LETTERS TO THE EDITOR

Re: The Use of Selective Serotonin Reuptake
Inhibitors in the Elderly

Dear Sir:

In his recent critique of Duckworth and McBrides’ (1) article on suicide in old age, Harris (2) made a number of anecdotal, scientifically unfounded statements about the use of selective serotonin reuptake inhibitors (SSRIs) in the elderly. Given the important clinical implications of Harris’s comments, I feel that they require a response.

First, he claims that SSRIs are less well tolerated than secondary amine tricyclic antidepressants (TCAs) in old age, and as a result, elderly patients’ compliance with SSRIs is “exceedingly low” (2, p 535). To the contrary, a recent metaanalysis of randomized, controlled trials evaluating the efficacy and tolerability of antidepressant medications in the elderly found that there was no significant difference between SSRIs and TCAs in the frequency of adverse events (3). Dropout rates for elderly patients on SSRIs are comparable to those of patients treated with secondary amine TCAs (4). Although TCAs and SSRIs have similar rates of adverse events, it is important to note the qualitative difference of these effects. Patients who are vulnerable to the anticholinergic or cardiovascular effects of TCAs may be better managed with SSRIs.

Harris also contends that the use of SSRIs in medically compromised elderly people is “very hazardous indeed” (2, p 535). There are few data pertaining to the treatment of depression in older patients with serious physical or neurological illness. Antidepressant pharmacotherapy can be problematic in these individuals (5), but there is no available evidence that SSRIs are less safe than other antidepressants in this population. In fact, citalopram has been shown to be well tolerated as a treatment of poststroke depression (6) and depression complicating dementia (7), and only mild side effects were noted with fluoxetine treatment of frail nursing home residents (8). As Harris notes, the capacity of SSRIs for hepatic-mediated drug interactions can be a concern, but this is not a reason to automatically exclude the use of SSRIs in medically compromised patients. Instead, the interactive potential of each agent should be considered on a case-by-case basis and treatment decisions made accordingly.

Particularly troubling is Harris’s unsubstantiated assertion that the “mortality associated with [SSRI] drug interactions may be considerably higher than the risk of death by suicide” (2, p 535). Depression is the main risk factor for suicide in old age (9). There is considerable evidence that patients in primary care are often prescribed TCAs at doses which are unlikely to be effective in treating depression (10). Most SSRIs have a flat dose-response curve, and as a result, underdosing with these drugs is less likely to occur. By implication, elderly patients who are prescribed an SSRI may be more likely to receive effective treatment and, therefore, be at less risk of suicide.

No antidepressant is ideal. Newer drugs such as SSRIs, however, have broadened the range of therapeutic options. Insofar as this facilitates the effective treatment of depression, it can only be considered a positive development.

References

1. Duckworth G, McBride H. Suicide in old age: a tragedy of neglect. Can J Psychiatry 1996;41:217–22.

2. Harris DJ. Re: suicide in old age [letter]. Can J Psychiatry 1996;41:535–6.

3. Mittman N, Shear NH, Einarson TR, Naranjo CA. Are selective serotonin reuptake inhibitors superior to tricyclic antidepressants in the elderly? [abstract]. Clin Pharmacol Ther 1995;57:200.

4. Schneider LS. Pharmacologic considerations in the treatment of late-life depression. American Journal of Geriatric Psychiatry 1996;4(1 Suppl):51S–65S.

5. Koenig HG, Breitner JCS. Use of antidepressants in medically ill older patients. Psychosomatics 1990;31:22–32.

6. Andersen G, Vestergaard K, Lauritzen L. Effective treatment of poststroke depression with the selective serotonin reuptake inhibitor citalopram. Stroke 1994;25:1099–104.

7. Nyth A, Gottfries CG, Lyby K, Smedegaard-Andersen L, Gylding-Sabroe J, Kristensen M, and others. A controlled, multicenter clinical study of citalopram and placebo in elderly depressed patients with and without concomitant dementia. Acta Psychiatr Scand 1992;86:138–45.

8. Trappler B, Cohen CI. Using fluoxetine in “very old” depressed nursing home residents. American Journal of Geriatric Psychiatry 1996;4:258–62.

