% incidence) adverse effects include:
Uncommon (0.1-1% incidence) adverse effects include:
Rare (<0.1% incidence) adverse effects include:
Unknown incidence adverse effects include:
It should not be used concomitantly with medications known to prolong the QTc interval (e.g. 5-HT3 antagonists, tricyclic antidepressants, citalopram, etc.) as this may lead to an increased risk of QTc interval prolongation. Neither should it be given concurrently with lithium (medication) as it may increase the risk of lithium toxicity and neuroleptic malignant syndrome. It should not be given concurrently with other antipsychotics due to the potential for this to increase the risk of side effects, especially neurological side effects such as neuroleptic malignant syndrome. It should be avoided in patients on CNS depressants such as opioids, alcohol and barbiturates.
It should not be given in the following disease states:
Flupentixol/melitracen (trade name Frenxit, Placida, Deanxit, Anxidreg, Danxipress) is a combination of two psychoactive agents flupentixol (a typical antipsychotic drug of the thioxanthene class) and melitracen, a tricyclic antidepressant (TCA) which has antidepressant properties.
It is designed for short term usage only. It is produced by Lundbeck.
In pharmacology, a psycholeptic is a medication which produces a calming effect upon a person.
Refer to Analeptic.
Such medications include barbiturates, benzodiazepines, nonbenzodiazepines, phenothiazines, opiates/opioids, carbamates, ethanol, 2-methyl-2-butanol, cannabinoids (in some classifications), some antidepressants, neuroleptics, and some anticonvulsants.
Many herbal medicines may also be classified as psycholeptics (e.g. kava).
Psycholeptics are classified under N05 in the Anatomical Therapeutic Chemical Classification System.
A paradoxical reaction or paradoxical effect is an effect of a chemical substance, typically a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.
Paradoxical reactions are more commonly observed in people with attention deficit hyperactivity disorder (ADHD).
Amphetamines are a class of psychoactive drugs that are stimulants. Paradoxical drowsiness can sometimes occur in adults.
The paradoxical effect or Eagle effect (named after H. Eagle who first described it) refers to an observation of an increase in survivors, seen when testing the activity of an antimicrobial agent. Initially when an antibiotic agent is added to a culture media, the number of bacteria that survive drops, as one would expect. But after increasing the concentration beyond a certain point, the number of bacteria that survive, paradoxically, increases.
In rare cases antidepressants can make users obsessively violent or have suicidal compulsions, which is in marked contrast to their intended effect. This can be regarded as a paradoxical reaction but, especially in the case of suicide, may in at least some cases be merely due to differing rates of effect with respect to different symptoms of depression: If generalised overinhibition of a patient’s actions enters remission before that patient’s dysphoria does and if the patient was already suicidal but too depressed to act on their inclinations, the patient may find themselves in the situation of being both still dysphoric enough to want to commit suicide but newly free of endogenous barriers against doing so. Children and adolescents are more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking antidepressants but cases are still very rare.
Chlorpromazine, an antipsychotic and antiemetic drug, which is classed as a “major” tranquilizer may cause paradoxical effects such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states.
Phenobarbital can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days. Prerequisity for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital.
Benzodiazepines, a class of psychoactive drugs called the “minor” tranquilisers, have varying hypnotic, sedative, anxiolytic, anticonvulsant, and muscle relaxing properties, but they may create the exact opposite effects. Susceptible individuals may respond to benzodiazepine treatment with an increase in anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behaviour, and even convulsions. Paradoxical adverse effects may even lead to criminal behaviour. Severe behavioural changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity, and hypomania.
Paradoxical rage reactions due to benzodiazepines occur as a result of an altered level of consciousness, which generates automatic behaviours, anterograde amnesia and uninhibited aggression. These aggressive reactions may be caused by a disinhibiting serotonergic mechanism.
Paradoxical effects of benzodiazepines appear to be dose related, that is, likelier to occur with higher doses.
