Antidepressant drugs

P.J. C o w e n

Antidepressant drugs

2 MONOAMINE INHIBITORS

OXIDASE ( M A O I s ) (SED-12, 34;

SEDA-17, 16; SEDA-18, 14) Conventional non-selective MAOIs are most often used for the treatment of depressive states that have not responded to other classes of antidepressant drugs. In a comparative trial of 93 depressed inpatients, Volz et al. (1 c) found that the reversible type A-MAO inhibitor, brofaromine (150 mg daily), produced a similar rate of clinical remission (74%) to that seen with tranylcypromine (72%), though the dose of tranylcypromine (up to 30 mg daily) was less than that usually given to depressed in-patients. Perhaps because of this, similar rates of insomnia (20%), and tremor (4%) were seen in each group but the incidence of hypotension was higher in the brofaromine-treated patients (11 vs. 4%). Brofaromine, of course, has the advantage that is much less likely than tranylcypromine to cause tyramine interactions (the 'cheese reaction'). Although type A and type B selective MAOs cause less food and drug interactions than non-selective MAOIs, the type A-inhibitor, moclobemide, can potentiate the effects of serotonergic agents and sympathomimetics (see SEDA-18, 15). Livingstone (2r) described a number of case reports involving interactions of selegiline at type B selective doses. The other drugs implicated in the interactions were fluoxetine, maprotiline and ephedrine, and pethidine. There was also a hypertensive reaction in a patient taking selegiline 20 mg daily who ate cheese. Interactions

9 1996 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 19 J.K. Aronson and C.J. van Boxtel, eds,

TRICYCLIC ANTIDEPRESSANTS

(SED-12, 40; SEDA-17, 17; SEDA-18, 16)

GENERAL Cardiovascular The most serious adverse effect of tricyclic antidepressants is cardiotoxicity, particularly cardiac arrhythmias, although in standard clinical doses the risk is small, certainly less than the mortality of untreated depressive illness. There has been great concern about the risk of sudden death in children taking desipramine (see SEDA-18, 18). Walsh et al. (3 c) assessed the cardiovascular effects of desipramine (mean dose 164 mg daily) in 11 young patients (age range 7--29 years). Overall there were significant increases in mean heart rate (20 beats per minute) and systolic and diastolic blood pressure (each by 10 mmHg). Reductions in the frequency of heart period variability suggested a lessening of parasympathetic influence on the heart with a relative predominance of sympathetic activity. Taken together these changes could predispose to the development of arrhythmias. The increase in heart rate with desipramine was greater in these young subjects than would be expected in older patients. In addition, tricyclic antidepressant treatment in older patients does not usually cause increases in blood pressure. The cardiovascular effects of desipramine in younger subjects could reflect the relative predominance of parasympathetic control in this age group. Rechlin et al. (4c) studied the effect of amitriptyline (150 mg daily) on cardiovascular function in 24 patients (mean age 43 years) with major depression. As with the desipramine study cited above patients experienced an increase in mean heart rate (15 beats per minute). In addition heart rate variability was decreased, again consistent with anticholinergic blockade by the tricyclic. This study confirms the striking effect of tricyclic antidepressants on the autonomic regulation of the heart.

8

Clomipramine (SEDA-1L l& SEDA-18, 18) Risk situations Depression in medically ill elderly inpatients is common and difficult to treat. Complications include poor tolerance of antidepressant drugs and interactions with medication used for concomitant general medical disorders. Bocksberger et al. (5 c) reported a retrospective study of clomipramine in 69 depressed medically ill inpatients (age 63--98 years). Nearly all the patients (86%) were taking other medication. Patients received up to 75 mg daily of clomipramine. Plasma monitoring showed that with this dosage regime, 57% of patients achieved combined concentrations of clomipramine and desmethylclomipramine within the accepted therapeutic range (160--400 ng/ml), while most of the remainder (39%) had levels below the lower limit. Overall the pharmacokinetic data suggested that elderly patients have decreased demethylation of clomipramine compared to younger subjects because they achieve higher plasma levels of clomipramine with an elevated ratio of clomipramine to desmethylclomipramine. The rate of clinical antidepressant response to clomipramine in the patients was 65%, but 20% had severe side effects including hypotension and confusion. There was no clear relationship between adverse effects and plasma drug levels, although two of three patients with combined drug levels of >400 ng/ml experienced postural hypotension. Tricyclic antidepressants such as clomipramine can cause significant adverse effects in the elderly due to blockade of muscarinic cholinergic receptors and c~l-adrenoceptors. Newer antidepressants such as selective serotonin re-uptake inhibitors (SSRIs) are probably better tolerated in this age group but there is concern that they may be less efficacious (6r). Plasma monitoring of tricyclic antidepressant levels may be advisable in the medically ill elderly, particularly those receiving concomitant medication.