9. Conwell Y. Suicide in the elderly. In: Schneider LS, Reynolds CF III, Lebowitz BD, Friedhoff AJ, editors. Diagnosis and treatment of depression in late life. Washington (DC): American Psychiatric Press; 1994. p 397–418.

10. Beaumont G, Baldwin D, Lader M. A criticism of the practice of prescribing subtherapeutic doses of antidepressants for the treatment of depression. Human Psychopharmacology 1996;11:283–91.

Alastair J Flint, MB, ChB, FRCPC, FRANZCP
Toronto, Ontario

The Author Responds

Dear Sir:

I am happy to respond to the challenge of Dr Flint’s criticisms of my letter on suicide in old age (1). It is not helpful to dismiss clinical observations as merely anecdotal—especially when there is supporting evidence in the scientific literature. It is frequently difficult even with metaanalysis to sort out the facts. Cole and Bellavance (2) have commented how difficult it is to study the prognosis of depression in old age by metaanalysis when the original studies vary so much in composition and extraneous factors. Just as clinical observations may lead to misconceptions of the larger picture, so indeed may metaanalyses. Eggar and Smith (3), in a critique of the concept of metaanalysis, refer to selective identification of positive studies and publication bias in original studies—and the selective nonpublication of negative trials. This is certainly a risk with new drugs and may lead to misleading analysis findings. At best, metaanalysis is a valuable guide, but not an absolute measure. Further research in this area is merited, both in nongeriatric and geriatric populations (4,5).

To qualify my original letter, in my experience in community psychogeriatric practice, tolerance of selective serotonin reuptake inhibitors (SSRIs) is frequently poor, even when introduced slowly. A greater proportion of my (community) sample may have the milder depressive syndromes, which may be in line with Tan and others’ observations (6) that the more mildly depressed patients were intolerant of medication and the more major depressions responded to relatively low doses of lofepramine. In our own clinic, many of the milder depressive reactions would be seen supportively, and antidepressants would be started only if the patients failed to respond or continued to deteriorate. Roose and others (7) found fluoxetine to be significantly less effective than nortriptyline for treating hospitalized elderly patients with unipolar major affective disorder, especially for those with the melancholic subtype and concurrent vascular disease. A study of fluoxe-tine in unipolar depression showed rather low efficacy for fluoxetine (8). SSRIs are widely prescribed in family practice, and in my secondary referral practice, it is common to see SSRI-nonresponders who do very well on a secondary amine tricyclic antidepressant (TCA). Just as we may be reluctant to use monoamine oxidase inhibitors (MAOIs) because of their risk factors, we may have become too reluctant to use TCAs.

Most antidepressants are not prescribed by psychiatrists. We can measure suicides and label them psychiatric deaths. We can measure dropout rates in clinical trials and label them psychiatric failures. We do not know the true incidence of SSRI or TCA morbidity and mortality in the general medical population. Even when such cases are identified, the role of the antidepressant is at best speculative (9–11). Delirium associated with SSRI-induced hyponatremia is not without its hazards for those with preexisting reduced cerebral reserve (12). In the short term, one cannot look at the P450 enzyme issues without concern (13,14). The psychiatrist may apparently avoid drug interactions now only to expose the patient inadvertently to new risks if readmitted medically shortly thereafter; likewise, if there is a long washout period, this treatment course could limit the therapeutic choices of the internist. P450 enzymes are involved in a wide range of degradation activities, including those of pesticides with possible long-term hazards (15)—admittedly less of a risk factor for elderly patients at the end of their lifespan.

We criticize low dose regimens. Yet Tyrer and others (16) found excellent results for minor depression, anxiety disorders, and panic disorders with 45 mg/day of dothiepin. Parker and others (17), when using lithium to augment relatively low doses of TCAs (nortriptyline, mean dose 43.8 mg/day) in outpatients, found success. Presumably these low doses were the only ones tolerated—and yet apparently had good effect. A Swedish study (18) suggests that undiagnosed depression was not the major cause of suicide. The bulk of patients who committed suicide in that study were in fact receiving the SSRI citalopram (admittedly the antidepressant prescribed most frequently in Sweden at that time).

