(British Approved Name, rINN)

Citalopram Hydrobromide

(British Approved Name Modified, rINNM)

Drug Nomenclature

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Citalopram Hydrobromide). A white to almost white, crystalline powder. Freely soluble in water, in alcohol, and in chloroform. A 0.5% solution in water has apH of 5.5 to 6.5.

Citalopram Hydrochloride

Drug Approvals

(British Approved Name Modified, rINNM)

Adverse Effects, Treatment, and Precautions

As for SSRIs in general (see Fluoxetine) although increased appetite and weight gain have also been reported with citalopram. Citalopram may be more cardiotoxic in overdosage than other SSRIs for further details.

Breast feeding. For comments on the use of SSRIs in breast feeding patients, see under Precautions for Fluoxetine.

Children. SSRIs are associated with an increased risk of potentially suicidal behaviour when used for the treatment of depression in children and adolescents under 18 years old for further details, see under Effects on Mental State in Fluoxetine.

Interactions

For interactions associated with SSRIs, see Fluoxetine.

Pharmacokinetics

Citalopram is readily absorbed from the gastrointestinal tract and maximum plasma concentrations are reached 2 to 4 hours after oral doses. Citalopram is widely distributed throughout the body protein binding is less than 80%. Citalopram is metabolised by demethylation, deamination, and oxidation to active and inactive metabolites. The demethylation of citalopram to one of its active metabolites, demethylcitalopram, involves the cytochrome P450 isoenzymes CYP3A4 and CYP2C19 the metabolism of citalopram is also partly dependent on CYP2D6. Didemeth-ylcitalopram has also been identified as a metabolite of citalopram. The elimination half-life of citalopram is reported to be about 36 hours. It is excreted mainly via the liver (85%) with the remainder via the kidneys. About 12% of the daily dose is excreted in the urine as unchanged drug. Citalopram is distributed into breast milk in very low concentrations (see Breast Feeding under Precautions in Fluoxetine).

Uses and Administration

Citalopram, a phthalane derivative, is an SSRI with actions and uses similar to those of fluoxetine. Citalopram is given orally as the hydrobromide or hydrochloride, usually as a single daily dose. Doses are expressed in terms of citalopram citalopram hydrobromide 25.0 mg and citalopram hydrochloride 22.3 mg are each equivalent to about 20.0 mg of citalopram.

In the treatment of depression, the initial dose (given as tablets or a liquid) is the equivalent of 20 mg daily by mouth. After at least one week, the dose may be increased to 40 mg daily a dose of 60 mg daily may be necessary in some patients. In the UK citalopram is also given as the hydrochloride in the form of concentrated oral drops containing the equivalent of 40 mg/mL of citalopram. The bioavailability of the drops is about 25% greater than that of the tablets and consequently daily doses appear to be lower: a 20-mg tablet dose is equivalent to a 16-mg (8 drops) dose of the concentrate. In some countries, citalopram hydrochloride has also been given by intravenous infusion in doses of 20 to 40 mg when the oral route is impracticable.

In the treatment of panic disorder with or without agoraphobia, the initial oral dose is 10 mg (or the equivalent as the concentrate) daily increasing to 20 mg daily after one week. The dose may be increased thereafter as required up to a maximum of 60 mg daily. In some countries citalopram is also used in the treatment of obsessive-compulsive disorder in doses similar to those used in depression (see above). A dose of 20 mg daily, up to a maximum of 40 mg (or their equivalents as the concentrate), should be used in elderly patients. For dosage in hepatic and renal impairment see below.

Citalopram should be withdrawn gradually to reduce the risk of withdrawal symptoms.

The S-enantiomer of citalopram, escitalopram is given for the treatment of depression and some anxiety disorders.

Administration in hepatic or renal impairment. Licensed drug information suggests that dosage of citalopram should be restricted to the lower end of the dose range in patients with hepatic impairment. A usual oral dose for depression in this group would be 20 mg daily although the dose may be increased up to 40 mg daily, if necessary.

There is no need for dose adjustment in mild to moderate renal impairment although information is lacking on appropriate dosage in severe impairment.

Anxiety disorders. Citalopram has been given in anxiety disorders including panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and social anxiety disorder (see under Phobic Disorders.

Depression. As discussed, there is very little difference in efficacy between the different groups of antidepressant drugs. SSRIs such as citalopram are widely used as an alternative to the older tricyclics as they have fewer adverse effects and are safer in overdosage.

Pathological crying or laughing. Inappropriate or uncontrolled crying or laughing can occur in patients with lesions in certain areas of the brain. Attempts at treatment have mostly been with antidepressant drugs, including SSRIs. Favourable results with citalopram have been reported in a double-blind placebo-controlled study and in case reports.

Schizophrenia. The treatment of schizophrenia consists mainly of a combination of social therapy and antipsychotic drugs. Like other antidepressants, citalopram has been examined for its potential value as an adjuvant in schizophrenia. In a preliminary placebo-controlled study in 15 patients with chronic schizophrenia who exhibited signs of impulsive aggression, adding citalopram to existing antipsychotic therapy significantly reduced the frequency, but not the average severity, of aggressive incidents. In a subsequent study involving 90 patients, citalopram appeared to improve subjective well-being but had no clear effect onpsychopathological symptoms.

Sexual dysfunction. SSRIs have been tried in the treatment of premature ejaculation, but results with citalopram have been conflicting, see under Fluoxetine.

Preparations

The United States Pharmacopeia 31, 2008: Citalopram Tablets.

Proprietary Preparations

Argentina: Humorap Psiconor Seropram Zentius

Australia: Celapram Ciazil Cipramil Talam Talohexal

Austria: Apertiaf Cipram † Cital hexal † Citalon † Citalostad Citarcana Citor Eostar Pram Sepramf Seropram

Belgium: Cipramil

Brazil: Alcytam Cipramil Citta Denyl Prodmax

Canada: Celexa

Chile: Actipram Cimal Cipramil Cortran Finap Pramcil Prisma Semax Setronil Temperax Zebrak Zentius

Czech Republic: Apertiaf Apo-Cital Cerotor Cipram Cita Citalec Citalon Citaratio Dalsan Pram Sepramf Seropram Zyloram

Denmark: Akarin Cipramil Citadur Citaham

Finland: Cipramil Emocalf Sepram

France: Seropram

Germany: Cilex Cipramil Citadura CitaLich Citalo-Q Citalon Sepramf Serital

Hong Kong: Cipram Cital

Hungary: Citagen Citalodep Citalon Citalowin Citapram Dalsan Oropram Seropram Serotor Zyloram

India: Citadep Citopam

Indonesia: Cipram

Ireland: Ciprager Cipramil Ciprapine Ciprotan Citrol

Israel: Cipramil Recital

Italy: Elopram Felipram Feliximir Frimaind Kaidor Lampopram Marpram Percital Pramexyl Reap Seropram Verisan

Malaysia: Cipram

Mexico: Citox Seropram Xylorane

The Netherlands: Cipramil Ciprapine Lontax

Norway: Cipramil Desital

New Zealand: Celapram Cipramil

South Africa: Adco-Talomil Cilift Cipramil CitaloHexal Depramil Talomil

Singapore: Cipram

Spain: Citalvir Genprol Presar Prisdal Relapaz Seropram Somac

Sweden: Cipramil Citavie

Switzerland: Alutan Claropram Rudopram Seropram

Thailand: Cipram

Turkey: Cipram Citara Citol Citolap

UK: Cipramil

USA: Celexa

Venezuela: Seropram

(BANM, US Adopted Name, rINNM)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Bupropion Hydrochloride). A white powder. Soluble in water, in alcohol, and in 0.1N hydrochloric acid. Protect from light.

Adverse Effects and Treatment

Agitation, anxiety, and insomnia often occur during the initial stages of bupropion therapy. Other relatively common adverse effects reported with bupropion include fever, dry mouth, headache or migraine, dizziness, urinary frequency, nausea and vomiting, constipation, tremor, sweating, and skin rashes. Hypersensitivity reactions, ranging from pruritus and urticaria to, less commonly, angioedema, dyspnoea, and anaphylactoid reactions, have occurred, as have symptoms suggestive of serum sickness. There have been rare reports of Stevens-Johnson syndrome and erythema multiforme. Tachycardia, chest pain, and hypertension (sometimes severe), or occasionally vasodilatation, orthostatic hypotension, palpitations, and syncope have been reported. Psychotic episodes, confusion, nightmares, impaired memory, dysgeusia, anorexia with weight loss, paraesthesia, tinnitus, and visual disturbances have also been reported. Hyponatraemia, possibly due to inappropriate secretion of antidiuretic hormone, has been associated with the use of antidepressants, particularly in the elderly. Seizures, which appear to be partially dose-related, may occur with bupropion and have been particularly notable in patients with anorexia nervosa or bulimia nervosa the risk is also increased in patients with a history of seizure disorders or other predisposing factor. The manufacturers state that the overall incidence of seizure in patients receiving bupropion at recommended doses is about 0.1 to 0.4%.

Symptoms of overdosage include hallucinations, nausea and vomiting, tachycardia, loss of consciousness, and death (following massive overdose) seizures have occurred in about one-third of all bupropion overdose cases. Activated charcoal should be considered in adult patients who have taken more than 450 mg and in all children, if they present within 1 hour of ingestion gastric lavage may also be used to decrease absorption. Treatment is supportive. Benzodiazepines may be tried for seizures. Diuresis, dialysis, and haemoperfusion are unlikely to be of benefit.

Incidence of adverse effects. Up to 24 July 2002 (the first 25 months of marketing), the UK CSM had received 7630 reports of suspected adverse reactions associated with the use of bupropion. Of these reports, 60 were associated with a fatal outcome although in most cases underlying conditions could have been responsible. Cardiovascular and cerebrovascular disorders such as myocardial infarction and stroke were reported as the cause of death in 70% of cases. The CSM also commented that adverse reactions were mainly recognised ones and listed in the licensed product information.

In January 2005 the German pharmacovigilance network reviewed 273 reports of adverse effects associated with bupropion, received between June 2000 and September 2004. The most frequent adverse effects were: psychiatric disorders (79.3%), including suicide attempts (17.6%), and tachycardia (11.15%), seizures (8.8%), and dyspnoea (8.8%). There were also 4 cases of pancreatitis and one of raised pancreatic enzyme activity three times greater than normal.

Effects on the cardiovascular system. Up to the end of December 2001 the national pharmacovigilance centre in the Netherlands had received 591 adverse reaction reports associated with the use of bupropion for smoking cessation since its marketing 2 years earlier of these, 45 concerned cardiac complaints such as palpitations (21), arrhythmias (7), myocardial infarction (3), anginal pain (2), and cardiac arrest (1). Twenty-two reports also mentioned chest pain or tightness, although these were considered to be of noncardiac origin. In another report a 43-year-old male suffered an acute myocardial infarction 2 weeks after starting bupropion for smoking cessation he had experienced central chest and arm pain 3 days before the infarction. The authors of the report said that up to 30 April 2001 the UK CSM had received 23 8 reports of chest pain and 134 reports of chest tightness associated with bupropion use.

Effects on the cerebrovascular system. A 67-year-old male had paraesthesia, dizziness, tinnitus, confusion, and gait impairment after taking bupropion for smoking cessation. Although a transient ischaemic attack was suspected symptoms resolved on stopping bupropion and recurred on rechallenge.

Effects on the pancreas. See under Incidence of Adverse Effects, above.

Effects on the skin. Erythema multiforme developed in a 31-year-old woman several weeks after starting modified-release bupropion for depression. Symptoms resolved on drug withdrawal. In another report, 3 patients with controlled psoriasis had an exacerbation of their psoriatic symptoms after starting bupropion for smoking cessation. All 3 patients required hospitalisation to control their symptoms. There have also been several reports of patients developing generalised acute urticaria systemic symptoms resembling serum sickness were also reported in 1 case (see also Hypersensitivity, below).

Extrapyramidal effects. A 44-year-old man had acute head and neck dystonia while taking buspirone and modified-release bupropion. No recurrence was noted on rechallenge with buspirone although symptoms did develop on rechallenge with bupropion when the dose was increased from 150 mg once daily to 150 mg twice daily. In another case, a 42-year-old woman had gross involuntary movements of her torso, arms, and legs (diagnosed as ballism) 8 days after starting bupropion for smoking cessation the dose had been increased from 150 mg once daily to 150 mg twice daily on the fourth day. She recovered when bupropion was stopped and treatment with haloperidol and ox-azepam was given.

Hypersensitivity. Eosfnophilia has been reported in a patient 12 days after bupropion was added to her existing treatment regimen of glibenclamide and tolmetin. The eosinophil count returned to normal after all medication was stopped. Bupropion appeared to be the causative drug.

Serum sickness or symptoms suggestive of serum sickness has also been associated with bupropion use. In one case, although the initial presentation resembled serum sickness, the patient went on to develop multisystem complications that included hepatitis, cholestasis, and myocarditis. See also Effects on the Skin, above.

Overdosage. Unlike the tricyclic antidepressants, bupropion appears to lack any significant cardiovascular or antimuscarinic adverse effects when taken in overdose. In an early review of 5 8 overdose cases involving immediate-release bupropion alone, the most common symptoms were sinus tachycardia, lethargy, tremor, and seizures other effects included confusion, lighthead-edness, hallucinations, paraesthesias, and vomiting. Most patients had minor effects or none at all. Similar symptoms have also been noted in reviews of overdose cases involving modified-release bupropion. UK licensed prescribing information for bupropion also lists ECG changes such as conduction disturbances, arrhythmias, and tachycardia although a literature review concluded that cardiotoxicity appeared to be rare with bupropion overdosage. Although rare, there have been fatalities after overdose in some cases other drugs may have been involved.

More recent case reports and reviews with modified-release preparations have highlighted that seizures are a particular feature of bupropion overdose.

Precautions

Bupropion may induce seizures and consequently its use is contra-indicated in patients with epilepsy. It is also contra-indicated in patients with a history of anorexia nervosa or bulimia nervosa, as a higher incidence of seizures has been noted in such patients treated with bupropion, and in those undergoing abrupt withdrawal from alcohol or benzodiazepines. It should be used with extreme caution, if at all, in patients with a history of seizure disorders or other predisposing factors such as severe hepatic cirrhosis or a CNS tumour. The use of bupropion in patients with other risk factors for seizures (for example, alcohol abuse, a history of head trauma, diabetes, and drugs known to lower the seizure threshold) should only be undertaken when there are compelling clinical reasons.

