Antidepressant drugs

Martin Elphick

2

Antidepressant drugs

ANTIDEPRESSANTS IN GENERAL

MONOAMINE OXIDASE (MAO) INHIBITORS (SED-12, 34; SEDA-12, 8;

The true significance of an observed association between the administration of a drug and the occurrence of a presumed adverse event is often difficult to assess. Yet decisions must be taken, on the withdrawal of a drug for instance, by the pharmaceutical companies and drug regulatory bodies. Naranjo et al. (1 c) have attempted to apply Bayesian methods to the problem. They developed BARDI (Bayesian Adverse Reaction Diagnostic Instrument) and applied it to the association of zimeldine with Guillain-Barr6 syndrome. The method calculates the probability that a drug caused an adverse event, given all the background and case information, divided by the probability that the drug did not cause the event, given the same information (i.e. the posterior odds). The method does not lend itself to brief summary, but it is worthy of attention and it may be comforting to note that the instrument reached the established conclusion in the example set: that it was correct to withdraw zimeldine.

SEDA-13, 6; SEDA-14, 11; SEDA-15, 11)

Nervous system Deptula and Pomara (2R) have reviewed the effect of antidepressants on human psychomotor performance. Their tentative conclusions were as follows: impairment of performance is correlated with sedating effects in single-dose studies; adaptation occurs commonly in the first several weeks; ageing and higher drug plasma concentrations increase vulnerability; drug effect interactions with diagnosis, severity of illness, dosage, drug plasma concentration and age deserve further research.

Attention was drawn in SEDA-15 to the development of reversible MAO inhibitors. In the meantime overdoses of standard irreversible inhibitors will continue. Lipson and Stern have reviewed the current state of knowledge so far as treatment of each toxic effect is concerned (3R).

Moclobemide (SED-12, 40; SEDA-15, 12) Studies of this reversible, MAO-A-selective inhibitor continue to suggest that it has a low rate of adverse effects, both in comparison with older MAO inhibitors and with tricyclics, even in overdosage. In particular, Moll and Hetzel reported an evaluation of the adverse effects in 2203 patients on moclobemide compared with 1214 patients on other antidepressants (4c). Nausea and dizziness early in treatment appear to be the most common complaints. Nervous system Psychomotor performance after moclobemide (150 mg 3 times daily for 7 days in healthy volunteers) was assessed by Berlin et al. (5c). Measures of memory function, vigilance, subjective feelings of alertness, and sleep characteristics were all unaltered. Furthermore, Miller reported in his review of the subject that there was no potentiation of alcohol-induced psychomotor impairment, and in some tests there was actually a partial reduction (6R). However, in a comparative trial against desipramine, one patient dropped out because of acute confusion and agitation (7e). Toloxatone

@ 1993 Elsevier Science Publishers. All rights reserved Side Effects of Drugs Annual 16 M.N.G. Dukes and J.K. Aronson, eds.

Liver This is a new reversible MAO Type-A inhibitor. Two women developed fulminant hepatitis 20 days after starting, and 138 days after reintroduction of the drug. Hepatic cell necrosis in the centrilobular area was the

8 predominant histological abnormality. Both patients died. There was no past history of liver disorder or risk factors for hepatitis in either case (8c).

Tranylcypromine (SEDA-14, 12, SEDA-15, 11) Nervous system Briggs et al. (7c) have collected reports of addiction to tranylcypromine, wich has some amphetamine-like stimulant effects. They found a total of 18 cases, and there seems to he a pattern of development of tolerance to the stimulant effect, resulting in an escalation of dose. Some of the cases had a history of drug abuse. A withdrawal state similar to that of amphetamine withdrawal may also occur (9R). Somewhat in contrast was a report by Joffe of afternoon somnolence and fatigue in 38 patients (10c), of whom 4 suffered quite profound drowsiness in the late afternoon, resolving in the evening. Their sleep at night was mildly disturbed, but not as severely as when they had been depressed.