Jick and others (19) found the risk of suicide was similar among 10 study antidepressants. The risk of suicide was not determined by the antidepressant treatment. Admittedly, suicide by TCAs was higher than with other antidepressants, but suicide by other means was higher in patients taking the other antidepressants. Those intent on committing suicide will find some way to do so. In Manchester (20), antidepressants were implicated in only 5 out of 44 suicides, even though 25% of the victims were receiving antidepressant pharmacotherapy. Coexisting physical illness and poor pain control were major comorbid risk factors. In the Duckworth and McBride study (21), it was particularly distressing that some suicides occurred the day prior to the first scheduled appointment with the psychiatry team. While these tragedies were ascribed to the fear of the stigma of being involved with psychiatry, they could also reflect the lack of an established psychotherapeutic relationship at that point in time.

Nevertheless, in my own practice, if I see a young patient whom I regard as a high suicide risk, I would indeed use an SSRI. Among the elderly, if I regard a patient as a high suicide risk, again I might start with an SSRI. In those patients for whom I assess the suicide risk as relatively low and for whom other medical risk factors are minimal, I see the options as being less clear. As mentioned by other authors (18,22), probably the most important thing is the ability to do a comprehensive assessment of the depressed patient and to identify high suicidal risk, hospitalizing the patients if necessary with a view to treating him or her in a sheltered setting. We know that the risk of suicide is heavily affected by cultural and social factors. We live in cruel times, and we are now living in a culture where the elderly are expected to feel guilty about being consumers of government services. It is often the role of the psychiatrist to emphasize to the patient that depression is a treatable disorder, and the psychiatrist will stick by and make every effort to assist the patient during this time. Yes, the choice of antidepressant will depend on the various risk factors, but secondary amine TCAs will certainly continue to have a valuable role with this section of the population.

References

1. Harris DJ. Re: suicide in old age [letter]. Can J Psychiatry 1996;41:535–6.

2. Cole MG, Bellavance F. The prognosis of depression in old age. American Journal of Geriatric Psychiatry 1997;5:4–14.

3. Eggar M, Smith GD. Misleading metanalysis—lessons from an “effective safe and simple” intervention that wasn’t. BMJ 1995;310:752–4.

4. Kennedy SH, Bagby RM. Efficacy and effectiveness in the antidepressant treatment of depression: beyond metaanalysis [editorial]. Can J Psychiatry 1996;41:609–10.

5. Joffe R, Sokolov S, Streiner D. Antidepressant treatment of depression: a metaanalysis. Can J Psychiatry 1996;41:613–6.

6. Tan RS, Barlow RJ, Abel C, Reddy S, Palmer AJ, Fletcher AE, and others. The effect of low dose lofepramine in depressed elderly patients in general medical wards. Br J Clin Pharmacol 1994;37:321–4.

7. Roose SP, Glassman AH, Attia E, Woodring S. Comparative efficacy of SSRI’s and TCA’s in the treatment of melancholia. American Journal of Geriatric Psychiatry 1994;151:1735–9.

8. Tolefson GD, Holman SI. Analysis of the Hamilton Depression Rating Scale factors for double blind, placebo control trial of fluoxetine in geriatric major depression. Int Clin Psychopharmacol 1993;8:253–9.

9. Spier SA, Frontera MA. Unexpected deaths in depressed medical inpatients treated with fluoxetine. J Clin Psychiatry 1991;52:377–82.

10. Buff DD, Brenner R, Kirtane SS, Gilboa R. Dysrhythmia associated with fluoxetine treatment in an elderly patient with cardiac disease. J Clin Psychiatry 1991;52:174–6.

11. Ellison J, Milofsky J, Ely E. Fluoxetine induced bradycardia and syncope in 2 patients. J Clin Psychiatry 1990;51:385–6.

12. Liu BA, Mittman N, Knowles SR, Shear NH. Hyponatremia and the syndrome of inappropriate ADH secretion associated with the use of SSRI’s. Can Med Assoc J 1996;155:519–27.