Bupropion should be used with caution in patients with bipolar disorder or psychoses because of the risk of precipitating mania use for smoking cessation in such patients may be contra-indicated. It should also be used cautiously in patients with a recent history of myocar-dial infarction or unstable heart disease, and in hepatic or renal impairment.

When bupropion is used for depression, patients should be closely monitored during early therapy until significant improvement is observed because suicide is an inherent risk in depressed patients. For further details, see under Depression. Suicidal thoughts and behaviour may also develop during early treatment with antidepressants for other disorders the same precautions observed when treating patients with depression should therefore be observed when treating patients with other disorders.

As with other CNS-active drugs, the ability to perform tasks requiring motor or cognitive skills or judgement may be impaired by bupropion, and patients, if affected, should not drive or operate machinery.

Breast feeding. The American Academy of Pediatrics considers that the effect of bupropion on nursing infants is unknown but may be of concern.

There has been a report of accumulation of bupropion in human breast milk in concentrations higher than those in maternal plasma. However, neither bupropion nor its metabolites were detected in the plasma of the infant who was breast fed twice daily by the affected mother, and no adverse effects were noted in the infant. Similar findings have been noted in a more recent study in 2 breast-fed infants whose mothers took bupropion for post-partum depression. However, in another report, a 6-month-old infant had a seizure after being fed breast milk that had been expressed and stored 2 days earlier, after the infant’s mother had taken a single dose of bupropion. Before the seizure, the mother had taken 2 doses of bupropion and breast fed the infant several times with no adverse effects.

Children. Bupropion has not been studied for the treatment of depression in adolescents and children consequently its use in patients under 18 years of age, regardless of indication, is not recommended. In addition, other antidepressants have been shown to increase the risk of suicidal thoughts and behaviour in these patients (see Effects on Mental State, under Fluoxetine).

Pregnancy. The safety of bupropion in pregnancy has not been established. In a study of 136 women who took bupropion for either depression or smoking cessation in at least the first trimester of pregnancy, there were 105 live births, 20 spontaneous abortions, 10 therapeutic abortions, 1 still-birth, and 1 neonatal death no major congenital malformations were reported.^l Compared to a control group not exposed to teratogens, the rate of spontaneous abortions was significantly higher in the bupropion group when both indications were considered however, there was no difference in the rate when women taking bupropion for depression were compared to this control group and another control group of women taking other antidepressants.

Complications at birth requiring prolonged hospitalisation, breathing support, and tube feeding have been reported with some of the newer antidepressants such as bupropion. Other reported symptoms have included seizures, muscle rigidity, jitteriness, and prolonged crying. It is not known whether such symptoms represent a direct toxicity of bupropion or a possible withdrawal syndrome.

Interactions

Bupropion should not be given with or within 14 days of stopping an MAOI however, no treatment-free period is necessary after stopping a reversible inhibitor of monoamine oxidase type A (RIMA) and starting bupropion.

The use of alcohol with bupropion should be minimised or avoided completely because it may alter the seizure threshold. Similarly, extreme caution is needed if other drugs that lower the seizure threshold, such as other antidepressants, antimalarials, antipsychotics, sedating antihistamines, quinolones, tramadol, theophylline, or systemic corticosteroids are used with bupropion. In the UK, where it is licensed as a modified-release product for smoking cessation, a maximum dose of 150 mg daily is recommended if patients are also taking such drugs.

Use of nicotine transdermal patches with bupropion has been associated with hypertension, and patients using both should therefore have their blood pressure monitored.

Caution has been advised in patients receiving either amantadine or levodopa with bupropion because of reports of a higher incidence of adverse effects in patients receiving these combinations.

Animal studies have indicated that bupropion may induce drug-metabolising enzymes and pharmacokinetic interactions with other drugs are therefore a possibility. Bupropion is itself metabolised by hepatic enzyme systems and drugs known to affect such systems may interact with bupropion. For example carbamazepine, phenobarbital, or phenytoin may induce the metabolism of bupropion while other drugs such as cimetidine or valproate may inhibit its metabolism. In-vitro studies have shown that bupropion is metabolised by the cytochrome P450 isoenzyme CYP2B6. Consequently interactions may occur between bupropion and drugs that affect this isoenzyme, for example orphenadrine, cyclophosphamide, and ifosfamide.

In-vitro studies have also shown that bupropion is also an inhibitor of the isoenzyme CYP2D6 caution should be exercised when it is given with drugs metabolised by this isoenzyme and they should be started at the lower end of their dose range. Such drugs include some antidepressants, antipsychotics, beta blockers, and type Ic antiarrhythmics.

Antiepileptics. Plasma-bupropion concentrations became un-detectable in 2 patients who were also receiving carbamazepine, plasma concentrations of hydroxybupropion, an active metabolite of bupropion, were high.

Antivirals. There is some evidence from study in vitro that the antivfrals efavirenz, nelfinavir and ritonavir can inhibit the cytochrome P450 isoenzyme CYP2B6, and licensed product information for ritonavir mentions the possibility of an interaction with bupropion. However, evidence of clinically significant interaction is lacking: a small case series of 10 patients who took bupropion with low-dose ritonavir (100 mg twice daily), or efavirenz or nelfinavir, did not note any episodes of seizures. A study in 7 healthy male subjects also found that 2 days of low-dose ritonavir (200 mg twice daily) had little impact on the pharmacokinetics of a single bupropion dose. In contrast, the UK licensed product information for bupropion describes a study in healthy subjects in which 20 days of full-dose ritonavir (600 mg twice daily) reduced the area under the concentration-time curve (AUC) and maximum plasma concentration of bupropion, possibly by inducing its metabolism. Plasma concentrations of bupropion’s active metabolites were also reduced. In another study in healthy subjects, the plasma concentrations and AUC of bupropion and its active metabolite hydroxybupropion, from a single dose of bupropion, were reduced by about 50% after 14 days of a lopinavir/ritonavir combination (400 mg/100 mg twice daily). This effect was attributed to induction of CYP2B6 and UDP-glucuronosyltransferase by the HIV-protease inhibitor combination. In discussing the contrasting results that have been reported, the authors suggested that the higher ritonavir concentrations achieved in-vitro had an inhibitory effect, compared with the inducing effect of lower steady-state concentrations achieved in-vivo.

Histamine H₂-antagonists. A randomised controlled study in 24 subjects found that cimetidine had no effect on the pharma-cokinetics of modified-release bupropion or its active metabolite, hy droxybupropion.

Pharmacokinetics

Bupropion is well absorbed from the gastrointestinal tract but may undergo extensive first-pass metabolism. Several metabolites of bupropion are pharmacologically active and have longer half-lives, and achieve higher plasma concentrations, than the parent compound. Hydroxybupropion is the major metabolite, produced by the metabolism of bupropion by the cytochrome P450 isoenzyme CYP2B6 in animal studies hydroxybupropion was one-half as potent as bupropion. Threohyd-robupropion and erythrohydrobupropion are produced by reduction and are about one-fifth the potency of the parent compound. Bupropion is 80% or more bound to plasma proteins. The terminal plasma half-life of immediate-release bupropion is about 14 hours the terminal plasma half-life of modified-release bupropion is about 20 hours. The metabolites of bupropion are excreted primarily in the urine less than 1% of the parent drug is excreted unchanged. Bupropion and its metabolites cross the placenta and are distributed into breast milk.

Smoking. No clinically significant differences were seen between the pharmacokinetics of bupropion or its metabolites in cigarette smokers and non-smokers.

Uses and Administration

Bupropion is a chlorpropiophenone antidepressant chemically unrelated to other classes of antidepressants but similar in structure to the central stimulant diethylpropion. It is a weakblocker of neuronal reuptake of serotonin and noradrenaline compared with tricyclic antidepressants it also inhibits the neuronal reuptake of dopamine. The antidepressant effect may not be evident until after 4 weeks of therapy. Bupropion is also used as an aid to smoking cessation.

Bupropion is given orally as the hydrochloride. To minimise agitation, anxiety, and insomnia often experienced at the start of therapy, and to reduce the risk of seizures, doses should be increased gradually the total daily dose should be given in equally divided doses and the maximum recommended single and total daily doses should not be exceeded. Insomnia at the start of therapy may be minimised by avoiding bedtime doses. Patients with hepatic or renal impairment should be given reduced doses and monitored for toxic effects (see below).

In the treatment of depression bupropion hydrochloride is given in initial doses of 100 mg twice daily increased, if necessary, after at least 3 days to 100 mg three times daily. In severe cases, if no improvement has been observed after several weeks of therapy, the dose may be increased further to a maximum of 150 mg three times daily. Bupropion hydrochloride is also available as a modified-release preparation given in an initial dose of 150 mg once daily in the morning increased, if necessary, after at least 3 days to 150 mg twice daily in severe cases, the dose of the modified-release preparation may be increased further after several weeks to 200 mg twice daily. A modified-release preparation that is given once daily is also available the maximum daily dose for this preparation is 450 mg as a single dose in the morning. A modified-release preparation is also licensed for the prevention of depression in patients with seasonal affective disorder the maximum dose for this disorder is 300 mg once daily.

Bupropion hydrochloride is given as a modified-release preparation as an aid to smoking cessation in an initial dose of 150 mg once daily for 6 days, increasing to 150 mg twice daily on day 7. In the USA, the dose may be increased after 3 days. In the UK, the maximum recommended dose in the elderly, or in patients with predisposing risk factors for seizure (see Precautions, above), is 150 mg daily. Treatment should be started about 1 to 2 weeks before the patient attempts to stop smoking, to allow steady-state blood levels of bupropion to be reached, and normally continues for 7 to 12 weeks if there is no significant progress towards smoking abstinence by the seventh week, then therapy should be stopped. Use with nicotine transdermal patches may be warranted in some patients, although there is a risk of hypertension with such therapy (see Interactions, above).

Administration in hepatic impairment. When used as an aid to smoking cessation in patients with mild to moderate hepatic impairment, bupropion should be given at a reduced frequency UK licensed product information suggests an oral dose of 150 mg once daily. The use of bupropion in patients with severe hepatic cirrhosis is contra-indicated in the UK although doses of 150 mg every other day are permitted in the USA.

In the treatment of depression, a reduction in the frequency and/or the dose of bupropion should be considered in patients with mild to moderate impairment. In patients with severe hepatic cirrhosis the dose varies according to the preparation given for modified-release bupropion the suggested maximum oral dose is 100 mg once daily or 150 mg every other day while the maximum dose of immediate-release bupropion is 75 mg once daily.

Administration in renal impairment. When used as an aid to smoking cessation in patients with renal impairment, bupropion should be given at a reduced frequency UK licensed product information suggests an oral dose of 150 mg once daily.

In the treatment of depression, a reduction in the frequency and/or the dose of bupropion should be considered.

Depression. As discussed, there is very little difference in efficacy between the different groups of antidepressant drugs, and choice is often made on the basis of adverse effect profile. Bupropion has a different biochemical profile from both the tricyclics and the SSRIs however, like the SSRIs, it may be safer in overdosage than the older tricyclics.

Hyperactivity. When drug therapy is indicated for attention deficit hyperactivity disorder initial treatment is usually with a central stimulant. Antidepressants may be used for patients who fail to respond to, or who are intolerant of, central stimulants. Data from open and controlled studies involving small numbers of patients suggest that bupropion is effective in adults and children.

Smoking cessation. Bupropion is effective in the management of smoking cessation and may be used as a first-line alternative to nicotine replacement therapy (NRT) its action is said to be independent of its antidepressant activity. Bupropion with NRT has also been used successfully although there is an increased risk of hypertension with this combination (see Interactions, above). References:

Preparations

The United States Pharmacopeia 31, 2008: Bupropion Hydrochloride Extended-Release Tablets Bupropion Hydrochloride Tablets.

Proprietary Preparations

Argentina: Odranal Wellbutrin

Australia: Clorpax Prexaton Zyban

Austria: Quomem Zyban

Belgium: Zyban

Brazil: Bup Wellbutrin Zetron Zyban

Canada: Wellbutrin Zyban

Chile: Buxon Dosier Mondrianl Wellbutrin

Czech Republic: Elontril Wellbutrin Zyban

Denmark: Zyban

Finland: Zyban

France: Zyban

Germany: Zyban

Greece: Zyban

Hong Kong: Wellbutrin Zyban

Hungary: Wellbutrin Zyban

India: Nicotex Zyban

Ireland: Zyban

Israel: Zyban

Italy: Quoinem! Zyban

Malaysia: Zyban

Mexico: Butrew Wellbutrin

The Netherlands: Quomem Zyban Zyntabac

Norway: Zyban

New Zealand: Zyban

Poland: Zyban

Portugal: Elontril Wellbutrin Zyban Zyntabac

South Africa: Wellbutrin Zyban

Singapore: Wellbutrin Zyban

Spain: Quomem Zyntabac

Sweden: Zyban

Switzerland: Zyban

Thailand: Quomem

Turkey: Zyban

UK: Zyban

USA: Budeprion Wellbutrin Zyban

Venezuela: Wellbutrin Zyban

(British Approved Name, US Adopted Name, rINN)

Pharmacopoeias. In Japan and US.

The United States Pharmacopeia 31, 2008 (Amoxapine). A white to yellowish crystalline powder. Practically insoluble in water slightly soluble in acetone freely soluble in chloroform sparingly soluble in methyl alcohol and in toluene soluble in tetrahydrofuran. Store in airtight containers.

Adverse Effects, Treatment, and Precautions

As for tricyclic antidepressants in general (see amitriptyline“>Amitriptyline).

Rare cases of tardive dyskinesias and the neuroleptic malignant syndrome have been reported with amoxapine.

Antidopaminergic effects. Amoxapine is a derivative of the antipsychotic and possesses some antipsychotic activity. It also has dopamine-receptor blocking properties as do its hydroxylated metabolites. Adverse effects that are symptoms of such blockade have been reported and reviewed’ and include akinesia, akathisia, withdrawal dyskinesia, reversible tardive dyskinesia, persistent dyskinesia, elevated serum concentration of prolactin, and galactorrhoea. Chorea and oculogy-ric crisis have also been reported.