Dothiepin Risk situations Depression following childbirth is common and not infrequently requires treatment with antidepressant medication.

Chapter 2

P.J. Cowen

Antidepressant drugs are lipophilic and therefore enter breast milk. While the actual dose an infant would receive has been calculated to be very low, there has been concern that exposure of the developing nervous system to even minimal amounts of a psychotropic agent might alter cognitive and social development. Buist and Janson (7r) followed-up 30 women who had been depressed post-partum; half of these subjects had breast-fed while receiving dothiepin (150--225 mg daily) for periods ranging from 4 to 134 weeks. Levels of dothiepin in breast milk ranged from 0 to 138/zg/ml with levels of northiaden being consistently lower. When the children were between 3 and 5 years, no significant differences were found in behavioural or cognitive measures between those whose mothers had received antidepressant drug treatment and those who had not. While the study was small it does provide some reassurance that children who are breast-fed while their mothers receive dothiepin do not show impaired development subsequently.

Imipramine Genital The effects of antidepressant treatment on sexual behaviour are of increasing importance in view of recommendations that patients with recurrent depression should receive long-term maintenance pharmacotherapy. Karp et al. (8 c) studied 90 remitted depressed patients who received 6 months maintenance treatment with imipramine and psychotherapy in a double-blind, placebocontrolled design. Overall, imipramine was not associated with changes in sexual interest or sexual function. In the male patients imipramine appeared to decrease sexual interest to some extent but did not alter the frequency of sexual intercourse. Not surprisingly, decreases in sexual interest and behaviour were correlated with levels of depressive symptomatology. The authors conclude that in contrast to short-term treatment with tricyclic antidepressants, maintenance therapy has relatively little effect on sexual function.

Antidepressant drugs

Chapter2

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SED-12, 56;

SEDA-17, 18; SEDA-18, 19) SSRIs have a different adverse effect profile to that of tricyclic antidepressants but there has been much debate as to whether their use is associated with lower drop-out rates in clinical trials than tricyclics. Earlier metaanalyses have not been conclusive but a careful investigation by Anderson and Tomenson (9 R) suggests that in published randomized studies, overall discontinuation rates are 10% lower with SSRIs than with tricyclics, while drop-out rates due to adverse effects are 25% less. The overall difference in discontinuation rates is not large and SSRIs are more expensive than tricyclics. Whether or not SSRIs are cost-effective relative to tricyclic antidepressants is difficult to calculate on the available data. Information about discontinuation rates in standard clinical settings would be helpful. Nervous system It is well recognised that tricyclic antidepressants can predispose to epileptic seizures. Similar adverse reactions have been reported with SSRIs but it is not clear whether their frequency differs from that of tricyclics. Levine et al. (10 c) reported seven patients in whom grand real seizures were associated with fluoxetine treatment. The cases were not straightforward and four of the patients at the time of the seizure were withdrawing from clonazepam, a benzodiazepine with anticonvulsant properties. In addition, the doses of fluoxetine (40--100 mg daily) were higher than those used in the usual treatment of major depression (20 mg daily). The findings suggest that higher doses of fluoxetine may be associated with seizures, particularly in the presence of other predisposing factors. SSRIs, particularly paroxetine and fluoxetine have been associated with acute dystonia and akathisia. A similar reaction was reported with sertraline (llC). A 35-year-old man was treated with sertraline for major depression. He had suffered a subarachnoid hemorrhage 8 years previously but had made a good recovery. The sertaline was increased over 2 weeks to 200 mg daily and 3 days later he complained of jaw stiffness and demonstrated a left sided torticollis. He was unable to sleep