In a letter to the British Medical Journal, it was reported that a high proportion of parents referred for actual or threatened child abuse were taking medication at the time, often a combination of benzodiazepines and tricyclic antidepressants. Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilisers may precipitate a child abuse event.
Self aggression has been reported and also demonstrated in laboratory conditions in a clinical study. Diazepam was found to increase people’s willingness to harm themselves.
Benzodiazepines can sometimes cause a paradoxical worsening of EEG readings in patients with seizure disorders.
Barbiturates such as pentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of attention deficit hyperactivity disorder. Intravenous caffeine administration can return these patients’ behaviour to baseline levels.
The mechanism of a paradoxical reaction has as yet (2019) not been fully clarified, in no small part due to the fact that signal transfer of single neurons in subcortical areas of the human brain is usually not accessible.
There are, however, multiple indications that paradoxical reactions upon – for example – benzodiazepines, barbiturates, inhalational anaesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABAA receptors. The combination of the five subunits of the receptor (see image) can be altered in such a way that for example the receptor’s response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one.
There are estimates that about 2-3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.
Adinazolam (marketed under the brand name Deracyn) is a tranquiliser of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring.
It possesses anxiolytic, anticonvulsant, sedative, and antidepressant properties. Adinazolam was developed by Dr. Jackson B. Hester, who was seeking to enhance the antidepressant properties of alprazolam, which he also developed. Adinazolam was never approved by the US Food and Drug Administration (FDA) and never made available to the public market, however it has been sold as a designer drug.
Overdose may include muscle weakness, ataxia, dysarthria and particularly in children paradoxical excitement, as well as diminished reflexes, confusion and coma may ensue in more severe cases.
A human study comparing the subjective effects and abuse potential of adinazolam (30 mg and 50 mg) with diazepam, lorazepam and a placebo showed that adinazolam causes the most “mental and physical sedation” and the greatest “mental unpleasantness”.
Adinazolam binds to peripheral-type benzodiazepine receptors that interact allosterically with GABA receptors as an agonist to produce inhibitory effects.
Adinazolam was reported to have active metabolites in the August 1984 issue of The Journal of Pharmacy and Pharmacology. The main metabolite is N-desmethyladinazolam. NDMAD has an approximately 25-fold high affinity for benzodiazepine receptors as compared to its precursor, accounting for the benzodiazepine-like effects after oral administration. Multiple N-dealkylations lead to the removal of the dimethylaminomethyl side chain, leading to the difference in its potency. The other two metabolites are alpha-hydroxyalprazolam and estazolam. In the August 1986 issue of that same journal, Sethy, Francis and Day reported that proadifen inhibited the formation of N-desmethyladinazolam.
Lofepramine, sold under the brand names Gamanil, Lomont, and Tymelyt among others, is a tricyclic antidepressant (TCA) which is used to treat depression.
The TCAs are so named as they share the common property of having three rings in their chemical structure. Like most TCAs lofepramine is believed to work in relieving depression by increasing concentrations of the neurotransmitters norepinephrine and serotonin in the synapse, by inhibiting their reuptake. It is usually considered a third-generation TCA, as unlike the first- and second-generation TCAs it is relatively safe in overdose and has milder and less frequent side effects.
Lofepramine is not available in the United States, Canada, Australia or New Zealand, although it is available in Ireland, Japan, South Africa and the United Kingdom, among other countries.
Lofepramine was developed by Leo Läkemedel AB. It first appeared in the literature in 1969 and was patented in 1970. The drug was first introduced for the treatment of depression in either 1980 or 1983.
In the United Kingdom, lofepramine is licensed for the treatment of depression which is its primary use in medicine.
Lofepramine is an efficacious antidepressant with about 64% patients responding to it.
To be used with caution, or not at all, for people with the following conditions:
And in those being treated with amiodarone or terfenadine.
Lofepramine use during pregnancy is advised against unless the benefits clearly outweigh the risks. This is because its safety during pregnancy has not been established and animal studies have shown some potential for harm if used during pregnancy. If used during the third trimester of pregnancy it can cause insufficient breathing to meet oxygen requirements, agitation and withdrawal symptoms in the infant. Likewise its use by breastfeeding women is advised against, except when the benefits clearly outweigh the risks, due to the fact it is excreted in the breast milk and may therefore adversely affect the infant. Although the amount secreted in breast milk is likely too small to be harmful.