Antimuscarinic effects. Amoxapine therapy has been reported to produce adverse effects associated with antimuscarinic activity (such as constipation, blurred vision, and dry mouth), but

such reports did not reflect in-vitro findings that amoxapine had considerably less affinity for muscarinic binding sites than amitriptyline this was supported by results in healthy subjects. The adverse effects described as antimuscarinic could possibly be explained by amoxapine affecting noradrenergic mechanisms.

Breast feeding. For comments on the use of tricyclic antidepressants in breast feeding patients, see under Precautions for Amitriptyline.

Effects on the endocrine system. Reversible nonketotic hy-perglycaemia developed in a 49-year-old woman with no history of diabetes mellitus within 5 days of oral therapy with amoxapine 50 mg three times daily. She had previously had nonketotic hyperglycaemic coma after loxapine 150 mg daily. 7-Hydroxyamoxapine, a metabolite common to both amoxapine and loxapine, was implicated.

See also Antidopaminergic Effects, above, for mention of galactorrhoea andhyperprolactinaemia.

Overdosage. In overdosage, amoxapine is reported to cause acute renal failure with rhabdomyolysis, coma, and seizures. Although there has been some debate as to whether the incidence of seizures and death is higher with overdosage of amoxapine than with other tricyclic antidepressants, some consider that evidence does seem to favour increased neurological consequences.

It has been reported that amoxapine is not cardiotoxic in overdosage but later evidence would suggest that there is cardiotoxic potential.

Interactions

For interactions associated with tricyclic antidepressants, see Amitriptyline.

Pharmacokinetics

Amoxapine is readily absorbed from the gastrointestinal tract. It bears a close chemical relationship to loxapine and is similarly metabolised by hydroxylation. It is excreted in the urine, mainly as its metabolites in conjugated form as glucuronides.

Amoxapine has been reported to have a plasma half-life of 8 hours and its major metabolite, 8-hydroxyamoxapine, has been reported to have a biological half-life of 30 hours 7-hydroxyamoxapine has been identified as another metabolite. Both metabolites are pharmacologically active. Amoxapine is about 90% bound to plasma proteins.

Amoxapine and its metabolite 8-hydroxyamoxapine are distributed into breast milk.

Uses and Administration

Amoxapine, the N-desmethyl derivative of loxapine, is a dibenzoxazepine tricyclic antidepressant with actions and uses similar to those of amitriptyline. Amoxapine is one of the less sedating tricyclics and its antimuscarinic effects are mild it also inhibits the reuptake of dopamine.

In the treatment of depression amoxapine is given in oral doses of 50 mg two or three times daily initially, gradually increased up to 100 mg three times daily as necessary. In the USA, higher doses of up to 600 mg daily may also be given, if required, in severely depressed patients in hospital. A suggested dose for the elderly is 25 mg two or three times daily initially, increased after 5 to 7 days to up to 150 mg daily as necessary in the USA further increases to a maximum of 300 mg daily are permitted, if required.

Once-daily dosage regimens, usually given at night, are suitable for amoxapine up to 300 mg daily divided-dosage regimens are recommended for doses above 300 mg daily. It has been claimed that, in the treatment of depression, amoxapine has a more rapid onset of action than amitriptyline or imipramine with a clinical effect possibly appearing 4 to 7 days after starting therapy, although this has been disputed. Amoxapine should be withdrawn gradually to reduce the risk of withdrawal symptoms.

Amoxapine has also been investigated for its potential as an antipsychotic.

Preparations

The United States Pharmacopeia 31, 2008: Amoxapine Tablets.

Proprietary Preparations

Denmark: Demolox

France: Defanyl

India: Demolox

Indonesia: Asendin

United Kingdom: Asendis

USA: Asendin

Interactions involving tricyclic antidepressants often result from additive toxicity or from altered metabolism of one drug by the other. Drugs that inhibit or induce the cytochrome P450 isoenzyme CYP2D6 may affect tricyclic metabolism and produce marked alterations in plasma concentrations. Adverse effects may be enhanced by antimuscarinic drugs or CNS depressants, including alcohol. Barbiturates and other enzyme inducers such as rifampicin and some antiepileptics can increase the metabolism of tricyclic antidepressants and may lower plasma concentrations and reduce antidepressant response. Cimetidine, methylphenidate, antipsychotics, and calcium-channel blockers can reduce the metabolism of the tricyclics, leading to the possibility of increased plasma concentrations and accompanying toxicity. Patients taking thyroid preparations may show an accelerated response to tricyclic antidepressants and occasionally liothyronine has been used to produce this effect in patients with refractory depression. However, the use of tricyclics with thyroid hormones may precipitate cardiac arrhythmias.

The antihypertensive effects of debrisoquine, guanethidine, and clonidine may be reduced by tricyclic antidepressants. The pressor effects of sympathomimetics, especially those of the direct-acting drugs adrenaline and noradrenaline, can be enhanced by tricyclic antidepressants however, there is no clinical evidence of dangerous interactions between adrenaline-containing local anaesthetics and tricyclic antidepressants. Great care should, however, be taken to avoid inadvertent intravenous injection of the local anaesthetic preparation.

Drugs that prolong the QT interval, including antiarrhythmics such as amiodarone or quinidine, the antihistamines astemizole and terfenadine, some antipsychotics (notably pimozide, sertindole, and thioridazine), cisapride, halofantrine, and sotalol, may increase the likelihood of ventricular arrhythmias when taken with tricyclic antidepressants. This may be exacerbated where the interacting drug (such as quinidine or some antipsychotics) also reduces tricyclic metabolism.

Although different antidepressants have been used together under expert supervision in refractory cases of depression, severe adverse reactions including the serotonin syndrome (see) may occur. For this reason an appropriate drug-free interval should elapse between stopping some types of antidepressant and starting another. Tricyclic antidepressants should not generally be given to patients receiving MAOIs or for at least 2 weeks (3 weeks if starting clomipramine or imipramine) after their withdrawal. No treatment-free period is necessary after stopping a reversible inhibitor of monoamine oxidase type A (RIMA) and starting a tricyclic. At least 1 to 2 weeks (3 weeks in the case of clomipramine or imipramine) should elapse between withdrawing a tricyclic antidepressant and starting any drug liable to provoke a serious reaction (e.g. phenelzine).

Further details concerning some of the above interactions, and others, are given below.

Alcohol. For reference to the effect of alcohol on amitriptyline“>amitriptyline, see under CNS depressants, below.

Analgesics. Doubling of plasma-doxepin concentrations with associated lethargy has been reported in a patient after the addition of dextropropoxyphene to the tricyclic. This was consistent with previous studies indicating that dextropropoxyphene can impair the hepatic metabolism of other drugs.

For general reference to the effect of tricyclic antidepressants, notably amitriptyline and clomipramine, on opioid analgesics, see under Morphine.

Antiarrhythmics. Antiarrhythmics that prolong the QT interval may increase the likelihood of ventricular arrhythmias when given with tricyclic antidepressants. This includes various class I antiarrhythmics such as disopyramide,flecainide,procainamide, propafenone, and quinidine, and the class III antiarrhythmic amiodarone.

Raised serum- desipramine concentrations and signs of toxicity were noted in a patient taking desipramine after starting treatment with digoxin and propafenone for paroxysmal atrial fibrillation. It was considered that propafenone probably reduced the metabolism and clearance of desipramine.

Anticoagulants. For the effect of tricyclic antidepressants on anticoagulants, see under Warfarin.

Antidepressants. Combination therapy with differing classes of antidepressants has been used successfully in the treatment of drug-resistant depression. It should be emphasised, however, that such combinations may result in interactions or enhanced adverse reactions, and should be used only under expert supervision. This practice is considered unsuitable or controversial by some authorities. For further details of the interactions between different antidepressants when used together, see Phenelzine. For details of the serotonin syndrome that can arise when two serotonergic drugs with different mechanisms of action are given, see under Adverse Effects of Phenelzine.

Antid iabetics. For the effect of tricyclic antidepressants on sulfonylureas and insulin, see Interactions, respectively.

Antiepileptics. Antidepressants may antagonise the activity of antiepileptics by lowering the convulsive threshold. A review of drug interactions with phenytoin noted that although there had been reports of interactions between antiepileptics and tricyclic or related antidepressants, most involved enzyme-inducing antiepileptics other than phenytoin or phenytoin with other drugs. In the only report where phenytoin could be identified as the sole antiepileptic used, 2 patients required high doses of desipramine to achieve an antidepressant effect and to maintain plasma-desipramine concentrations in the range usually associated with therapeutic efficacy.

Carbamazepine has been reported to induce the metabolism of a number of tricyclic antidepressants (amitriptyline, desipramine, doxepin, imipramine, and nortriptyline) and to reduce their plasma concentrations. The clinical importance of the interaction is unclear. Use of nortriptyline with carbamazepine in a patient led to a decrease in serum-nortriptyline concentration requiring an increase in nortriptyline dose. In another patient a prolonged QT interval was noted after use of desipramine with carbamazepine the authors hypothesised that the accelerated metabolism of desipramine had resulted in high levels of a cardiotoxic metabolite.

Valproate has been reported to increase plasma concentrations of amitriptyline, clomipramine, and nortriptyline. For the effect of the cyclic antidepressants desipramine and viloxazine on carbamazepine. For the effects of tricyclic antidepressants on phenytoin.

Antifungals. Increased serum concentrations of nortriptyline or amitriptyline‘ have occurred in patients also taking fluconazole. In some patients the use of amitriptyline with fluconazole has led to syncope or torsade de pointes. Raised serum concentrations of nortriptyline and associated symptoms of intoxication have been reported in 2 patients during treatment with terbinafine the interaction was confirmed on rechallenge. In another case, dizziness, dry mouth, and muscle twitching were reported in a patient on long-term imipramine treatment after starting terbinafme serum imipramine concentrations were found to be elevated and symptoms subsided after the dose of imipramine was reduced. A study in healthy subjects also indicated that terbinafine similarly inhibited the metabolism of desipramine.

Antihypertensives. In general, the hypotensive effect of anti-hypertensives is enhanced by tricyclic antidepressants, but there may be antagonism of the effect of adrenergic neurone blockers and of clonidine.

Antimigraine drugs. For the effects when some tricyclics are used with dihydroergoiamine.

A nti neoplasties. For the effects when tricyclic antidepressants are used with altretamine.

Antiprotozoals. Toxic psychosis developed in a patient on amitriptyline after starting furazolidone, an antiprotozoal with monoamine oxidase inhibiting activity.

Antipsychotics. For a discussion of interactions between antipsychotics and tricyclic antidepressants, see Chlorpromazine. For details of a possible interaction between clomipramine and clozapine.

Antivirals. HIV-protease inhibitors may increase the plasma concentrations of tricyclic antidepressants whose metabolism is mediated through common cytochrome P450 isoenzymes. Ritonavir has produced moderate increases in the plasma concentrations of desipramine and a lower initial dose of desipramine may be appropriate. Ticensed product information for ritonavir has warned that a similar increase may occur for other tricyclics monitoring of therapeutic and adverse effects is recommended when tricyclics are used with ritonavir.

Anxiolytics. For a suggestion that benzodiazepines may increase the oxidation of amineptine to a toxic metabolite, see under Effects on the Tiver in Adverse Effects, above. For a possible interaction of desipramine and other antidepressants with zolpidem.

Barbiturates. Antidepressants may antagonise the antiepileptic activity of some barbiturates by lowering the convulsive threshold.

Barbiturates can increase the metabolism of tricyclic antidepressants and thereby produce lower plasma concentrations. For details of the interaction of tricyclic antidepressants with barbiturate anaesthetics, see under Anaesthesia in Precautions, above.

Beta blockers. Raised imipramine plasma concentrations were noted in two 9-year-old children also given propranolol in both cases, no significant adverse effects were reported. Labetalol has also increased the bioavailability of imipramine in healthy subjects and inhibited its metabolism.

The risk of ventricular arrhythmias may be increased when tricyclic antidepressants are taken with sotalol.

Calcium-channel blockers. Diltiazem and verapamil each increased the bioavailability of imipramine in healthy subjects second-degree heart block developed in 2 subjects. Diltiazem also increased the bioavailability of nortriptyline in one patient, probably by reducing the first-pass metabolism of nortriptyline. Increased serum concentrations of trimipramine have been reported when taken with diltiazem, although there was no evidence of toxicity.

CNS depressants. Drugs with depressant actions on the CNS may be expected to enhance the drowsiness and related effects produced by the sedating type of tricyclic antidepressants. Such an interaction may occur between alcohol and tricyclic antidepressants and a study has shown that alcohol decreases the hepatic first-pass extraction of amitriptyline resulting in increased free plasma-amitriptyline concentrations, especially during the period of drug absorption.

The problems that may be encountered with barbiturate anaesthetics are discussed under Anaesthesia in Precautions, above.

Disulfiram. Acute organic brain syndrome has been reported in 2 patients receiving disulfiram after the addition of amitriptyline to their treatment. It was suspected that the syndrome was potentiated by the combined action of the drugs and the synergistic elevation in dopamine concentration.

For a report of the enhancement of the disulfiram-alcohol reaction by amitriptyline.

Dopaminergics. Serious adverse effects have been reported when selegiline, an irreversible selective inhibitor of monoamine oxidase type B, was used with tricyclic antidepressants. In some instances effects resembled the potentially fatal serotonin syndromes reported when tricyclics are given with non-selective MAO Is (see under Phenelzine).

Some manufacturers of selegiline advise that tricyclic antidepressants should not generally be given at the same time, or for at least 2 weeks after it has been discontinued. Similarly, at least one week should elapse between withdrawing a tricyclic antidepressant and starting selegiline.

For reference to the effect of tricyclic antidepressants on levodopa.

General anaesthetics. For the effect of amitriptyline on enflurane. For the effects of using tricyclic antidepressants with barbiturates see under Anaesthesia in Precautions, above.