9 because his legs were restless. He was treated with diphenhydramine and the sertraline was withdrawn. His symptoms settled and he was subsequently treated safely with nortriptyline. This report suggests that sertraline, like other SSRIs, can cause acute dystonia together with akathisia. The dose used in the case was at the upper limit of the usual range and the patient may have been predisposed to develop neurotoxicity because of the history of subarachnoid hemorrhage. There has been concern about adverse behavioural effects of SSRIs, particularly aggression and suicidal behaviour (SEDA-17, p. 19). Diaferia and Mundo (12 c) reported five male patients receiving fluvoxamine (200-300 mg daily) for the treatment of obsessive compulsive disorder. The subjects presented with aggression, impulsivity and mood changes. Three of the subjects had first-degree relatives with a mood disorder, so it is possible that fluvoxamine could have precipitated a mixed affective state. It is also possible that increasing brain 5-HT function can in some circumstances cause behavioural disinhibition. Fluoxetine sometimes causes activation with nervousness and agitation. Some patients, however, can develop daytime somnolence which may be helped by administering medication in the evening. A n 18-year-old woman was treated with fluoxetine 20 mg in the morning for major depression. One of her symptoms was insomnia with early morning waking. Within 1 week of starting fluoxetine she developed troublesome daytime sedation. The dosing of fluoxetine was switched to the evening which relieved the daytime sedation, but her early morning waking continued until the depression remitted about 4 weeks later (13c). Insomnia is a relatively common side effect of fluoxetine. Lepkifker et al. (14 c) reported seven patients receiving treatment with fluoxetine who suffered recurrent nightmares often with themes of dreadful violence. The nightmares could usually be lessened by decreasing the dose of fluoxetine or adding a sedative drug such as clonazepam. In one patient, however, they persisted after remission of the depressive symptoms and only disappeared when fluoxetine was withdrawn. A 42-year-old man was treated with fluoxetine

10 20 mg daily for major depression. When the dose was increased to 40 mg daily he began to experience frequent horrifying nightmares in which his child died and he and his wife committed murderous acts. On one occasion he experienced sleep-walking, Fluoxetine was stopped and fluvoxamine 300 mg daily substituted. The nightmares disappeared, but the depression worsened. Finally he was treated with fluoxetine, maprotiline, brotizolam and clonazepam with steady improvement in his depression and lessening of the nightmares. The nightmares, however, only disappeared completely when fluoxetine was withdrawn after 6 months stable remission. Depression itself can be associated with nightmares but the relationship to fluoxetine treatment is convincing in these cases. Like many other antidepressant drugs, fluoxetine decreases rapid eye movement (REM) sleep which is the stage of sleep when nightmares occur. It is possible that in some patients nightmares are associated with a rebound of REM sleep in the latter part of the night. Sudden withdrawal of tricyclic antidepressants also causes nightmares; this may be due to rebound of previously suppressed R E M sleep. Endocrine, metabolic Both fluoxetine and paroxetine can cause low sodium states presumably due to inappropriate secretion of antidiuretic hormone ( A D H ) (see SEDA-18, 20). Similar reports have now implicated sertraline (15 c, 16c). In one case, a 72-year-old woman developed delirium with a plasma sodium of 105 meq/liter, 4 days after starting sertraline 75 mg daily. Withdrawal of sertraline and fluid restriction led to normalization of the plasma sodium. The elderly appear particularly vulnerable to SSRI-induced low-sodium states. Skin and appendages Occasional reports have suggested that fluoxetine may cause excessive hair loss. Mareth (17 c) reported that fluoxetine was associated with hair loss in two first-degree relatives, a mother and daughter. The hair loss reversed when fluoxetine was discontinued. Genital SSRIs like other antidepressants can be associated with sexual dysfunction. Delayed orgasm and anorgasmia, however, seem