TRICYCLIC ANTIDEPRESSANTS (SED-

12, 40; SEDA-13, 8; SEDA-14, 12; SEDA-15, 12) Dziukas and Vohra (11 R) analyzed 250 items of literature on poisoning with tricyclics. Their review is concise, factual, and practical. The death rate among those who reach hospital is 2 - 3070, most of those deaths being cardiac in origin and caused by direct depression of myocardial function rather than cardiac dysrhythmias. They recommend that all patients seen within 6 hours of overdose should have their stomachs emptied. All patients should receive activated charcoal. Coma, convulsions, respiratory depression, and hypotension should be treated with standard resuscitation techniques and drugs. Patients with significant cardiotoxicity or cardiac arrest should be alkalinized with sodium bicarbonate or hyperventilation, aiming for an arterial pH of 7.45 7.55. Lidocaine should be used for ventricular dysrhythmias. Other antidysrhythmic drugs are contraindicated (Class IA, Class IC), potentially lethal (Class II), of no benefit (phenytoin), or unproven (Class III and Class IV).

Chapter 2 M. Elphick Physostigmine has no role at all. Hemodialysis and hemoperfusion are of no benefit.

Nervous system

Preskorn and Jerkovich (12 R) found a 6~ incidence of 'CNS toxicity' in 976 tricyclic-treated patients. Risk was correlated with plasma concentrations, age, and female gender, and the delirium took on average 2 weeks to develop. The authors emphasized the variability of symptoms such as disorientation, memory impairment, agitation, and confusion, which may be mistaken for symptoms of depression, thus leading to a further increase in dosage.

Metabolic

Much speculation has surrounded the topic of antidepressant-provoked weight gain. Fernstrom (13 c) has reported the preliminary results of a study of 4 different antidepressants (amitriptyline, nortriptyline, desipramine, and zimeldine) using the Pittsburgh Appetite Test. She concluded that weight gain was due to increased energy efficiency (of about 16-24070) rather than to an increase in 'carbohydrate craving'. Highly palatable foods may be preferred during a depressive episode, but these may be rich in fats, carbohydrates, or both, and that is not a treatment effect.

Amineptine (SED-12, 53; SEDA-15, 12) Amineptine increases the release of dopamine and reduces its re-uptake, and it is therefore not surprising that it can lead to abuse in common with other drugs sharing these properties. There have been 2 recent reports from France. Castot et al. reported 186 cases in which there was a preponderance of women, risk factors such as substance abuse or bulimia, and the constant search for a stimulant effect (14R). Bertschy et al., who collected 8 cases, found a common pattern of multiple small doses during the day in an apparent effort to maintain the effect. A withdrawal state occurs, but the symptoms of this vary greatly from patient to patient (15R). This withdrawal state may be improved by treatment with clonidine (16c).

Amoxapine (SED-12, 53; SEDA-12, 15; SEDA-14, 13; SEDA-15, 13) Amoxapine, which has dopamine-blocking

Antidepressant drugs Chapter2 actions, has been compared with amitriptyline in a continuation trial. Of 47 patients on amoxapine, 32 had drug-related adverse effects (10 withdrawn as a consequence), compared with 34 of 45 in the other group. Thus, amoxapine did not seem to offer any advantage over traditional treatments (17c).