Histamine H₂-antagonists. Cimetidine is a known inhibitor of hepatic metabolism of drugs and symptoms of tricyclic toxicity have been reported in patients receiving cimetidine with desipramine, doxepin, and imipramine there has been a report of psychosis developing in a patient given imipramine and cimetidine. Elevated tricyclic concentrations during combined therapy or reductions in tricyclic concentrations after withdrawal of cimetidine have been reported for imipramine and nortriptyline. Studies in healthy subjects have also indicated increased bioavailability and/or impaired hepatic metabolism of amitriptyline, doxepin, and imipramine during cimetidine therapy. Adjustment of tricyclic antidepressant dosage may therefore be required if cimetidine therapy is begun or stopped. Ranitidine has been reported not to alter the pharmacokinetics of amitriptyline, doxepin, or imipramine.

Muscle relaxants. There has been an isolated report of a patient taking baclofen for spasticity who experienced leg weakness and was unable to stand after starting treatment with nortriptyline. Symptoms improved on stopping nortriptyline but recurred when imipramine was given.

Sex hormones. There have been anecdotal reports of interactions between tricyclic antidepressants and oestrogens resulting in a lack of antidepressant response and/or tricyclic toxicity the significance of these interactions is not, however, established.

Smoking. Tobacco smoke has been reported to reduce the plasma levels of tricyclic antidepressants. The clinical significance is not, however, fully established as the plasma concentration of unbound drug may not be affected. The mechanism is probably by stimulation of hepatic drug metabolism by components present in cigarette smoke.

Sympathomimetics. The pressor effects of sympathomimetics can be enhanced by tricychc antidepressants. For precautions to be observed in patients on tricychc therapy who may require sympathomimetics during anaesthesia, see under Anaesthesia in Precautions, above.

Thyroid hormones. An increase in receptor sensitivity to catecholamines produced by thyroid hormones has been proposed as the reason for an increase in response to tricyclic antidepressants given with liothyronine.

Pharmacokinetics

Amitriptyline is readily absorbed from the gastrointestinal tract, peak plasma concentrations occurring within about 6 hours after oral doses. Amitriptyline undergoes extensive first-pass metabolism and is demethylated in the liver by the cytochrome P450 isoenzymes CYP3A4, CYP2C9, and CYP2D6 to its primary active metabolite, nortriptyline. Other paths of metabolism of amitriptyline include hydroxylation (possibly to active metabolites) by CYP2D6 and N-oxidation nortriptyline follows similar paths. Amitriptyline is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated form. Amitriptyline and nortriptyline are widely distributed throughout the body and are extensively bound to plasma and tissue protein. Amitriptyline has been estimated to have an elimination half-life ranging from about 9 to 25 hours, which may be considerably extended in overdosage. Plasma concentrations of amitriptyline and nortriptyline vary very widely between individuals and no simple correlation with therapeutic response has been established.

Amitriptyline and nortriptyline cross the placenta and are distributed into breast milk (see Breast Feeding under Precautions, above).

Uses and Administration

Tricyclic antidepressants such as amitriptyline were developed from phenothiazine compounds related to chlorpromazine and, as the name suggests, possess a 3-ring molecular structure. They inhibit the neuronal reuptake of noradrenaline in the CNS some, in addition, inhibit the reuptake of serotonin (5-HT). Prevention of the reuptake of these monoamine neurotransmitters, which potentiates their action in the brain, appears to be associated with antidepressant activity. Tricyclic antidepressants also possess affinity for muscarinic and histamine H1 receptors to varying degrees, see under Adverse Effects, above. Amitriptyline is one of the more sedating tricyclics. Antidepressants with one, two, or four rings have also been developed, and these share only some of the properties of the tricyclics. While the sedative action and other adverse effects of amitriptyline and other tricyclics are soon apparent, it may be several weeks before any antidepressant effect is seen. After a response has been obtained, maintenance therapy should be continued at the optimum dose for at least 4 to 6 months (12 months in the elderly) to avoid relapse on stopping therapy. Patients with a history of recurrent depression should continue to receive maintenance treatment for at least 5 years and possibly indefinitely. It is important to use doses that are sufficiently high for effective treatment, but not so high as to cause toxic effects.

Amitriptyline, a dibenzocycloheptadiene, is usually given orally as the hydrochloride and doses are expressed in terms of this salt. Amitriptyline hydrochloride is also given by intramuscular or slow intravenous injection doses may be expressed in terms of the base or the hydrochloride. Amitriptyline hydrochloride 75 mg is equivalent to about 66.3 mg of the base. Amitriptyline has also been given orally as the embonate and as the oxide (amitriptylinoxide). In the treatment of depression, amitriptyline hydrochloride is given initially in a daily dose of 50 to 75 mg orally in divided doses (or as a single dose at night). Thereafter, the dose may be gradually increased, if necessary, to 150 mg daily, the additional doses being given in the late afternoon or evening. Doses of up to 200 mg daily and, occasionally, up to 300 mg daily have been used in severely depressed patients in hospital.

Adolescent and elderly patients often have reduced tolerance to tricyclic antidepressants and UK licensed drug information states that initial doses of amitriptyline hydrochloride as low as 25 mg daily may be used in these groups, given either in divided doses or as a single dose, preferably atbedtime. TheBNFsuggests a minimum initial dose of 30 mg daily. In the UK, the use of amitriptyline in children under 16 years for the treatment of depression is not recommended. In the initial stages of treatment, if dosage by mouth is impracticable or inadvisable, amitriptyline hydrochloride may be given by intramuscular injection, but the oral route should be substituted as soon as possible. Doses are similar to those usually given orally. The intravenous route has also been used. Amitriptyline is also used for the treatment of nocturnal enuresis in children in whom organic pathology has been excluded. However, drug therapy for nocturnal enuresis should be reserved for when other methods have failed and should preferably only be given to cover periods away from home tricyclic antidepressants are not recommended in children under 6 years of age (the BNF recommends that they should not be given until 7 years of age). Oral doses of amitriptyline hydrochloride that may be used are:

• 10 to 20 mg for children aged 6 to 10 years

• 25 to 50 mg for children 11 years and over

The dose should be given 30 minutes before bedtime and treatment, including a period of gradual withdrawal, should not continue for longer than 3 months. A full physical examination is recommended before a further course.

Tricyclic antidepressants, including amitriptyline, may be helpful in some anxiety disorders such as panic disorder, and in the management of neuropathic pain (see below).

Amitriptyline should be withdrawn gradually to reduce the risk of withdrawal symptoms.

Anxiety disorders. For the use of tricyclic antidepressants in anxiety disorders, see under Clomipramine.

Bulimia nervosa. A combination of counselling, support, psychotherapy, and antidepressants is the usual treatment for bulimia nervosa. Antidepressants can help to reduce the frequency of overeating and some other symptoms of bulimia but relapse tends to occur when stopped. Many antidepressants have been tried, but the tricyclic desipramine and the SSRI fiuoxetine have been the most commonly used and are considered to be well tolerated. References.

Ciguatera poisoning. Amitriptyline has relieved some of the neurological symptoms associated with ciguatera poisoning (see Mannitol).

Cocaine dependence. For the use of tricyclic antidepressants in cocaine dependence, see under Desipramine.

Depression. As discussed, there is very little difference in efficacy between the different groups of antidepressant drugs, and choice is often made on the basis of adverse effect profile. Although less well tolerated than the newer antidepressants, tricyclic antidepressants may still be chosen because of wide experience with their use and familiarity with their pharmacological actions. The more sedating tricyclics such as amitriptyline, clomipramine, dosulepin, doxepin, and trimipramine may be of value in depression with associated agitation or anxiety. The less sedating tricyclics such as amoxapine, desipramine, imipramine, lofepramine, nortriptyline, and protriptyline may be of value for withdrawn or apathetic depressed patients. Combination therapy with differing classes of antidepressants, including the tricyclics, has been used in the treatment of refractory or drug-resistant depression. However, such therapy may result in enhanced adverse reactions or interactions and requires expert supervision it is considered unsuitable or controversial by some. For further details, see Antidepressants under Interactions of Phenelzine.

Headache. Tricyclic antidepressants can be effective in the management of some types of headache and, although they are especially useful when the headache is accompanied by depression, their beneficial effects appear to be independent of their antidepressant action. They are used for the prophylaxis of migraine when drugs such as propranolol have proved ineffective. Amitriptyline is the tricyclic usually used but others have been tried. It has also been investigated in children. The BNF suggests an adult dosage for amitriptyline in the prophylaxis of migraine of 10 mg at night, increased to a maintenance dose of 50 to 75 mg at night the need for continuing prophylaxis should be reviewed at intervals of about 6 months. Tricyclics are also used prophylactic ally in the control of chronic tensiontype headache although benefit is rarely complete. Improvement is generally seen with low doses, but full antidepressant doses are necessary in the presence of underlying depression. References.

Hiccup. Amitriptyline is one of many drugs for which there are anecdotal reports of success in the treatment of intractable hiccup.

Hyperactivity. When drug therapy is required for attention deficit hyperactivity disorder, initial treatment is usually with a central stimulant. Tricyclic antidepressants such as imipramine or desipramine are reserved for patients who fail to respond to or who are intolerant of stimulants. They may also be of use for selected patients with certain co-existing disorders.

Interstitial cystitis. Tricyclic antidepressants have been found to be of benefit in the treatment of interstitial cystitis. In a placebo-controlled trial in 48 patients with interstitial cystitis, amitriptyline treatment (in doses ranging from 25 to 100 mg daily) significantly reduced the symptom score and improved pain and urgency when compared to placebo however, in some patients the antimuscarinic adverse effects of amitriptyline were troublesome. Amitriptyline or imipramine have also been given at night, together with methenamine hippurate during the day, in the treatment of interstitial cystitis.

Irritable bowel syndrome. A tricyclic antidepressant may be tried in irritable bowel syndrome, particularly where diarrhoea and abdominal pain are presenting symptoms.

Micturition disorders. Tricyclic antidepressants are among the drugs used as an alternative or adjunct to nonpharmacological methods for the treatment of nocturnal enuresis in children

in whom organic pathology has been excluded. However, because of their potentially fatal toxicity in overdosage, there has been concern over the safety of using tricyclics in households with children. Most experience in nocturnal enuresis has been with imipramine, but other tricyclics such as amitriptyline, nortriptyline, and clomipramine have also been used. Their mechanism of action in nocturnal enuresis is unclear. It may be the result of their antimuscarinic and antispasmodic actions as well as their effect on sleep patterns and possible stimulation of antidiuretic hormone secretion. Imipramine appears to be most effective in older children, but many patients develop tolerance and increasingly higher doses are required. Tricyclic antidepressants are also sometimes used in the management of urinary incontinence.

Narcoleptic syndrome. Tricyclic antidepressants are the primary treatment for cataplexy and sleep paralysis associated with narcolepsy. Imipramine has been widely used for these symptoms although some consider clomipramine more effective. The onset of action is quicker than when used for depression and doses required appear to be lower (typically 10 to 75 mg of imipramine daily) although tolerance may develop. Doses should be titrated to provide maximal protection for the time of day when symptoms usually occur.

Pain. Tricyclic antidepressants, usually amitriptyline, are useful in alleviating some types of pain when given in subantidepres-sant doses. An initial oral dose of amitriptyline hydrochloride 10 to 25 mg at night increased gradually if necessary to about 75 mg daily has been suggested by the BNF for the management of neuropathic pain in adults. Similar doses of amitriptyline hydrochloride are also suggested by the BNFC for the treatment of neuropathic pain in palliative care in children aged 12 years and over in addition, younger children aged 2 years and above may receive an initial dose of 200 to 500 micrograms/kg (to a maximum of 25 mg) once daily at night, increased if necessary to a maximum of 1 mg/kg twice daily. See also Choice of Analgesic on p.2. Chronic neuropathic pain as seen in cancer, central post-stroke pain, diabetic neuropathy, phantom limb pain, and postherpetic neuralgia responds to therapy with tricyclics. Tricyclics are also often of benefit in the treatment of idiopathic orofacial pain, and may be of value for patients with complex regional pain syndrome. Pain and sleep quality may be improved by tricyclics in patients with fibromyalgia (see Soft-tissue Rheumatism), a condition that responds poorly to analgesics and anti-inflammatory drugs. Patients with migraine or chronic tension-type headache may also benefit from tricyclics (see Headache, above). There is little evidence for an analgesic effect of tricyclics in acute or arthritic pain. References.

Pathological crying or laughing. Pathological crying or laughing can result from lesions in certain areas of the brain. Attempts at treatment have mostly been with antidepressants and favourable results have been reported in double-blind studies with amitriptyline and nortriptyline.

Premenstrual syndrome. For reference to the tricyclic antidepressant, clomipramine, in premenstrual syndrome.

Schizophrenia. Antidepressants such as the tricyclics are considered worth trying as an adjunct in the treatment of patients with schizophrenia who develop depression during the recovery phase after an acute episode of psychosis. There is, however, no clear evidence that they are effective during acute psychotic episodes or for depression during periods of remission in patients with chronic schizophrenia.

Sexual dysfunction. Impotence or ejaculatory problems have been reported as adverse effects of tricyclic antidepressants.

Effects on Sexual Function in Adverse Effects, above). Such properties have been studied as a potential form of treatment for men with premature ejaculation (see Clomipramine).

Skin disorders. See under Doxepin, for use of tricyclic antidepressants in skin disorders.

Smoking cessation. Tricyclic antidepressants are among the drugs that have been tried with varying degrees of success as alternatives to nicotine replacement therapy (NRT) to alleviate the withdrawal syndrome associated with smoking cessation. Nortriptyline is recommended by some as a second-line treatment in those patients who cannot tolerate or relapse after NRT. References.

Preparations

British Pharmacopoeia 2008: Amitriptyline Tablets

The United States Pharmacopeia 31, 2008: Amitriptyline Hydrochloride Injection Amitriptyline Hydrochloride Tablets Chlordiazepoxide and Amitriptyline Hydrochloride Tablets Perphenazine and Amitriptyline Hydrochloride Tablets.