Chapter 2

P.J. Cowen

to be more common with SSRIs than with tricyclics. Benazzi and Mazzoli (18 c) treated 19 consecutive outpatients with fluoxetine (20 mg daily). None reported sexual dysfunction prior to treatment (which is unusual in patients with major depression). After 3 months of treatment, 14 patients responded to fluoxetine. Of the responders, four female patients developed decreased libido, two men developed anorgasmia and another man had erectile failure. In the responding patients the dose of fluoxetine was lowered to 20 mg every other day which improved the sexual function of five of the seven affected patients. This small open study suggests that sexual dysfunction may be relatively common in outpatients treated with fluoxetine but that dose reduction, when clinical circumstances allow it, may ameliorate these symptoms. A number of drug treatments have been suggested to be helpful in the management of SSRI-induced sexual dysfunction including cyproheptadine, yohimbine and amantadine (19c). Norden (20 c) added buspirone (15-60 mg) to the medication of 16 patients who experienced decreased libido and delayed orgasm while receiving SSRI treatment. Sexual function was rated as much improved in 11 of the 16 subjects. However, four patients noted increased irritability. The mechanism of these various effects is unclear but the ability of buspirone to lower ,5-HT neurotransmission through activation of 5-HTIA autoreceptors may be involved. Withdrawal effects Reports continue to appear of withdrawal symptoms following discontinuation of SSRIs with shorter half-lives notably paroxetine, fluvoxamine and sertraline. Principal symptoms include nausea, diarrhea, light-headedness, dizziness and fatigue. Shock-like sensations have also been reported. Even very slow tapering of medication may not completely avoid this syndrome, although it is likely to reduce its severity (21 c 23c). Interactions The ability of SSRIs to inhibit the cytochrome P450 system in the liver is well-recognized. This can lead to elevated blood levels of co-administered drugs which are metabolized principally by these hepatic enzymes. Many of the interactions stem from

Antidepressant drugs

Chapter2

inhibition of the P450 isoenzymes, CYPIID6 and CYPIIIA4. Sertraline and citalopram are less potent inhibitors of P450 enzymes and produce, for example, smaller increases in plasma tricyclic levels than fluoxetine, fluvoxamine and paroxetine (24R). Addicts receiving methadone maintenance treatment are at increased risk for depressive disorders. In addition there are some indications from pre-clinical and clinical studies that SSRIs may be helpful in reducing craving for psychoactive substances. Bertschy et al. (25 c) reported five patients who received fluvoxamine (50--250 mg) in addition to methadone maintenance treatment (40--90 mg daily). In three subjects there was a significant increase in plasma methadone levels (40-100%). In one of these patients, sudden discontinuation of fluvoxamine led to signs of opiate withdrawal. Caution is needed when methadone is combined with SSRI treatment. SSRIs are often used to treat depression in medically ill patients and unexpected drug interactions may occur. A patient receiving cyclosporin (450 mg daily) as an immunosuppressant following cardiac transplantation developed a depressive illness and was treated with fluoxetine (20 mg) (26c). After 10 days treatment his plasma cyclosporin levels had increased from 300 to 588/zg/liter. The dose of cyclosporin was reduced to 150 mg daily achieving satisfactory plasma levels of 250 /xg/liter. When, however, fiuoxetine was discontinued because of lack of efficacy, plasma cyclosporin levels fell to 95/xg/liter. SSRI interactions can be problematic where drugs need be to maintained within a fairly narrow plasma range, In the case of cyclosporin, raised plasma concentrations can cause renal damage while subtherapeutic levels can result in graft rejection. A study in healthy volunteers who received fluvoxamine (100--150 mg) for 4 days showed an increase in peak plasma levels of co-administered diazepam with a marked prolongation of diazepam half-life (51--118 hours) (27c). The magnitude of this effect is likely to be clinically significant. Fluvoxamine can also interact with theophylline. Administration of fluvoxamine (50 mg daily) to a 78year-old woman for 4 days increased serum theophylline levels from 74 to 197 mmol/liter. She experienced a grand mal seizure, coma