The most common adverse effects (occurring in at least 1% of those taking the drug) include agitation, anxiety, confusion, dizziness, irritability, abnormal sensations, like pins and needles, without a physical cause, sleep disturbances (e.g. sleeplessness) and a drop in blood pressure upon standing up. Less frequent side effects include movement disorders (like tremors), precipitation of angle closure glaucoma and the potentially fatal side effects paralytic ileus and neuroleptic malignant syndrome.
Dropout incidence due to side effects is about 20%.
Side effects with unknown frequency include (but are not limited to):
If abruptly stopped after regular use it can cause withdrawal effects such as sleeplessness, irritability and excessive sweating.
Refer to Tricyclic Antidepressant Overdose.
Compared to other TCAs, lofepramine is considered to be less toxic in overdose. Its treatment is mostly a matter of trying to reduce absorption of the drug, if possible, using gastric lavage and monitoring for adverse effects on the heart.
Lofepramine is known to interact with:
Lofepramine is a strong inhibitor of norepinephrine reuptake and a moderate inhibitor of serotonin reuptake. It is a weak-intermediate level antagonist of the muscarinic acetylcholine receptors.
Lofepramine has been said to be a prodrug of desipramine, although there is also evidence against this notion.
Lofepramine is extensively metabolised, via cleavage of the p-chlorophenacyl group, to the TCA, desipramine, in humans. However, it is unlikely this property plays a substantial role in its overall effects as lofepramine exhibits lower toxicity and anticholinergic side effects relative to desipramine while retaining equivalent antidepressant efficacy. The p-chlorophenacyl group is metabolised to p-chlorobenzoic acid which is then conjugated with glycine and excreted in the urine. The desipramine metabolite is partly secreted in the faeces. Other routes of metabolism include hydroxylation, glucuronidation, N-dealkylation and N-oxidation.
Lofepramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include imipramine, desipramine, clomipramine, and trimipramine. Lofepramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine. Unlike other tertiary amine TCAs, lofepramine has a bulky 4-chlorobenzoylmethyl substituent on its amine instead of a methyl group. Although lofepramine is technically a tertiary amine, it acts in large part as a prodrug of desipramine, and is more similar to secondary amine TCAs in its effects. Other secondary amine TCAs besides desipramine include nortriptyline and protriptyline. The chemical name of lofepramine is N-(4-chlorobenzoylmethyl)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine and its free base form has a chemical formula of C26H27ClN2O with a molecular weight of 418.958 g/mol. The drug is used commercially mostly as the hydrochloride salt; the free base form is not used. The CAS Registry Number of the free base is 23047-25-8 and of the hydrochloride is 26786-32-3.
Lofepramine is the generic name of the drug and its INN and BAN, while lofepramine hydrochloride is its USAN, BANM, and JAN. Its generic name in French and its DCF are lofépramine, in Spanish and Italian and its DCIT are lofepramina, in German is lofepramin, and in Latin is lofepraminum.
Brand names of lofepramine include Amplit, Deftan, Deprimil, Emdalen, Gamanil, Gamonil, Lomont, Tymelet, and Tymelyt.
In the United Kingdom, lofepramine is marketed (as the hydrochloride salt) in the form of 70 mg tablets and 70 mg/5 mL oral suspension.
A formulation containing lofepramine and the amino acid phenylalanine is under investigation as a treatment for fatigue as of 2015.
Phenelzine, sold under the brand name Nardil, among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class which is used as an antidepressant and anxiolytic. Along with tranylcypromine and isocarboxazid, phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use. It is taken by mouth.