Proprietary Preparations

Argentina: Tryptanol Uxen

Australia: Endep Tryptanol

Austria: Saroten Tryptizol

Belgium: Redomex Tryptizol

Brazil: Amytril Neurotrypt Protanol Tripsol Tryptanol

Canada: Elavilf Novo-Triptyn

Denmark: Saroten Tryptizol

Finland: Saroten † Triptyl

France: Elavil Laroxyl

Germany: Amineurin Amioxid Equilibria Novoprotect Saroten Syneudon

Greece: Maxivalet Saroten Stelminal

Hong Kong: Qualitriptine Tryptanol

Hungary: Teperin

India: Sarotena Tryptomer

Ireland.: Lentizoll

Israel: Elatrol Elatrolet Tryptal

Italy: Adepril Laroxyl Triptizol

Malaysia: Endep Tripta Tryptanol

Mexico: Anapsique Tryptanol

Norway: Sarotex Tryptizol

New Zealand: Amitrip

Portugal: ADT Tryptizol

Russia: Amyzol Eliwel Saroten

South Africa: Noriline Saroten Trepiline Tryptanol

Singapore Tripta

Spain: Deprelio Tryptizol

Sweden: Saroten Tryptizol

Switzerland: Saroten Tryptizol

Thailand: Polytanol Tripsyline † Tripta Triptyline Tryptanol

Turkey: Laroxyl Triptilin

UK: Elavil

USA: Elavil

Venezuela: Tryptanol

Multi-ingredient

Argentina: Mutabon D

Austria: Limbitrol

Brazil: Lirnbitrol

Canada: PMS-Levazine Triavil

Chile: Antalin Limbatrilin Morelin Mutabon D Tiperin

Finland: Klotriptyl Limbitrol Pertriptyl

Greece: Minitran

India: Emotrip

Indonesia: Limbritol Mutabon-D Mutabon-M

Italy: Diapatol Limbitryl Mutabon Sedans

Mexico: Adepsique

Portugal: Mutabon

Russia: Amixide

South Africa: Etrafonl Limbitrol

Spain: Mutabase Nobritol

Switzerland: Limbitrol

Thailand: Anxipress-Df Neuragon Polybon

UK: Triptafen

USA: Etrafon Limbitrol Triavil

(British Approved Name, rINN)

Amitriptyline Embonate

(British Approved Name Modified, rINNM)

Drug Nomenclature

Pharmacopoeias. In British.

British Pharmacopoeia 2008 (Amitriptyline Embonate). A pale yellow to brownish-yellow, odourless or almost odourless powder. Practically insoluble in water slightly soluble in alcohol freely soluble in chloroform. Protect from light.

Amitriptyline Hydrochloride

Drug Approvals

(British Approved Name Modified, rINNM)

Pharmacopoeias. In China, Europe, Int., Japan, and US.

European Pharmacopoeia, 6th ed. (Amitriptyline Hydrochloride). A white or almost white powder or colourless crystals. Freely soluble in water, in alcohol, and in dichloromethane. Protect from light.

The United States Pharmacopeia 31, 2008(Amitriptyline Hydrochloride). A white or practically white, odourless or practically odourless, crystalline powder or small crystals. Freely soluble in water, in alcohol, in chloroform, and in methyl alcohol insoluble in ether. pH of a 1 % solution in water is between 5.0 and 6.0.

Stability. Decomposition occurred when solutions of amitriptyline hydrochloride in water or phosphate buffers were autoclaved at 115° to 116° for 30 minutes in the presence of excess oxygen.

The decomposition of amitriptyline as the hydrochloride in buffered aqueous solution stored at 80° in the dark was accelerated by metal ions.Disodiumedetate 0.1% significantly reduced the decomposition rate of these amitriptyline solutions but propyl gallate and hydroquinone were less effective. Sodium metabi-sulfite produced an initial lowering of amitriptyline concentration and subsequently an acceleration of decomposition. The rate of decomposition was also much greater in amber glass ampoules than in clear glass ones (the metal ion content of amber glass is higher than that of clear glass). However, there were considerable variations between different batches of amber glass and, since amitriptyline is photolabile, its solutions are likely to be stored in amber containers.

Solutions of amitriptyline hydrochloride in water are stable for at least 8 weeks at room temperature if protected from light either by storage in a cupboard or in amber containers. Decomposition to ketone and, to a lesser extent, other unidentified products was found to occur on exposure to light.

Adverse Effects

Many adverse effects of amitriptyline and similar tricyclic antidepressants are caused by their antimuscarinic actions. Antimuscarinic effects are relatively common and occur before an antidepressant effect is obtained. They include dry mouth, constipation occasionally leading to paralytic ileus, urinary retention, blurred vision and disturbances in accommodation, increased intra-ocular pressure, and hyperthermia. Tolerance is often achieved if treatment is continued and adverse effects may be less troublesome if treatment is begun with small doses and then increased gradually, although this may delay the clinical response. Drowsiness may also be common, although a few tricyclic antidepressants possess little or no sedative potential and may produce nervousness and insomnia. Other neurological adverse effects include headache, peripheral neuropathy, tremor, ataxia, epileptiform seizures, tinnitus, and occasional extrapyramidal symptoms including speech difficulties (dysarthria). Confusion, hallucinations, or delirium may occur, particularly in the elderly, and mania or hypomania, and behavioural disturbances (particularly in children) have been reported.

Gastrointestinal complaints include sour or metallic taste, stomatitis, and gastric irritation with nausea and vomiting.

Effects on the cardiovascular system are discussed in more detail below. Orthostatic hypotension and tachycardia can occur in patients without a history of cardiovascular disease, and may be particularly troublesome in the elderly.

Hyper sensitivity reactions, such as urticaria and angioedema, and photosensitisation have been reported and, rarely, cholestatic jaundice and blood disorders, including eosinophilia, bone-marrow depression, thrombocytopenia, leucopenia, and agranulocytosis.

Endocrine effects include testicular enlargement, gynaecomastia and breast enlargement, and galactorrhoea. Sexual dysfunction may also occur. Changes in blood sugar concentrations may also occur, and, very occasionally, hyponatraemia associated with inappropriate secretion of antidiuretic hormone. Other adverse effects that have been reported are increased appetite with weight gain (or occasionally anorexia with weight loss). Sweating may be a problem.

Symptoms of overdosage may include excitement and restlessness with marked antimuscarinic effects, including dryness of the mouth, hot dry skin, dilated pupils, tachycardia, urinary retention, and intestinal stasis. Severe symptoms include unconsciousness, convulsions and myoclonus, hyperreflexia, hypothermia, hypotension, metabolic acidosis, and respiratory and cardiac depression, with life-threatening cardiac arrhythmias that may recur some days after apparent recovery. Delirium, with confusion, agitation and hallucinations, is common during recovery.

Antimuscarinic and antihistaminic properties. Studies in vitro showed antidepressant affinities for human muscarinic acetylcholine receptors and therefore the likelihood of antimuscarinic effects to be, in descending order:

• amitriptyline

• protriptyline

• clomipramine

• trimipramine

• doxepin

• imipramine

• nortriptyline

• desipramine

• amoxapine

• maprotiline

• trazodone

The effect of affinities for other receptor sites was less certain, although those antidepressants with high affinity for histamine H_: receptors might be expected to be more sedating. Affinities for murine histamine H_: receptors in descending order were:

• doxepin

• trimipramine

• amitriptyline

• maprotiline

• amoxapine

• nortriptyline

• imipramine

• clomipramine

• protriptyline

• trazodone

• desipramine

Effects on the blood. After a case report of agranulocytosis linked with imipramine, review of the literature suggested that agranulocytosis associated with tricyclic antidepressant use was a rare idiosyncratic condition, resulting from a direct toxic effect rather than an allergic mechanism, and particularly affected the elderly from 4 to 8 weeks after beginning treatment. Between 1963 and 1993 the UK CSM received 912 reports of drug-induced agranulocytosis of which 38 were due to tricyclic antidepressants (12 fatal) and 1499 cases of neutropenia of which 46 were due to tricyclics (none fatal). In a report on a patient who developed aplastic anaemia associated with use of remox-ipride and dosulepin it was noted that up to May 1993 the CSM had also received 11 reports of aplastic anaemia secondary to use of dosulepin.

Neutropenia reported in a patient after separate exposure to imipramine and nortriptyline, indicated that there might be cross-intolerance between the tricyclic antidepressants and if neutropenia developed with one member of the group the use of others on future occasions should be avoided.

Effects on the cardiovascular system. The cardiotoxic potential of tricyclic antidepressants after overdosage is widely acknowledged symptoms include arrhythmias, conduction defects, and hypotension. This factor was, in part, responsible for the development of antidepressants with different chemical structures and pharmacological properties that are less cardiotoxic. It also led to some concern over whether tricyclic antidepressants had adverse effects on the heart or cardiovascular system when used in usual therapeutic doses.

Since the introduction of the tricyclic antidepressants, reports, often anecdotal, have been published of adverse cardiovascular effects at therapeutic doses and have included malignant hypertension with amitriptyline, and cardiomyopathy in a patient who had received amitriptyline and imipramine. QT prolongation, which in some cases progressed to torsade de pointes, has also been associated with the use of some tricyclics. Sudden cardiac death in patients with pre-existing cardiac disease has been linked with amitriptyline or imipramine, although the Boston Collaborative Drug Surveillance Program failed to substantiate these findings. In a more recent analysis, it has been suggested that the risk of sudden cardiac death may increase with high doses of tricyclic antidepressants. Using patient medication records, it was found that the rate of sudden cardiac death in patients taking less than 100 mg of amitriptyline or its equivalent, [presumably as a daily dose although this is not specified], did not differ from that among non-users of antidepressants even in those with cardiovascular disease or other conditions considered to increase the risk of sudden death however, the risk was significantly increased in those patients on doses of 100 mg or greater when compared to non-users, regardless of any predisposing conditions.

There have also been reports of sudden death in children given desipramine or imipramine in at least some of these cases plasma concentrations were not elevated and the children had no cardiac abnormality. Again, however, evaluation of much of the evidence for the association suggests it is weak nonetheless, the American Heart Association recommends baseline ECG monitoring in children who are to be treated with tricyclic antidepressants, and a repeat ECG when steady-state dosage is achieved.

Re-evaluations and reviews of this topic concluded that the only significant or serious cardiovascular adverse effects, seen in patients with no history of cardiovascular disease given therapeutic doses of tricyclic antidepressants, are orthostatic hypotension and tachycardia, and that these effects may be particularly troublesome in elderly patients. However, a later study also considered that prolongation of the QT interval might occur with therapeutic doses of tricyclics in non-risk patients. In patients with overt heart disease it was considered that increased risk was likely in those with intraventricular conduction abnormalities in patients with a history of myocardial infarction or angina, but free of conduction defects, the use of tricyclics appeared to be primarily limited by how often they developed orthostatic hypotension and to what degree. In a re-evaluation of the risks and benefits of tricyclics in patients with ischaemic heart disease no consensus was reached. In practice the authors used SSRIs or bupropion as first-choice therapy in patients with ischaemic heart disease who were mildly or moderately depressed tricyclics were reserved for unresponsive patients and were also used as first-choice therapy for patients with more severe depression despite cardiac risks. More recently an increased risk of myocardial infarction has been found in patients taking tricyclic antidepressants (but not S SRIs) with treatment for heart disease. Results of a later case-control study examining the risk of ischaemic heart disease for different types of antidepressants and individual antidepressants support these findings. After adjustment for confounders and use of other antidepressants the risk of ischaemic heart disease was significantly raised in patients who had ever taken tricyclics but not in those who had received other antidepressants. When the risk was calculated for the tricyclics amitriptyline, dosulepin, and lofepramine, and con-founders had been adjusted for, an increased risk of ischaemic heart disease remained only for dosulepin with evidence of a dose-response relationship.

EFFECTS ON THE PERIPHERAL CIRCULATION. Painful vasospastic

episodes, characterised by cold and blue hands and feet, occurred in a woman each time she received imipramine 150 mg daily and also with amitriptyline, but only when the dose was increased to 200 mg daily. This suggested that the ability of tricyclic antidepressants to induce vasospasm was not limited to imipramine and that the effect might be partly dose-dependent. Additionally, acrocyanosis of the hands and feet has been reported in a child receiving imipramine for nocturnal enuresis.

Effects on the endocrine system. The syndrome of inappropriate antidiuretic hormone secretion with hyponatraemia has been reported in patients receiving tricyclics and other antidepressants. The UK CSM, commenting on reports it had received of hyponatraemia associated with antidepressants (fluoxetine, paroxetine, lofepramine, clomipramine, and imipramine), considered that it was likely to occur with any antidepressant and usually involved elderly patients. Case reports of hyponatraemia in 24 patients treated with tricyclics and 20 patients treated with other antidepressants have been summarised. In a review covering the effects of drugs onprolactin secretion it was stated that antidepressants could affect prolactin secretion by disturbing the balance of catecholaminergic inhibition and se-rotonergic stimulation of prolactin release, although any change is less than with antipsychotic therapy. Clomipramine and nortriptyline had been reported to stimulate prolactin release whereas amitriptyline, desipramine, and imipramine had been reported to be without effect. Such stimulation may account for symptoms of galactorrhoea or amenorrhoea reported with some tricyclics.

Effects on the gastrointestinal tract. Rare cases of ileus and pseudo-obstruction have apparently resulted from the antimus-carinic effects of tricyclic antidepressants. An early report from the UK CSM noted no evidence that any tricyclic was especially liable to cause ileus.

Effects on the kidneys and urine. Haematuria has been seen in a patient receiving amitriptyline and carbamazepine carbamazepine had previously been taken alone for a long period without producing this effect.

Amitriptyline may have produced a blue-green colour in urine, although it was considered to be a rare phenomenon.

Effects on the liver. In a report of 91 cases of hepatitis due to antidepressant therapy, 63 occurred in patients receiving the tricyclic antidepressant amineptine, sometimes with other psychotropic drugs in about 50% of these amineptine cases, benzodi-azepines had also been taken and it was postulated that the benzodiazepines may have increased the oxidation of amineptine to a toxic metabolite. Most patients presented with abdominal pain and mixed liver damage with predominant cholestasis. One died after myocardial infarction, but all the others recovered. The mean amineptine dosage was 200 mg daily. In comparison, only a few cases were attributed to other tricyclic antidepressants — amitriptyline (4), clomipramine (3), and dibenzepin (1). Cross-hepatotoxicity between amineptine and clomipramine has also been reported in a patient.

Hepatotoxicity has also been noted with lofepramine. The UK CSM had by the end of 1987 received 57 reports of abnormal liver function tests associated with lofepramine. They included hepatic failure (1), jaundice (9), and hepatitis (5). All reactions occurred within the first 8 weeks of treatment and all were reversible on stopping the drug.

