Drug Approvals
(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:
• trimipramine
• doxepin
• imipramine
• maprotiline
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
• maprotiline
• imipramine
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.
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