Nervous system A case of "neuroleptic'malignant syndrome has been reported from Japan: about 2 weeks after starting amoxapine the patient had a sudden disturbance o f consciousness, muscle rigidity, fever, leukocytosis, and elevated CPK. Rapid improvement followed withdrawal of the drug and fluid replacement. This case-report further confirms that the syndrome can be triggered by any drugs which block dopamine receptors (18c). Clomipramine (SED-12, 54; SEDA-15, 13) Nervous system A rare case of clomipramineinduced dystonia has been described by Chithiramohan et at. (19c). A 36-year-old woman developed an oculogyric crisis, torticollis, and rigidity 5 days after starting clomipramine 75 mg. The symptoms resolved after a phase of choreo-athetoid movements once the tricyclic was stopped and procyclidine was given. Desipramine (SEDA-14, 13; SEDA-15, 13) Cardiovascular Sudden death, possibly related to cardiac effects in children and adolescents, was discussed in SEDA- 15. Subsequently the subject has been well discussed in a review by Riddle et al. (20R), and a suggested protocol including electrocardiography before treatment and plasma drug concentrations during long-term therapy was included. A case report by Babb et al. has reinforced the wisdom of a gradual tapering of tricyclic dosages in all patients, although their report of protracted ventricular dysrhythmias accompanying symptoms of nausea, headaches, and insomnia after the withdrawal of desipramine must be regarded as a rarity (21c). A study of the ECG effects of desipramine in young adults indicated that the 2-hydroxydesipramine and desipramine concentrations were both significantly correlated with effects (22c).

9 Trimipramine (SEDA-15, 14) Allergy A 58-year-old man developed an acute influenza-like syndrome, with eosinophilic pleurisy and biochemical evidence of liver function abnormality after a few days of trimipramine (maximum dose 400 rag/day) (23c). This combination of features of allergy appears to be rare as a response to a tricyclic, although it is not unknown for other drugs.

SELECTIVE SEROTONIN (5-HT) RE-UPTAKE INHIBITORS (SEDA-15, 14)

Fluoxetine (SED-12, 5C SEDA-12, 17; SEDA-13, 12; SEDA-14, 13; SEDA-15, 15) Cardiovascular Although fluoxetine is relatively innocuous so far as the cardiovascular system is concerned compared with tricyclics, 5-HT is involved in the conduction system of the heart and in the control of vascular tone. Thus, in patients with existing abnormalities there may be clinically troublesome effects. Buff et al. (24 c) have given the example of an elderly man who developed atrialfibrillation and bradycardia shortly after starting fluoxetine, and again on re-challenge. Ellison et at. (25 c) and Feder (26 c) have described dose-dependent bradycardia accompanied by dizziness and syncope in patients with apparently normal cardiovascular systems. By contrast, Gardner et al. have reported a case of supraventricular tachycardia in a 52-year-old woman with no relevant past medical history taking only 20 m g / d of fluoxetine. There was no rechallenge and the association was therefore only presumed (27c). Nervous system The controversial report on psychic disturbances by Teicher described in SEDA-15 (p. 15) has led to a number of further case reports of suicidal ideation arising or worsening during fluoxetine treatment in adults (28 c, 29 c) and adolescents (30c). However, 3 papers have provided reasurrance: Miller (31 R) reported no increase in suicidal ideas in his experience of 100 patients, using lower doses of fluoxetine than Teicher. He also commented that 'the hypersomnia, akathisia and fatigue noted in the author's patients would have led

10 me to decrease the dose, not increase it'. De Jonghe et al. (32 R) recorded no increase in suicidal ideation in a controlled trial of 196 depressed patients. However, the best, though still not perfect, evidence comes from Fava and Rosenbaum (33R). They sent a questionnaire to psychiatrists before the publication by Teicher, specifically asking for information on suicidal ideation; 27 psychiatrists recorded information retrospectively on 1017 depressed outpatients. The groups treated with fluoxetine alone and fluoxetine together with other antidepressants did not have a statistically significant increase in suicidal ideation. Post hoc interviews with clinicians suggested that most of the patients who did develop suicidal tendencies had either borderline personality disorder, psychosis, or worsening depression. This is an observation of possible clinical significance, but it also points to a weakness of the method: the groups treated with different antidepressants were not randomly allocated, so the psychiatrists might well have selected patients of differing suicidality for different treatments. As the authors themselves pointed out, 'only a very large, prospective study could determine whether such ideation occurs less frequently among patients treated with fluoxetine than patients treated with any other antidepressant'. In the meantime it may be wise to take note of Miller's comment quoted above, especially in the groups of patients in whom there may already be a greater risk.