Effects on the mouth. The inhibition of salivation caused by tricyclic antidepressants (in this case clomipramine) has been implicated in dental caries formation.

Effects on the nervous system. Effects on the nervous system attributed to tricyclic antidepressants include drowsiness (especially with those with antihistaminic activity), peripheral neuropathy, tremor, ataxia, confusion, and delirium. Of particular concern is a reduction in the seizure threshold (see Epileptogenic Effect, below). Extrapyramidal effects and neuroleptic malignant syndrome (see below) may also occasionally occur.

Effects on sexual function. Loss of libido and impotence are common in depression, often making the role of drugs in producing sexual dysfunction difficult to assess. Sedation due to tricyclic antidepressants may lead to loss of libido and many of the tricyclics have been reported to cause impotence. Amitriptyline, clomipramine, desipramine, doxepin, nortriptyline, and trimipramine have been stated to delay or inhibit ejaculation, and amoxapine, imipramine, and protriptyline, also to cause painful ejaculation. However, some tricyclics have been used for their effect on ejaculation in the management of premature ejaculation (see Clomipramine).

In women, anorgasmia or delayed orgasm has been reported with amitriptyline, amoxapine, clomipramine, and imipramine, although spontaneous orgasm associated with yawning has been reported with clomipramine.

Effects on the skin. Hypersensitivity reactions to tricyclic antidepressants are said to be uncommon. Urticaria and angioedema have occurred, the urticaria occasionally clearing without drug withdrawal. Pruritus is also uncommon, but may be associated with transient erythema. Photosensitivity reactions are far less common than with phenothiazines protriptyline has been the tricyclic most frequently implicated. Rarely, exfoliative dermatitis has developed, and purpura, pigmentation, and lichen planus have been noted in isolated reports. In some cases pigmentation changes may be permanent Toxic epidermal necrolysis has been reported in a patient 2 weeks after starting therapy with amoxapine. Hypersensitivity reactions to tricyclic antidepressants usually occur between 14 and 60 days after the start of treatment.

Amitriptyline and fluoxetine have been implicated in the development of atypical cutaneous lymphoid hyperplasia in 8 patients, 7 of whom either had an underlying immunosuppressant systemic disease or were also receiving immunomodulatory drugs.The lesions improved or resolved on stopping the antidepressant, although in some patients other factors may have contributed to lesional resolution.

Epileptogenic effect. Seizures have been reported after therapeutic doses of tricyclic antidepressants as well as after overdos-age, although the mechanism by which the seizures are induced is unclear. Seizures usually appear within a few days of starting the drug or changing to a higher dose but in patients with no history of epilepsy or no predisposing medical condition the frequency seems to be very low with an incidence of about 1 in 1000. An incidence of 0.4 per 1000 was reported based on 16 cases out of an estimated group of 42 000 patients receiving tricyclics and who had no predisposing factors, but in another review a reasonable estimate of the incidence was considered to be 3 to 6 per 1000. However, it is widely agreed that tricyclics should be used very cautiously in patients with epilepsy or those with a low convulsive threshold.

In a retrospective analysis of 1313 cases of overdosage involving cyclic antidepressants, seizures occurred more commonly with the tricyclics amoxapine (24.5%) and desipramine (17.9%), and the tetracyclic maprotiline (12.2%). In another analysis of 302 consecutive cases of tricyclic overdosage a higher rate of seizures was seen with dosulepin in overdosage (13%) than other tricyclics.

Extrapyramidal effects. Extrapyramidal effects such as oro-facial and choreoathetoid movements, and dyskinesias have been attributed to treatment with tricyclic antidepressants. Dysarthria has also been reported and was said to be not uncommon in those taking higher doses of tricyclic antidepressants, but unusual at lower doses.

Some patients with panic disorder may be sensitive to imipramine, developing symptoms of insomnia, jitteriness, and irritability. Symptoms have also been seen in patients with panic disorder treated with low doses of desipramine although the symptoms usually subsided when the dose of the tricyclic was gradually increased. It has been suggested that these symptoms may be related to akathisia and are more likely to occur with those tricyclics that have a more potent effect on inhibition of noradrenaline reuptake.

Reviews of adverse effects of drugs on the nervous system have also listed acute torsion dystonias and tremors as being caused or exacerbated by tricyclic antidepressants.

Hypersensitivity. A hypersensitivity syndrome developed in a 24-year-old woman 3 weeks after starting amitriptyline 50 mg daily for the treatment of depression symptoms included generalised erythroderma with mild scaling, sinus tachycardia, haema-tological abnormalities such as eosinophilia, and raised liver enzyme values. The patient recovered after drug withdrawal and treatment with intravenous prednisolone. See also under Effects on the Skin, above.

Hyponatraemia. See Effects on the Endocrine System.

Neuroleptic malignant syndrome. Of 16 cases of neuroleptic malignant syndrome reported to the UK CSM by July 1986, 3 cases occurred in patients receiving a tricyclic antidepressant amitriptyline with perphenazine had been taken by one patient and dosulepin or clomipramine alone by 2 other patients. The clomipramine case was fatal. Other reports have been associated with amoxapine, clomipramine alone, clomipramine with triazolam, and nortriptyline.

Overdosage. In a 1993 report tricyclic antidepressants were associated with a higher risk of fatality after suicide attempts by drug overdose compared with the non-tricyclics available at the time. Some reports have considered desipramine to be associated more frequently than other tricyclic antidepressants with fatal overdosage, although others assign this status to dosulepin. The BNF considers amitriptyline and dosulepin to be particularly dangerous in overdosage.

Later reviews continue to cite tricyclic antidepressants as one of the most commonly ingested substances in fatal cases of self-poisoning.

Treatment of Adverse Effects

The basis of the management of tricyclic antidepressant poisoning is intensive supportive care and symptomatic therapy.

Since tricyclic antidepressants slow gastrointestinal transit time, absorption may be delayed in overdosage. Activated charcoal may be given by mouth or nasogas-tric tube if more than 4 mg/kg of a tricyclic antidepressant has been ingested and the patient presents within 1 hour a second dose may be considered after 2 hours in patients with central features of toxicity. Gastric lavage is rarely used but may be considered in life-threatening overdoses. Multiple doses of charcoal may be appropriate in patients who have ingested modified-release preparations.

The patient should be monitored for cardiac arrhythmias. UK authorities consider that although cardiac arrhythmias are of concern they are best treated by correction of hypoxia and acidosis with intravenous sodium bicarbonate the use of antiarrhythmic drugs is best avoided. Intravenous sodium bicarbonate should also be given to treat arrhythmias or significant ECG abnormalities even in the absence of acidosis.

Convulsions can be managed by giving diazepam or lorazepam intravenously. Phenytoin should be avoided because it may increase the risk of arrhythmias. Diazepam by mouth is usually adequate to sedate delirious patients, although large doses may be needed.

Peritoneal dialysis, haemodialysis, and measures to increase urine production are not of value in tricyclic antidepressant poisoning, and charcoal haemoper-fusion is of doubtful benefit.

Precautions

The antimuscarinic effects of tricyclic antidepressants warrant care in patients with urinary retention, prostatic hyperplasia, or chronic constipation caution has also been advised in untreated angle-closure glaucoma and in phaeochromocytoma.

The epileptogenic potential of tricyclic antidepressants requires care in patients with a history of epilepsy. In addition, because of their potential cardiotoxicity, tricyclics should be used with caution in patients with cardiovascular disease and avoided in those with heart block, cardiac arrhythmias, or in the immediate recovery period after myocardial infarction. Caution has also been recommended in patients with hyperthyroidism as tricyclics may increase the risk of developing cardiac airhythmias.

Blood-sugar concentrations may be altered in diabetic patients.

Because tricyclic antidepressants are metabolised and inactivated in the liver they should be used with caution in patients with hepatic impairment and avoided in severe liver disease.

Patients should be closely monitored during early antidepressant therapy until significant improvement in depression is observed because suicide is an inherent risk in depressed patients. For further details, see under Depression. Suicidal thoughts and behaviour may also develop during early treatment with antidepressants for other disorders the same precautions observed when treating patients with depression should therefore be followed when treating patients with other disorders.

If tricyclic antidepressants are used for the depressive component of bipolar disorder, mania may be precipitated similarly, psychotic symptoms may be aggravated if tricyclics are used for a depressive component of schizophrenia.

Drowsiness often occurs, particularly at the start of therapy, and patients, if affected, should not drive or operate machinery.

Tricyclic antidepressants may inhibit salivation and regular dental check-ups are recommended for patients on long-term therapy, particularly when taking those with marked antimuscarinic actions. Elderly patients can be particularly sensitive to the adverse effects of tricyclic antidepressants and a reduced dose, especially initially, should be used. Tricyclic antidepressants are not recommended for depression in children. If they are used for nocturnal enu-resis in children they should be limited to short courses with a full physical examination before subsequent courses.

Tricyclic antidepressants should be withdrawn gradually to reduce the risk of withdrawal symptoms (see below).

Licensed drug information recommends that, where possible, tricyclic antidepressants should be stopped several days before elective surgery, and that they should be used with caution in patients requiring ECT however, see also under Anaesthesia, below.

Anaesthesia. Patients receiving tricyclic antidepressants are at an increased risk of developing hypotension or cardiac arrhythmias during anaesthesia. Tricyclics may also dangerously potentiate the cardiovascular effects of vasopressor drugs such as sym-pathomimetics that may be required during anaesthesia. Although some licensed drug information recommends stopping tricyclics several days before elective surgery where possible, the BNF advises that this is unnecessary as long as the anaesthetist is informed.

Commenting on the anaesthetic considerations relevant to ECT, it was considered that therapy with tricyclic antidepressants should not be a contra-indication to anaesthesia for ECT. A major consideration, though, was said to be the interaction of tricyclics with barbiturates resulting in increased sleep time and duration of anaesthesia. This meant that lower doses of barbiturate anaesthetics should be used.

Antidepressants with significant serotonergic effects such as the tricyclic clomipramine may increase the risk of bleeding during surgery for further details see under Precautions in Fluoxetine.

Breast feeding. In general, only small amounts of tricyclic antidepressants are distributed into breast milk. Nevertheless, the American Academy of Pediatrics considers that all antidepressants, including tricyclics, are drugs whose effect on nursing infants is unknown but may be of concern. In addition, most manufacturers advise that tricyclics should be avoided by the mother during breast feeding.

Case reports indicate that amitriptyline and its metabolite (nortriptyline), clomipramine, desipramine and its metabolite (2-hydroxydesipramine), dosulepin and its primary metabolites (nordothiepin, dothiepin-S-oxide, and nordothiepin-5-oxide), doxepin and its metabolite (N-desmethyldoxepin), imipramine and its metabolite (desipramine), and maprotiline are all present in breast milk in concentrations similar to those in maternal blood amoxapine and its metabolite (8-hydroxyamoxapine) have also been detected in breast milk but in concentrations lower than in maternal blood. In all but two of the above cases the infants were breast fed without experiencing adverse effects and tricyclics were undetectable in the infant’s blood or present only in minute amounts. In one of the affected infants, adverse effects included sedation and shallow respiration. The infant’s mother had received doxepin and, although doxepin was almost undetectable in the infant’s serum, the desmethyl metabolite appeared to have accumulated. In the other infant, drowsiness, poor suckling, and difficulty in swallowing were noted. In this case the levels of both doxepin and its desmethyl metabolite were below the lower level of quantification however, it was considered that the infant may have been at a greater risk for adverse effects because he had also developed hyperbilirubinae-mia. There were no data for the effects of amoxapine on breastfed infants because the case reported involved samples of milk taken from a woman who had galactorrhoea as an adverse effect of tricyclic use. No adverse effects were seen during a 27-month follow-up of 14 breast-fed infants whose mothers had received imipramine 100 to 225 mg daily for 4 to 24 weeks.

Cardiovascular disease. For comments on the potential cardiotoxicity of tricyclic antidepressants and precautions to be observed in patients with pre-existing cardiovascular disorders, see under Effects on the Cardiovascular System in Adverse Effects, above.

Contact lenses. Based on reports involving amitriptyline and maprotiline it has been considered that the antimuscarinic action of tricyclic antidepressants may decrease tear flow enough to cause corneal drying and staining of contact lenses.

Diabetes mellitus. The fact that tricyclic antidepressants may cause alterations in blood-glucose concentrations has led to the recommendation that these drugs should be used with caution in diabetic patients. Amitriptyline has also been reported to cause hypoglycaemic unawareness a patient did not experience the usual adrenergic symptoms that preceded or accompanied her hypoglycaemic episodes.

Driving. While affective disorders probably adversely affect driving skill, treatment with antidepressant drugs may also be hazardous, although patients may be safer drivers with medication than without. Impairment of performance is largely related to sedative and antimuscarinic effects both of which are more pronounced at the start of treatment sedative tricyclics, such as amitriptyline and doxepin, are likely to cause greater psychomo-tor impairment than less sedative tricyclics such as imipramine and nortriptyline. However, an epidemiological study was unable to confirm any increased risk of road-traffic accidents in those drivers receiving tricyclic antidepressants or SSRIs. In healthy subjects fluoxetine (an SSRI) and dosulepin appeared to have a similar but apparently small potential for impairing psy-chomotor and driving performance.

In the UK, the Driver and Vehicle Licensing Authority (DVLA) considers that drugs such as the older tricyclic antidepressants may have pronounced antimuscarinic and antihistaminic effects which may impair driving. In addition, all drugs acting on the CNS can impair alertness, concentration, and driving performance, particularly at the start of treatment or when the dose is increased driving must cease if patients are adversely affected. Patients with severe depressive illnesses complicated by significant memory or concentration problems, agitation, behavioural disturbances, or suicidal thoughts should cease driving pending the outcome of medical enquiry.

ECT. For comments concerning the precautions to be observed in patients receiving ECT, see under Anaesthesia, above.

Epilepsy. For comments on the epileptogenic effect of tricyclic antidepressants and the need for caution in patients with a history of epilepsy or other risk factors for development of seizures, see under Epileptogenic Effect in Adverse Effects, above.

Food. A high-fibre diet reduced or abolished the effectiveness of tricyclic antidepressant therapy in 3 patients the tricyclics involved were doxepin in two patients and desipramine in one.