13. Gelemberg AJ. The P450 family. Biological Therapies in Psychiatry Newsletter 1995;18(8):29–31.

14. Lane R, Baldwin D, Preskorn S. The SSRI’s advantages disadvantages and differences. Journal of Psychopharmacology 1995;9 Suppl 2:163S–178S.

15. Guengerich FP. Cytochrome P450 enzymes. American Science 1993;81:440–7.

16. Tyrer P, Murphy S, Kingdon D, Brothwell J, Gregory S, Seivewright N, and others. The Nottingham study of neurotic disorder: comparison of drug and psychological treatments. Lancet 1988;11:235–40.

17. Parker H, Mittman NH, Shear NH, Herrmann N, Shulman KI, Silver IL, and others. Lithium augmentation in geriatric depressed outpatients—a clinical review. International Journal of Geriatric Psychiatry 1994;9:995–1002.

18. Waern M, Beskow J, Runeson B, Skoog I. High rate of antidepressant treatment in elderly people who commit suicide. BMJ 1996;313:1118.

19. Jick SS, Dean AD, Jick H. Antidepressants and suicide. BMJ 1995;310:215–8.

20. Cattell H, Jolley DJ. 100 cases of suicide in elderly people. Br J Psychiatry 1995;166:451–7.

21. Duckworth G, McBride H. Suicide in old age: a tragedy of neglect. Can J Psychiatry 1996;41:217–22.

22. Edwards JG. Suicide and antidepressants: controversies on prevention, provocation and self poisoning continue. BMJ 1995;310:205–6.

David J Harris, LRCP, MRCS, FRCPC, MRCPsych
London, Ontario

Re: A Critical Review of Marital Therapy Outcome

Dear Sir:

I would like to comment on the article by Wesley and Waring on marital therapy (1). I appreciated finding a summary article on marital therapy outcomes in the Journal, and I find such an article timely and relevant. I would like to make 2 points in relation to the content of the article, however, which I believe warrant correction.

First, the authors cite one study on emotionally focused marital therapy by Goldman and Greenberg (2) in which some relapse did occur at follow-up and then go on to make the general statement that considerable relapse is usual in this approach. This inference from one study is unwarranted, particularly since there are other published studies that in fact suggest the opposite, namely, that there is a trend for couples treated with emotionally focused therapy (EFT) to continue to improve after the termination of treatment. It is not the norm that there is considerable relapse after this treatment, and indeed a 2-year follow-up (which was presented by Walker and Manion at a conference on child health psychology in 1994 and which is about to be submitted for publication) found evidence that the treatment effects for marital distress and depression in a very stressed population, namely the parents of chronically ill children, were stable over the 2-year period. A recent study (3) also documented that improvement continued to increase after the termination of active treatment. EFT explicitly creates self-reinforcing cycles of positive interaction that foster the development of a secure bond to prevent relapse.

Second, and more importantly in terms of the goals of the article, the authors suggest that the new “gold standard” for outcome in marital therapy is a 50% success rate. In fact, Neil Jacobson, the proponent of the approach to marital therapy that has received the most extensive empirical validation, after reporting that behavioural marital therapy achieved this success rate, concluded that it was unacceptable, both in terms of clinically significant and statistically reliable improvement and in terms of recovery from marital distress. As a result, he changed his model of therapy extensively to increase the level of success (4). He now, in a pilot study, reports a 75% recovery rate, that is, this percentage of couples are nondistressed at the end of therapy. In addition, in my own work with couples using EFT, my colleagues and I report a recovery rate of 70% and a clinically significant improvement rate of 82% at follow-up (5). There is also a study in the literature (6) that reports a 79% recovery rate after EFT.

In summary, the 50% success rate, whether success is defined as improvement or recovery, is in no way accepted by the leading proponents in the field of marital therapy as an acceptable or sufficient standard of success in this modality. I hope these comments are interesting and enlightening to your readers.