Endocrine, metabolic The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was mentioned as a possible adverse effect of fluoxetine in SEDA-14. At least 4 further case-reports have since been published, confirming this as a rare complication (34 C - 37c).

Immunological Three cases in which herpes simplex reactivation appeared to be caused by fluoxetine were described. Although the evidence seemed relatively weak in 2 of the 3 cases, other cases have been reported to the manufacturers (38c).

Hematological

Case-reports have recently appeared describing petechiae and prolongation of bleeding time (39c); melena (1 case), rectal bleeding (4 cases), bruising (1 case), nose

Chapter 2 M. Elphick bleeds (1 case), and small bowel bleeding and ulceration (1 case) (40c). This adverse effect is likely to be associated with blocked 5-HT reuptake into platelets, and should be borne in mind particularly when treating any patient with thrombocytopenia or poor platelet function.

Hair Jenike (41 c) has reported a case of general thinning o f the hair after 10 months of fluoxetine. Four months after stopping the drug the hair began to regrow. The author quoted 1% incidence of alopecia in a large previous study.

OTHER ANTIDEPRESSANTS

Bupropion (amfebutamone) (SED-12, 56; SEDA-14, 13) This aminoketone has been recently rereleased, having been withdrawn in the United States after reports of seizures in bulimics treated with it. Bupropion inhibits dopamine re-uptake but is a weak inhibitor of noradrenaline and 5-HT re-uptake. Two reports appeared almost simultaneously of 'delirium' associated with bupropion use, which may have been due to increased activity in the dopamine pathways. In one 48-year-old man, bupropion (450 mg/d), taken with lithium carbonate and propranolol, resulted in disorganized thinking with shortterm memory loss, agitation, and suspiciousness. The mental state improved on withdrawal and administration of benzodiazepines and haloperidol. Some months later the same patient was able to tolerate bupropion 300 m g / d without ill-effects. Plasma concentrations of the parent compound and metabolites did not show abnormal metabolism of the drug (42c). Another man, aged 41 years, first became edgy and anxious, then developed myoclonic jerks, and then became severely excited, saw snakes, and picked at his clothing. He improved 4 days after stopping bupropion. The authors referred to previous cases of psychosis induced by bupropion, but pointed out that those occurred in a clear sensorium (43c). In the first case described above, lithium might have prevented the down-regulation of dopamine postsynaptic receptors that would normally occur. In the second case, recent fluoxetine administration

Antidepressant drugs Chapter 2 m a y have reduced the m e t a b o l i s m o f b u p r o pion.

Mianserin (SED-12, 59; SEDA-12, 19; SEDA-13, 13; SEDA-14, 15; SEDA-15, 16)

Arthritis A letter f r o m N o r w a y (44 c) has d r a w n a t t e n t i o n to j o i n t s y m p t o m s a n d f r a n k arthritis occurring d u r i n g m i a n s e r i n t h e r a p y . T h e 8 patients developed j o i n t s y m p t o m s 1 - 4 weeks after starting rnianserin. T h e s y m p t o m s ,

11 m a i n l y of p a i n a n d swelling, i m p r o v e d in all cases on w i t h d r a w a l of t h e drug, a n d rechallenge in o n e of the cases resulted in relapse. A n analysis b y the W H O C o l l a b o r a t i v e C e n t r e for I n t e r n a t i o n a l Drug M o n i t o r i n g revealed 169 reports o f ' a r t i c u l a r e v e n t s ' , the largest g r o u p being ' a r t h r a l g i a ' . T h e r e was n o distinct distrib u t i o n p a t t e r n for t h e site o f the j o i n t p r o b l e m . This may be a m o r e c o m m o n adverse effect t h a n has been previously realized.

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