Gastro-oesophageal reflux disease. The antimuscarinic action of tricyclic antidepressants may cause relaxation of the lower oesophageal sphincter and could aggravate nocturnal symptoms of gastro-oesophageal reflux if given in the late evening.

Glaucoma. It has been considered by the manufacturers that tricyclic antidepressants, because of their antimuscarinic actions, should be used with caution in patients with angle-closure glaucoma or raised intra-ocular pressure. There have been few reports of glaucoma associated with tricyclics, although acute angle-closure glaucoma was reported in 4 patients with narrow angles while taking imipramine in usual doses, and in another patient taking clomipramine. In the latter case, the presenting sign was amaurosis fugax, caused by the combination of raised intra-ocular pressure and an abnormally large drop in blood pressure on standing.

Phaeochromocytoma. Use of imipramine’ or desipramine has caused adverse effects such as seizures and cardiovascular abnormalities (tachycardia and hypertension or hypotension) in patients with previously undiagnosed phaeochromocytoma. It has been suggested that imipramine and its metabolite, desipramine, may be particularly effective in unmasking phaeochromocytoma and that this may be a reflection of their relative potency in inhibiting the noradrenaline reuptake mechanism.

Porphyria. Amitriptyline has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Pregnancy. Management of depression during pregnancy can be difficult, and one report on experience in 8 pregnant women being treated with a tricyclic antidepressant suggested that the dose might need to be increased during the second half of pregnancy to achieve a response. There are obvious concerns about such treatment (see also Depression). However, although there have been isolated reports attributing congenital malformations to the use of tricyclic antidepressants during pregnancy, large-scale studies and case-control data have failed to substantiate any association.

The effects of tricyclics on fetal neurodevelopment were studied in 80 pregnant women by later assessing global IQ of the children no differences were seen in those exposed to tricyclics in utero in the first trimester compared with those exposed to fluoxetine or no adverse developmental influences. A subsequent study indicated that exposure to tricyclic antidepressants or fluoxetine throughout gestation did not appear to adversely affect cognition.

Fetal iachyarrhyihmia detected at 37 weeks of gestation was attributed to maternal use of dosulepin during pregnancy. When this was stopped, no abnormalities in fetal heart rate were found and an uneventful labour led to a healthy infant being delivered. However, the authors expressed concern that fetal tachycardias might result in in-utero cardiac failure and considered that tricyclic antidepressants should be used during pregnancy only if there were compelling reasons.

Withdrawal syndromes manifesting as hypothermia and jitteriness, convulsions, or myoclonus have been reported in neonates whose mothers took clomipramine during pregnancy. Management has been with phenobarbital or clomipramine. Licensed product information advises that if it is justifiable to do so, clomipramine should be withdrawn at least 7 weeks before the calculated date of delivery.

Surgery. For comments regarding the precautions to be observed in patients undergoing surgery, see under Anaesthesia, above.

Withdrawal. Suddenly stopping antidepressant therapy after regular use for 8 weeks or more may precipitate withdrawal symptoms. The symptoms associated with withdrawal of tricyclic antidepressants appear to form four distinct syndromes:

• gastrointestinal disturbances and generalised somatic symptoms such as malaise, chills, headache, and increased perspiration, which may also be accompanied by anxiety and agitation

• sleep disturbances characterised by insomnia followed by excessive and vivid dreams

• parkinsonism or akathisia

• hypomania or mania

Tricyclic withdrawal has also resulted in cardiac arrhythmias in some patients. Withdrawal symptoms seem to be more common and more severe in children.

Many of the symptoms associated with stopping tricyclics may be produced by cholinergic rebound and can be minimised by a gradual reduction in dosage. The BNF recommends that any antidepressant, including a tricyclic, that has been given regularly for 8 weeks or more should be stopped gradually over a period of at least 4 weeks, or as much as 6 months in patients who have been receiving long-term maintenance therapy. If withdrawal symptoms do occur, they can be managed by restarting at a dose sufficient to eliminate them, and then stopping gradually. On the occasions that it may be necessary to stop a tricyclic abruptly, the withdrawal symptoms can be treated with a centrally active antimuscarinic such as atropine or benzatropine, or alternatively, if withdrawal symptoms are just gastrointestinal, an antimuscarinic that does not cross the blood-brain barrier such as propantheline. Awareness of the possibility of withdrawal syndromes helps to avoid misinterpreting new symptoms after withdrawal as evidence of relapse.

Tricyclic antidepressants have been included in some classifications as drugs of dependence because of their potential to produce withdrawal syndromes, but a review of several substance abuse studies challenged this on finding no evidence of abuse or dependence of the barbiturate type developing with the tricyclics.

For reports of withdrawal symptoms in neonates born to mothers who took tricyclic antidepressants during pregnancy, and their management, see under Pregnancy, above.

1. All patients with acute major depression should be considered reasonable candidates for pharmacotherapy.

2. There is adequate evidence to make the same recommendation for other forms of depression. This is particularly true for dysthymia, and may be true for other minor forms of depression as well.

3. There is good evidence for the use of antidepressants for non-mood disorders as well, particularly the anxiety disorders.

4. There remains no strong evidence from choosing one medication over another, and treatment recommendations should be made on the basis of tolerability and, if appropriate, cost.

5. Extended treatment should be recommended both for patients with chronic depression and recurrent depression.

6. Maintenance treatment should consist of the same dose of antidepressant as used to achieve acute phase remission.

7. The exact length of maintenance treatment is not known. The decision for indefinite treatment should be a risks-benefit decision, made with the informed consent of the patient, who is entitled to be informed of the limitations in our knowledge.

Of these enzymes, most drugs are metabolized by the enzymes CYP3A4 (50%) and CYP2D6 (20%). Other clinically important CYP enzymes include CYP2C9, and CYP2C19 and CYP1A2, the latter which is found in the brain and may affect CNS distribution of antidepressants. A list of the enzymes and some drugs commonly affected by them is found in Table: Cytochrome P-450 Isoenzymes and Common Medications Inhibiting or Inducing Them.

Table: Cytochrome P-450 Isoenzymes and Common Medications Inhibiting or Inducing Them

Tricyclic Antidepressants

As with any combination therapy, the side effects described previously can be additive with other similar drugs. Most problematical are the antichohnergic effects of the tricyclic antidepressants (TCAs). Such cholinergic blockade is a property shared by many other medications, including numerous over-the-counter preparations. The general sedative properties of these medications can also augment any soporific. The slowing of cardiac conduction can also potentiate other medications that produce similar effects, such as type IA antiarrhythmics and antichohnergic medications. Adrenergic receptor blockade can worsen the orthostatic hypotension caused by other medications, including vasodilators and low-potency antipsychotic medications.

Pharmacokinetic Effects

Absorption of tricyclic antidepressants (TCAs) can be inhibited by cholestyramine, which therefore must be given at different time intervals than the antidepressants. Specific substances reported to increase TCA levels include fluoxetine, antipsychotic medications, methylphenidate, and cimetidine. Methylphenidate has been combined with desipramine to treat attention deficits and depression in children. The combination therapy had a higher incidence of ECG changes (particularly higher ventricular rates), nausea, dry mouth, and tremor. Enzyme “inducers” that can lower tricyclic agent levels include phenobarbital and carbamazepine. The nicotine from cigarettes can also induce enzyme activity.

Guanethidine is contraindicated with TCAs, as it relies on neuronal reuptake for its antihypertensive effect. Clonidine, a presynaptic alpha-₂-receptor noradrenergic agonist, is also contraindicated, as it works in an antithetical fashion to tricyclic medications.

Monoamine Oxidase Inhibitors

As with the dietary proscriptions, any medication that increases tyramine can precipitate a hypertensive crisis; such medications include numerous over-the-counter preparations for coughs, colds, and allergies. The same rule applies to sympathomimetic drugs (such as epinephrine and amphetamines or cocaine) and dopaminergic drugs such as anti-parkinsonian medications.

The combination of monoamine oxidase inhibitors (MAOIs) and narcotics, particularly meperidine, may cause a fatal interaction. The reaction can vary from symptoms of agitation and hyperpyrexia to cardiovascular collapse, coma, and death. A similar reaction has also been reported when propoxyphene, diphenoxylate hydrochloride, and atropine are used with MAOIs. The combination of MAOIs with agents such as selective serotonin reuptake inhibitors (SSRIs) can cause the serotonin syndrome.

Serotonin Reuptake Inhibitors

Serotonin reuptake inhibitors are potent inhibitors of the CYP2D6 pathway and can slow the metabolism of any drug that is also metabolized by that pathway. Such drugs include tricyclic antidepressants (TCAs), carbamazepine, phenothiazines, butyrophenones, opiates, diazepam, alprazolam, verapamil, diltiazem, cimetidine, and bupropion. Paroxetine appears to be the most potent inhibitor of this metabolic pathway, with fluoxetine also showing high potency. Sertraline is a somewhat less potent inhibitor. These pharmacokinetic interactions are best managed with dosage adjustment. Fluoxetine, for example, can be safely used with tricyclic medications if TCA blood levels and, possibly, electrocardiograms are monitored. Although it binds more weakly to the CYP2D6, sertraline has also been reported to raise the level of TCAs significantly. In the case of bupropion, this relative increase in the blood level can increase the risk for seizures.

Particular caution should be used when a patient using multiple medications starts a serotonin reuptake inhibitor, as the interactions with other drugs can cause dangerous increases in levels. For example, in the cardiac patient, levels of warfarin should be monitored as fluoxetine has been reported to raise these levels. Several case reports exist of increased antiarrhythmic levels after introduction of fluoxetine, which resulted in potential serious bradyarrhythmias.

Fluoxetine has also been reported to raise lithium levels. The mechanism for this is not clear, as lithium is primarily excreted through the kidneys.

Other Second-Generation Antidepressants

Few reports exist of interactions with other drugs and trazodone, although trazodone may increase levels of digoxin, phenytoin, and possibly warfarin. Bupropion causes few drug-drug interactions. The main interactions reported have occurred when bupropion is combined with another dopaminergic agent. For example, when bupropion was used with l-dopa, the combination caused excitement, restlessness, nausea, vomiting, and tremor.

Third-Generation Antidepressants

Venlafaxine does not substantially inhibit the CYP enzyme, and is not highly protein-bound, thus it tends to have few clinically significant drug-drug interactions. Duloxetine is metabolized by 1A2 and 2D6 P450 isoenzymes, and may increase plasma levels of other antidepressants, antipsychotics, and Type 1C antiarrhythmics, such as flecainide (Tambocor). Nefazodone is highly protein-bound, and has several active metabolites. It is also a strong inhibitor of CYP3A4, and affects other drugs also metabolized by that pathway; however, it has little affinity for the CYP2D6 enzyme. Mirtazapine is highly protein-bound as well, but appears to only weakly affect the cytochrome enzymes.

Table: SSRI, SNRI and TCA Side Effects

Anticholinergic Effects

Common side effects include dry mouth, constipation, urinary retention, blurred vision, and less commonly narrow-angle glaucoma. These effects are usually dose-related and worse in patients with pre-existing defects.

Dry mouth can be alleviated by saliva substitutes or sugar-free hard candy, over-the-counter bulk-forming laxatives can treat the constipation caused by some agents, and the cholinergic agonist bethanechol has been used to treat anticholinergic side effects, particularly urinary hesitancy and blurred vision. The usual adult dosage is 10 to 50 mg t.i.d. or q.i.d. Pilocarpine eye drops can also be used to treat blurred vision. Selective serotonin reuptake inhibitors (SSRIs) in general are free from these side effects, as is bupro-prion, although duloxetine and paroxetine may cause mild dry mouth and constipation.

Other effects include tachycardia, impaired memory and cognition (in severe cases leading to delirium), and exacerbation of texisting tardive dyskinesia.

Rarely, in combination with other anticholinergic drugs, tricyclic antidepressants (TCAs) can precipitate a central anticholinergic delirium and confusion. Patients with psychotic depression may be at higher risk as their treatment regimen may include a TCA, a low-potency antipsychotic, and an antiparkinsonism agent. If this syndrome is suspected, a physostigmine challenge can be diagnostic and may produce a dramatic reversal. Abrupt withdrawal of TCAs can put patients at risk of cholinergic rebound. This syndrome includes gastrointestinal distress, anxiety, and autonomic instability. Whenever possible, TCA doses should first be slowly tapered and then discontinued.

Autonomic Effects

The most frequent and treatment-limiting side effect of tricyclic antidepressants (TCAs) is orthostatic hypotension. The geriatric population is especially vulnerable to falls; patients should be educated in how to change position safely. Newer TCAs such as nortripty-line and doxepin have a lower risk of this side effect. Trazodone has significant etj-adrenergic blockade and as a result also induces significant orthostatic hypotension.

Both selective serotonin reuptake inhibitors (SSRIs) and TCAs may also cause sweating, palpitations, and increased blood pressure. Venlafaxine and duloxe-tine also cause sweating and tremor, and slightly increase blood pressure and heart rate; increases in blood pressure are most notable in doses of venlafaxine above 300 mg/day.

Neurologic Effects

Several tricyclic antidepressants (TCAs) may lower the threshold for epileptic seizures, although as a class they have relatively low risk for inducing seizures. Initial doses of TCAs should be reduced in epileptic patients. Some selective serotonin reuptake inhibitors (SSRIs) may increase the frequency of seizures at high dose, particularly fluoxetine at doses of 100 mg/day or more. Buproprion is the agent most likely to reduce the seizure threshold. In doses below 450 mg/d, the incidence of seizures is less than 0.5%. To avoid inducing a seizure, one should give bupropion in divided doses, with a maximum dose of 450 mg/d (400 mg/d for the extended release formulation). Seizure risk is likely to be lower with sustained or extended release forms of buproprion.

Myoclonic twitches and tremor of the tongue and upper limbs can occur in 5-10% of patients on SSRIs and less frequently with tricyclic antidepressants; this may respond to dose reduction or the addition of a low-dose beta blocker such as propranolol. Anxiety, nervousness, insomnia, and sedation may also occur with SSRI agents; these symptoms may respond to a dose reduction or to the short-term addition of a low-dose benzodiazepine. Insomnia is often already part of the depression; the addition of a low-dose of a sedating antidepressant such as trazodone, or a sedative-hypnotic, may allieviate symptoms in the short term. It is more common with high doses of fluoxetine. Headache may also occur with fluoxetine.