11 and supraventricular tachycardia but recovered with intensive care unit support (28c). The combination of fluoxetine and pimozide caused a severe bradycardia (35 beats per minute) in a 77-year-old man. Pimozide itself can cause cardiac arrhythmias and the authors speculated that fluoxetine may have increased plasma levels of pimozide (29c). A 9-yearold boy with Gille de la Tourette syndrome experienced an occulogyric crisis when paroxetine (10 mg daily) was added to co-existing pimozide treatment (6 mg daily) (30c). Paroxetine itself can cause acute dystonia but in this case it is likely to have potentiated the effects of pimozide. Presumably this might occur through pharmacokinetic or pharmacodynamic mechanisms. Lithium and SSRIs are often used together in treatment-refractory patients, although caution is recommended because of the risk of a serotonin syndrome. Hawley et al. (31 c) reported severe adverse effects in six of 14 patients in whom lithium was added to ineffective fluoxetine treatment. The major events were persistent nausea, vomiting and diarrhea. Only two of the patients discontinued treatment, however, and overall half the subjects had a reduction in depression rating scores of at least 50%, suggesting a useful clinical improvement. It seems likely that the adverse effects of lithium and fluoxetine potentiated each other, possibly through a serotonergic mechanism. However, the rate of complications seems unusually high for this combination. A possible explanation lies in the relatively high plasma lithium levels required by the protocol (0.8--1.2 mmol/liter). The usual plasma level of lithium recommended for antidepressant augmentation is 0.5--0.8 mmol/liter.

OTHER

ANTIDEPRESSANTS

Mianserin

Nervous system Mianserin lacks the anticholinergic effects of tricyclic antidepressants and may therefore be more suitable in the elderly. Bonne et al. (32c), however, reported that mianserin (30--75 mg daily) may have induced acute confusional states in five pa-

12 tients aged 60--71. Patients presented with agitation, disorientation, and impaired m e m ory. Visual hallucinations occurred in two subjects. The confusional states began within the first w e e k of mianserin t r e a t m e n t and remitted within 4 days of drug discontinuation.

Chapter 2

P.J. Cowen

These findings suggest that mianserin can cause delirium in the elderly but the relative frequency compared to tricyclics is unclear. The authors suggest that increasing the dose of mianserin slowly early in treatment may help prevent this adverse effect.

REFERENCES 1. Volz H-P, Faltus F, Magyar I, Moiler H-J. Brofaromine in treatment-resistant depressed patients--a comparative trial versus tranylcypromine. J Affect Disord 1994;30:209--217. 2. Livingstone MG. Interactions with selective MAOIs. Lancet 1995;345:533--534. 3. Walsh, BT, Giardina E-GV, Sloan RP, Greenhill L, Goldfein J. Effects of desipramine on autonomic control of the heart. J Am Acad Child Adolesc Psychiatry 1994;33:191--197. 4. Rechlin T, Claus D, Weis M. Heart rate analysis in 24 patients treated with 150 mg amitriptyline per day. Psychopharmacology 1994; 116:110--114. 5. Bocksberger JP, Gex-Fabry M, Gauthey L, Balant-Gorgia AE. Clomipramine therapy in the geriatric hospital: experience with therapeutic drug monitoring. Ther Drug Monit 1994;16:113-119. 6. Roose SP, Glassman AH, Attia E, Woodring S. Comparative efficacy of selective serotonin reputake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry 1994; 151:1735-1739. 7. Buist A, Janson H. Effect of exposure to dothiepin and northiaden in breast milk on child development. Br J Psychiatry 1995;167:370--373. 8. Karp JF, Frank E, Ritenour A, McEachran A, Kupfer DJ. Imipramine and sexual dysfunction during the long-term treatment of recurrent depression. Neuropsychopharmacology 1994;11: 21 --27. 9. Anderson IM, Tomenson BM. Treatment discontinuation with selective serotonin reuptake inhibitors compared with tricyclic antidepressants: a meta-analysis. Br Med J 1995;310:1433--1438. 10. Levine R, Kenin M, Hoffman JS, Day-Kneppie E. Grand mal seizures associated with the use of fluoxetine. J Clin Psychopharmacol 1994; 14:145--146. 11. Shihabuddin L, Rapport D. Sertraline and extrapyramidal side effects. Am J Psychiatry 1994;151:288. 12. Diaferia G, Mundo E, Bianchi Y, Ronchi P. Bahavioral side effects in obsessive-compulsive patients treated with fluvoxamine: a clinical description. J Clin Psychopharmacol 1994;14:78-79. 13. Gupta S, Rajaprabhakaran R. A case report of paradoxical sedation with fluoxetine therapy. J Clin Psychiatry 1994;55:118.