In June 2020, the Therapeutic Goods Administration (TGA) reported that the availability of phenelzine was discontinued in Australia due to global issues with the manufacture of the active pharmaceutical ingredient. However, unapproved phenelzine products may be accessed through alternative pathways, such as the Special Access Scheme (SAS) administered by the TGA. In October 2020, The TGA authorized two sponsors to supply an overseas-registered brand of phenelzine in Australia. In May 2020, the Specialist Pharmacy Service in the UK reported the unavailability of phenelzine from the sole supplier. In July 2020, supplies of unlicensed phenelzine 15mg capsule specials became available for UK patients. In February 2021, Phenelzine again became available in Australia as a subsidised medication through the Pharmaceutical Benefits Scheme.
Synthesis of phenelzine was first described by Emil Votoček and Otakar Leminger in 1932.
Phenelzine is used primarily in the treatment of major depressive disorder (MDD). Patients with depressive symptomology characterised as “atypical”, “nonendogenous”, and/or “neurotic” respond particularly well to phenelzine. The medication is also useful in patients who do not respond favourably to first and second-line treatments for depression, or are “treatment-resistant”. In addition to being a recognised treatment for major depressive disorder, phenelzine is effective in treating dysthymia, bipolar depression (BD), panic disorder (PD), social anxiety disorder, bulimia, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). Phenelzine showed promise in a phase II clinical trial from March 2020 in treating prostate cancer.
Phenelzine is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It inhibits both of the respective isoforms of MAO, MAO-A and MAO-B, and does so almost equally, with slight preference for the former. By inhibiting MAO, phenelzine prevents the breakdown of the monoamine neurotransmitters serotonin, melatonin, norepinephrine, epinephrine, and dopamine, as well as the trace amine neuromodulators such as phenethylamine, tyramine, octopamine, and tryptamine. This leads to an increase in the extracellular concentrations of these neurochemicals and therefore an alteration in neurochemistry and neurotransmission. This action is thought to be the primary mediator in phenelzine’s therapeutic benefits.
Phenelzine and its metabolites also inhibit at least two other enzymes to a lesser extent, of which are alanine transaminase (ALA-T), and γ-Aminobutyric acid transaminase (GABA-T), the latter of which is not caused by phenelzine itself, but by a phenelzine metabolite phenylethylidenehydrazine (PEH). By inhibiting ALA-T and GABA-T, phenelzine causes an increase in the alanine and GABA levels in the brain and body. GABA is the major inhibitory neurotransmitter in the mammalian central nervous system, and is very important for the normal suppression of anxiety, stress, and depression. Phenelzine’s action in increasing GABA concentrations may significantly contribute to its antidepressant, and especially, anxiolytic/antipanic properties, the latter of which have been considered superior to those of other antidepressants. As for ALA-T inhibition, though the consequences of disabling this enzyme are currently not well understood, there is some evidence to suggest that it is this action of the hydrazines (including phenelzine) which may be responsible for the occasional incidence of hepatitis and liver failure.
Phenelzine has also been shown to metabolise to phenethylamine (PEA). PEA acts as a releasing agent of norepinephrine and dopamine, and this occurs in the same manner as amphetamine (very similar in structure) by being taken up into vesicles, and displacing, and causing the release of those monoamines (though with markedly different pharmacokinetics such as a far shorter duration of action). Although this is indeed the same mechanism to which some (but not all) of amphetamine’s effects are attributable to, this is not all that uncommon a property among phenethylamines in general, many of which do not have psychoactive properties comparable to amphetamine. Amphetamine is different in that it binds with high affinity to the reuptake pumps of dopamine, norepinephrine, and serotonin, which phenethylamine and related molecules may as well to some extent, but with far less potency, such that it is basically insignificant in comparison. And, often being metabolized too quickly or not having the solubility to enable it to have a psychostimulant effect in humans. Claims that phenethylamine has comparable or roughly similar effects to psychostimulants such as amphetamine when administered are misconstrued. Phenethylamine does not have any obvious, easily discernible, reliably induced effects when administered to humans. Phenelzine’s enhancement of PEA levels may contribute further to its overall antidepressant effects to some degree. In addition, phenethylamine is a substrate for MAO-B, and treatment with MAOIs that inhibit MAO-B such as phenelzine have been shown to consistently and significantly elevate its concentrations.