More rarely, paresthesia, ataxia, and speech blockade may occur with both TCAs and selective serotonin reuptake inhibitors (SSRIs).

There is some question as to whether SSRIs can induce extrapyramidal-like symptoms, specifically akathisia. It remains unclear whether this is actually an extrapyramidal effect or part of the agitation and anxiety that these agents can produce. The TCA amoxapine can cause extrapyramidal side effects including acute dystonic reactions, parkinsonism symptoms, akathisia, tardive dyskinesia, and neuroleptic malignant syndrome. If akathisia is suspected, dosage reduction may be required.

Weight Gain

Both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) cause weight gain; up to 30% of patients on SSRIs experience this side effect, with increases of 8 kg or more. This is less of a concern during the acute phase of treatment, when insomnia and anorexia are often present, but they can be treatment limiting when long-term use is indicated. Medication switches to less weight-increasing medication may be helpful.

Gastrointestinal Symptoms

Nausea, vomiting, anorexia, and diarrhea are frequent complaints with selective serotonin reuptake inhibitors (SSRIs). They are often dose and titration dependent and can be lessened by dose reduction, a slower initial titration, and having the patient take medications with food. Anorexia usually occurs only early in treatment and is not persistent. Side effects and treatment discontinuation during the early days of treatment associated with paroxetine may be reduced by prescribing the modified-release formulation Paxil CR. Compared with immediate-release tablets, this formulation significantly reduces the incidence of nausea during the first week of therapy. The most frequent adverse effect associated with both venlafaxine and duloxetine is nausea.

Sexual Dysfunction

Every class of antidepressants is associated with some degree of sexual dysfunction. Difficulties can include problems with libido, impotence, ejaculatory dysfunction, and anorgasmy. The incidence of sexual dysfunction is as high as 30% with selective serotonin reuptake inhibitors (SSRIs). As with other side effects, some of these may be symptoms of the depression itself, and they may predate the initiation of the antidepressant trial. Treatment can include dose reduction, skipping of a dose of an SSRI with a short half-life (e.g., sertraline), or changing to an antidepressant of a different class. Anorgasmia may be treated by the addition of yohimbine or amantadine or by the use of bethanechol or cyproheptadine one to two hours before sexual activity. Decreased libido may be treated by the addition of the antidepressant bupropion; in general, this agent has the best profile with respect to sexual dysfunction. Trazodone has been associated with priapism in rare cases; this must be treated urgently to avoid long-term impairment.

Cardiac Conduction

Tricyclic antidepressants (TCAs) affect cardiac conduction; as a result, they have antiarrhythmic properties and can slow cardiac conduction. These effects are responsible for the cardiotoxicity of TCAs and their danger in overdose. TCAs do not affect cardiac output, however they should not be used in patients with a preexisting conduction delay greater than a first-degree block or in patients immediately after myocardial infarction.

Suicide Risk

Selective serotonin reuptake inhibitors (SSRIs) have a very wide therapeutic index and are not lethal in overdose. This has made them especially popular in the treatment of patients with a history of impulsivity. The possibility that treatment with any type of antidepressant may increase the risk of suicide in adults is currently under active review. It is clinically prudent to limit the amount prescribed during the initiation of therapy or when patients are only partially treated. The risk of suicide attempts during these intervals is high. More than a 1-week supply of a TCA is potentially lethal in an overdose attempt.

Pooled analysis of clinical trials involving children and adolescents suggests that antidepressants are associated with suicidal thinking or behavior in about 4% of patients compared with 2% receiving placebo during the early months of treatment.

All patients treated with an antidepressant (adults as well as children and adolescents) should therefore be closely monitored during the first few months. Treatment may need to be adjusted or discontinued if depression continues to worsen or suicidal ideation emerges, especially if the symptoms are severe, abrupt in onset, or not part of the patient’s presenting symptoms. Patients should be warned of this possibility and provided with information about the risk and advice on what precautions to take. They should be warned to report new or increased signs of irritability, agitation, or suicidality to a healthcare professional.

Allergic and Hematologic Effects

Tricyclic antidepressants (TCAs) are associated with exanthematous rashes in 4-5% of patients, while selective serotonin reuptake inhibitors (SSRIs) have been known to cause a variety of rashes in a similar percentage of patients.

Other Effects

TCA’s can cause gynecomastia and amenorrhea in some patients, while selective serotonin reuptake inhibitors (SSRIs) can cause increased prolactin levels causing mammoplasia and galactorrhea in both men and women. SSRIs have also been known to reduce blood glucose levels, though this is rare. Nefazodone has been associated with rare cases of life-threatening liver failure, and has been removed from the market in many European countries. As a result, nefazodone should not normally be considered for use before other antidepressants.

Central Serotonergic Syndrome

Any agent that increases serotonergic function can put patients at risk of a central serotonergic syndrome. This syndrome most commonly affects patients on multiple serotonergic drugs, and involves multiple systems. The syndrome can in rare cases progress to rhabdomyolysis, acidosis, respiratory compromise, disseminated intravascular coagulation, and cardiac collapse.

Monoamine Oxidase Inhibitors

The declining popularity of monoamine oxidase inhibitors (MAOIs) in the United States is primarily the result of the need for dietary restrictions and the potential for serious side effects. Use of MAOIs must be limited to patients who are compliant with a tyramine-free diet and do not use any medications that contain sympathomimetic amines. A hypertensive crisis is a potentially fatal, though rare, complication of these drugs. The crisis is usually preceded by a prodrome that includes increased blood pressure, headache, stiff neck, and vomiting. Treatment needs to be immediate and may include the administration of phentolamine, 5 mg i.v.

CONTINUATION PERIOD

This period usually lasts five to eight months after the end of the acute treatment period. The goal at this phase is the prevention of relapse. There is a high risk of relapse if treatment is discontinued after the acute treatment phase, with rates of 15% after six months and 22% after 12 months. The two best predictors of relapse are a high number of previous depressive episodes (greater than three predicted relapses) and underlying dysthymic disorder.

Once a patient has responded to medication, treatment should be continued for a minimum of four to six months from the point of initial response. This period should be lengthened for the patient with a history of longer depressive episodes.

In the past, it was suggested that, on achievement of euthymia, doses could be reduced. However, it is more likely that levels similar to those needed at the acute stage of treatment will be required throughout the continuation period.

MAINTENANCE PERIOD

The goal of the maintenance period is to prevent the recurrence of depression. There are a number of reasons to consider long-term prophylactic therapy for depression rather than medication withdrawal:

1. Depression is a lifelong disease, with recurrence being the norm rather than the exception

2. As the number of acute episodes increases, the risk of future episodes increases as well, and the interval between episodes shortens

3. Each subsequent episode carries a higher morbidity and disability

4. There is a fear that treatment response may decrease with an increasing number of depressive episodes

Several factors influence the decision to maintain long-term prophylaxis for depression, including the seriousness of previous episodes, the severity of impairment caused by such episodes, the degree of response to previous treatments, and the ability of the patient to tolerate the drug. Central in the decision process is the concept of recurrent depression: that some patients are more likely than others to have a recurrence of the disease. Three previous episodes of depression make recurrent depression likely.

The best predictors of the likelihood of recurrence appear to be older age of onset and number of episodes. Long-term maintenance is the treatment of choice for the following groups of patients:

1. 50 years old or more at the time of the first depressive episode

2. 40 years old or more at first episode and have had at least one subsequent recurrence

3. Anyone who has had more than three episodes

The recommended length of maintenance therapy varies from five years of treatment to indefinite continuation. Recent studies with both acute major depression and recurrent depression have shown significantly higher relapse rates 2-3 years post-discontinuation compared with patients on maintenance treatment.

Regarding choice of agent, there are no rigorous studies comparing different antidepressants during the maintenance period. It is usually assumed that the same agent used in the acute and continuation period will also be the preferred one in the maintenance period.

Equally important in preventing recurrence of depression is the problem of maintaining adherence to medication long after the acute episode has resolved. Proper education and support will help with compliance. Toleration of side effects is important; patients are more likely to comply with agents that have more favorable side effect profiles. selective serotonin reuptake inhibitors (SSRIs) or bupropion (sustained or extended release forms) are generally the best-tolerated antidepressants.

Although lower doses for prophylaxis have been recommended, there are few data to support this contention. Even though lower doses may increase compliance, full doses should be used until new information indicates otherwise.

DISCONTINUATION OF TREATMENT

Before discontinuing treatment with an antidepressant it is important to remember that depression is often a lifelong disease with a chronic course. One should always weigh the benefits of discontinuation against the risks of recurrent depression. Patients with a single episode of acute depression and who have an onset before age 50 are the best candidates for discontinuation.

For tricyclic antidepressants (TCAs), the usual strategy is to taper the dose at a rate of 25 to 50 mg/day every 2 to 3 days. Too rapid a decrease in dose may produce symptoms of cholinergic ‘rebound’ or supersensitivity (nausea, vomiting, cramps), other signs of autonomic hyperactivity (diaphoresis, anxiety, agitation, headache), and insomnia as early as 48 hours or as late as 2 weeks after discontinuation. These early symptoms may be mistaken for relapse of depression.

Monoamine oxidase inhibitors (MAOIs) may also have a withdrawal syndrome on abrupt cessation of treatment, including symptoms of psychosis; however, this is rarer than that seen with the TCAs.

Recommendations for discontinuing selective serotonin reuptake inhibitors (SSRIs) depend on the particular drug. Fluoxetine has a long half-life and abrupt withdrawal should be permissible. Shorter half-life drugs, such as sertraline, citalopram, escitalopram, and paroxetine, may require a 7-10-day taper. The withdrawal syndrome with shorter-acting agents includes symptoms of fatigue, insomnia, abdominal distress, and influenza-like symptoms. The same may be true for venlafaxine and duloxetine.

A first episode of depression has a high risk of recurrence and the risk is higher in patients who have only a partial response to treatment. After discontinuation the goal is to enable early intervention if symptoms recur. The patient should be educated to recognize the symptoms of depression and seek help at an early stage.

In patients showing an inadequate response after a reasonable time, the decision is either to continue with the same medication and augment with an additional agent, or to switch medications altogether, depending on whether the patient has shown any response to the current strategy. Partial responders may be more likely to benefit from treatment augmentations, whereas patients who show no response or worsen during treatment warrant a new agent.

Antidepressant Augmentation

Typical augmentation strategies shown in Table: Augmentation Strategies include the addition of lithium carbonate, thyroid hormone, a stimulant, an atypical antipsychotic, or by the use of antidepressant combinations.

Table: Augmentation Strategies

† Inadequate data.

LITHIUM AUGMENTATION

Lithium has been used successfully with most antidepressants, including tricyclic antidepressants (TCAs), serotonin reuptake inhibitors, and bupropion, with response rates as high as 65%. The blood level of lithium necessary for adjunctive use has not been well established. It is probably best to start at a low dose (300 mg b.i.d) and increase to a therapeutic blood level (0.8 to 1.2 mEq/L) if there is no response. It may take three to six weeks for augmenting effect. If augmentation is successful, it should be continued throughout the acute phase of treatment. This strategy can be limited by side effects and lithium’s narrow therapeutic index. It is associated with hypothyroidism, tremor, increased thirst, increased urination, nausea, weight gain, and acne. Patients should be cautioned to avoid dehydration, which can precipitate toxic lithium blood levels.

THYROID HORMONE AUGMENTATION

Starting dose is 25 µg/day of triiodothyronine, which can be increased to 50 µg/day in a week if there is no response. The trial should continue for at least three weeks. Reported response rates for thyroid augmentation are lower than those for lithium augmentation (25%). As with lithium augmentation, if there is a positive response, it occurs relatively early.

STIMULANT AUGMENTATION

Methylphenidate and dextroamphetamine at dosages between 5 and 20 mg have been used for antidepressant augmentation, but there are few systematic data regarding the proper dose or length of treatment for this potential use.

ANTIDEPRESSANT DRUG AUGMENTATION

Second-generation antipsychotic drugs are increasingly being used adjunctively with antidepressants for residual or treatment-resistant symptoms. APDs are generally used within their therapeutic range.

COMBINED ANTIDEPRESSANT THERAPY

Open trials have supported the use of combined therapy of a TCA and a serotonin reuptake inhibitor in patients for whom either class alone has failed. When antidepressants are combined, it is important to remember that the serotonin reuptake inhibitors can potentiate TCA levels, and this should be monitored carefully. Monoamine oxidase inhibitors (MAOIs) have also been used in combination with tricyclic antidepressants (TCAs), although this should be monitored closely given the risk of potential toxic interactions. Given the risk of a serotonin syndrome, MAOIs should not be combined with serotonin reuptake inhibitors. Bupropion is frequently added to an SSRI to enhance efficacy or to alleviate side effects such as decreased libido, fatigue, and sedation.

NONPHARMACOLOGICAL APPROACHES

A number of nonpharmacological augmentation options exist, particularly the concomitant use of psychotherapy. The combination of psychotherapy and medication may offer benefits that either therapy alone cannot offer, including additional efficacy as well as prevention of relapse. This has been shown to some degree for both cognitive-behavioral therapy and interpersonal therapy.

Changing to a New Agent

Patient showing no response or whose condition deteriorates during therapy should trial an alternative single agent. Recent studies support the belief that it is best to switch to an agent of a different class, and approximately 50% of patients unresponsive to a first trial respond to an antidepressant of a different class.

When the switch involves an MAOI, sufficient time must be given for medication clearance. Although seldom used, monoamine oxidase inhibitors (MAOIs) may be very effective in patients not responsive to other classes of antidepressants. Generally, 10 to 14 days is required for clearance of tricyclic antidepressants (TCAs) and MAOIs. Fluoxetine requires a much longer period — 6 weeks — whereas sertraline and paroxetine require about two weeks when switching to an MAOI. Another alternative is changing from an SSRI medication to an SNRI. There is some evidence that serotonin-norepinephrine reuptake inhibitors (SNRIs) may lead to higher rates of response and remission than selective serotonin reuptake inhibitors (SSRIs).

ECT ECT and other forms of stimulant therapies (e.g., vagal nerve stimulation) should be considered for patients who are non-responsive to pharmaco- and psychotherapies.