14. Lepkifker E, Dannon PN, Iancu I, Ziv R, Kotler M. Nightmares related to fluoxetine treatment. Clin Neuropharmacol 1995;18:90--94. 15. Jackson C, Carson W, Markowitz J, Mintzer J. SIADH associated with fluoxetine and sertraline therapy. Am J Psychiatry 1995;152:809--810. 16. Thornton SL, Resch DS. SIADH associated with sertraline therapy. Am J Psychiatry 1995; 152:809. 17. Mareth TR. Hair loss associated with fluoxetine use in two family members. Clin Psychiatry 1994 ;55:163. 18. Benazzi F, Mazzoli M. Fluoxetine-induced sexual dysfunction: a dose-dependent effect? Pharmacopsychiatry 1994;27:246. 19. Aizenberg D, Zemishlany Z, Weizman A. Cyproheptadine treatment of sexual dysfunction induced by serotonin reuptake inhibitors. Clin Neuropharmacol 1995;18:320--324. 20. Norden MJ. Buspirone treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors. Depression 1994;2:109--112. 21. Keuthen NJ, Cyr P, Ricciardi JA, Minichiello WE, Buttolph ML, Jenike MA. Medication withdrawal symptoms in obsessive-compulsive disorder patients treatedwith paroxetine. J Clin Psychopharmacol 1994;14:206--207. 22. Barr LC, Goodman WK, Price LH. Physical symptoms associated with paroxetine discontinuation. Am J Psychiatry 1994;151:289. 23. Mallya G, White K, Gunderson C. Is there a serotonergic withdrawal syndrome? Biol Psychiatry 1993;33:849--855. 24. Lane R, Baldwin D, Preskom S. The SSRIs: advantages, disadvantages and differences. J Psychopharmacol 1995;9(Suppl 2):163--178. 25. Bertschy G, Baumann P, Eap CB, Baettig D. Probable metabolic interaction between methadone and fluvoxamine in addict patients. Ther Drug Monit 1994;16:42--45. 26. Horton RC, Bonser RS. Interaction between cyclosporin and fluoxetine. Br Med J 1995; 311:422. 27. Perucca E, Gatti G, Cipolla G, Spina E, Barel S, Soback S, Gips M, Bialer M. Inhibition of diazepam metabolism by fluvoxamine: a pharmacokinetic study in normal volunteers. Clin Pharmacol Ther 1994;56:471--476. 28. van den Brekel AM, Harrington L. Toxic effects of theophylline caused by fluvoxamine. Can Med Assoc J 1994;151:1289--1290.

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29. Ahmed I, Dagincourt PG, Miller LG, Shader RI. Possible interaction between fluoxetine and pimozide causing sinus bradycardia. Can J Psychiatry 1993;38:62--63. 30. Horrigan JP, Bamhill I_J. Paroxetine-pimozide drug interaction. J Am Acad Child Adolesc Psychiatry 1994;33:1060-- 1061.

13 31. Hawley CJ, Roberts AG, Baldwin DS. Tolerability of combined treatment with lithium and fluoxetine: 14 cases treated under open conditions. Int Clin Psychopharmacol 1994;9:31--33. 32. Bonne O, Shalev AY, Bloch M. Delirium associated with mianserin. Eur Neuropsychopharmacol 1995;5:147--149.