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, 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.

Answer. Your story, unfortunately, echoes those of millions of individuals who suffer from severe, major depression. Some day, you may look back at what happened following your suicide attempt and feel that you were given a second chance to succeed at life. While I don’t have any magic solutions for you, I do want to offer you the perspective I have gained after having treated many hundreds of such patients.

First: Depression is a treatable and reversible condition, even when several therapies or medications have failed. There are still many treatments that could be tried and which I have seen work. It might be frustrating, but not all treatments are beneficial to an individual patient. You should talk to your psychiatrist about both your ongoing feelings of hopelessness and possible trials on some of the newer antidepressants, such as Effexor and Remeron. And, whatever you may have heard about ECT (electroconvulsive therapy), do not exclude this as a treatment option! I have seen ECT work for people who were virtually at death’s door. It is safe and very effective.

Second: In all my years of treating depressed patients and working with their families, I have never seen a single instance in which the family truly felt they would be better off without their depressed family member. That’s right, not once. This belief is virtually always a symptom of severe depression. In fact, suicide is usually a devastating emotional blow to a family, from which recovery is extremely difficult. Some families never recover from losing a loved one in this way.

Third: You are not alone. If you have not yet joined the National Depressive and Manic Depressive Association (NDMDA), I would urge you to do so. They provide support and peer counseling for thousands of individuals with depression; you can call 800-826-3632 for local referrals. You can also contact the National Mental Health Self-help Clearinghouse (800-553-4539). These groups should supplement, not replace, the help you are already receiving. Also keep in mind that the Samaritans provide 24-hour anonymous telephone counseling for suicidal individuals (ask your telephone operator for the number).

Finally, depending on your spiritual and religious orientation, consider some form of pastoral counseling; not as a replacement, but as a supplement to your therapy. I know it may be hard for you to believe there is a light at the end of the tunnel, but I hope you can believe that I believe that. Good luck…

Answer. I am providing you with a list of commonly used antidepressants, as well as their usual doses:

Maintenance Dosage and Tablet Size for Non-MAOI Antidepressants

With respect to non-addictive medications for anxiety, it is first important to realize that the term addiction is defined in many ways. The medications most commonly used in the treatment of anxiety – the benzodiazepines, such as Valium, Librium, Ativan, etc. – are not highly addictive for the vast majority of people who are prescribed them for the right reasons. These agents may be abused or become habit-forming, however, in individuals with a history of alcohol and substance abuse, and, very rarely, in individuals who do not have such problems. The antianxiety agent buspirone (BuSpar) is a good alternative, and is not habit-forming or prone to abuse; however, while buspirone is useful for generalized anxiety, it is not helpful for panic attacks or obsessive-compulsive states.

Sometimes, low doses of the older tricyclic agents, such as doxepin 15-25 mg/day, may be useful for generalized anxiety in patients who are not good candidates for benzodiazepines. If you want more details about available medications for mood and anxiety disorders, you may want to call the NIMH Depression Awareness program.