Phenelzine usually requires six to eight weeks of treatment, and a minimum dose of 60 mg/day, to achieve therapeutic effects. The reason for the delay in therapeutic effect is not fully understood, but it is believed to be due to many factors, including achieving steady-state levels of MAO inhibition and the resulting adaptations in mean neurotransmitter levels, the possibility of necessary desensitisation of autoreceptors which normally inhibit the release of neurotransmitters like serotonin and dopamine, and also the upregulation of enzymes such as serotonin N-acetyltransferase. Typically, a therapeutic response to MAOIs is associated with an inhibition of at least 80-85% of monoamine oxidase activity.
Phenelzine is administered orally in the form of phenelzine sulfate and is rapidly absorbed from the gastrointestinal tract. Time to peak plasma concentration is 43 minutes and half-life is 11.6 hours. Unlike most other drugs, phenelzine irreversibly disables MAO, and as a result, it does not necessarily need to be present in the blood at all times for its effects to be sustained. Because of this, upon phenelzine treatment being ceased, its effects typically do not actually wear off until the body replenishes its enzyme stores, a process which can take as long as 2-3 weeks.
Phenelzine is metabolised primarily in the liver and its metabolites are excreted in the urine. Oxidation is the primary routine of metabolism, and the major metabolites are phenylacetic acid and parahydroxyphenylacetic acid, recovered as about 73% of the excreted dose of phenelzine in the urine over the course of 96 hours after single doses. Acetylation to N2-acetylphenelzine is a minor pathway. Phenelzine may also interact with cytochrome P450 enzymes, inactivating these enzymes through formation of a heme adduct. Two other minor metabolites of phenelzine, as mentioned above, include phenylethylidenehydrazine and phenethylamine.
Common side effects of phenelzine may include dizziness, blurry vision, dry mouth, headache, lethargy, sedation, somnolence, insomnia, anorexia, weight gain or loss, nausea and vomiting, diarrhoea, constipation, urinary retention, mydriasis, muscle tremors, hyperthermia, sweating, hypertension or hypotension, orthostatic hypotension, paraesthesia, hepatitis, and sexual dysfunction (consisting of loss of libido and anorgasmia). Rare side effects usually only seen in susceptible individuals may include hypomania or mania, psychosis and acute liver failure, the last of which is usually only seen in people with pre-existing liver damage, old age, long-term effects of alcohol consumption, or viral infection.
The MAOIs have certain dietary restrictions and drug interactions. The amount of such restrictions and interactions is far less than previously thought, and MAOIs are generally safe medications when administered correctly. Hypertensive crisis is generally a rare occurrence while taking MAOIs, yet may result from the overconsumption of tyramine-containing foods. As a result, patients on phenelzine and other MAOIs must avoid excess quantities of certain foods that contain tyramine such as aged cheeses and cured meats, among others. Serotonin syndrome may result from an interaction with certain drugs which increase serotonin activity such as selective serotonin reuptake inhibitors, serotonin releasing agents, and serotonin agonists. Several deaths have been reported due to drug interaction-related serotonin syndrome such as the case of Libby Zion.
As is the case with other MAOIs, there is a concern regarding phenelzine and the use of both local and general anesthetics. Anyone taking phenelzine should inform their dentist before proceeding with dental surgery, and surgeon in any other contexts.
Phenelzine has also been linked to vitamin B6 deficiency. Transaminases such as GABA-transaminase have been shown to be dependent upon vitamin B6 and may be involved in a potentially related process, since the phenelzine metabolite phenylethylidenehydrazine (PEH) is a GABA transaminase inhibitor. Both phenelzine and vitamin B6 are rendered inactive upon these reactions occurring. For this reason, it may be recommended to supplement with vitamin B6 while taking phenelzine. The pyridoxine form of B6 is recommended for supplementation, since this form has been shown to reduce hydrazine toxicity from phenelzine and, in contrast, the pyridoxal form has been shown to increase the toxicity of hydrazines.
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