References

1. Wesley S, Waring EM. A critical review of marital therapy outcome research. Can J Psychiatry 1996;41:421–8.

2. Goldman A, Greenberg LS. Comparison of integrated systemic and emotionally focused approaches to couples therapy. J Consult Clin Psychol 1992;60:962–9.

3. Johnson SM, Talitman E. Predictors of success in emotionally focused marital therapy. Journal of Marital and Family Therapy 1997; Forthcoming.

4. Jacobson NS, Christensen A. Integrative couple therapy. New York: Norton; 1996.

5. Johnson SM. The practice of emotionally focused marital therapy: creating connection. New York: Brunner/Mazel; 1996.

6. James P. Effects of a communication training component added to an emotionally focused couples therapy. Journal of Marital and Family Therapy 1991;17:263–76.

Sue Johnson, EdD, CPsych
Ottawa, Ontario

The Author Responds

Dear Sir:

I was very pleased to see a letter from Professor Johnson, who is one of North America’s leading marital therapy outcome researchers, commenting on our recent summary article on marital therapy outcomes (1). Dr Johnson points out that on the basis of her one study, our inference that considerable relapse is usual at follow-up is unwarranted. I believe that it is unwarranted to expect us to be aware of work that has been submitted for publication or is in press. Nevertheless, I think we could both agree that the issue of whether or not improvement is maintained at 6 months, 1 year, or 2 years is an important issue in psychotherapy outcome research in general.

A second point raised by Dr Johnson and one that we hoped would stimulate debate is her concern that a 50% success rate may be unacceptable, as it apparently was to Dr Neil Jacobson, who was prompted to reevaluate and change his behavioural approach to marital therapy. The 75% recovery rate in a pilot study and Dr Johnson’s own 70% recovery rate, again in an article that is in press but was not available to the authors, raise a significant point. Dr Johnson’s argument is that the 50% success rate, whether success is defined as improvement or recovery, is not accepted by the leading proponents in the field of marital therapy. My response to this is that, if the leading proponents can obtain only 70% to 75% recovery rates practising the therapies they developed, would not a 50% success rate practised by people who are not leading proponents in the field be a reasonable standard of success? Let us hope that the interesting debate will continue and will encourage others who are not currently leading proponents in the field to evaluate and report their work in the marital therapy field.

Reference

1. Wesley S, Waring EM. A critical review of marital therapy outcome research. Can J Psychiatry 1996;41:421–8.

EM Waring, MD, FRCPC
Kingston, Ontario

Psychiatric Disorders in Multiple Sclerosis

Dear Sir:

Psychiatric manifestations of multiple sclerosis (MS) are still enjoying ongoing debate as evidenced by 2 recent articles published in The Canadian Journal of Psychiatry (1,2). Some clinical points, however, should have been discussed. The first relates to mood disorder, the second to frontal lobe dysfunction, and the third to treatment.

Three categories of symptoms are augmented in patients who suffer from MS (mood disorder, self-reproach, and somatic complaints), but the relationship between those symptomatological features and the severity of the disease is still subject to controversy (3,4). Our clinical assessment with Association Méthodologie Documentation en Psychiatrie (AMDP) (5) confirmed predominance of mood disorders, for instance, euphoria. We noted the coexistence of euphoria and sadness in 27% of the cases. In 88% of the cases where euphoria and sadness were present together, we found a dysphoria according to the AMDP definition, which measures stress, irritability, and aggressivity. According to AMDP, a particular psychopathological profile of MS patients emerged. The association of syndromes (dysphoria and depression) and symptoms (euphoria, sadness, and agnosia) does not correspond, to our knowledge, to any disorder except mixed episode of mood in DSM-IV.

According to Huber, depression in MS is not a simple reaction to a physical disability (3), and the etiology of psychopathology appears to be multifactorial (1). In fact, several factors can be mutually linked; thus we noted a significant correlation between level of disability on Kurtzke’s scale and mood disorders according to AMDP (mania and dysphoria) (4). The study demonstrated a significant relationship between the item euphoria and disturbance of motor organization and between this same item and the memory impairments (6). An analysis of correlations between the AMDP’s syndromes and the frontal dysfunction shows that the more severe dysphoria, depression, and mania are, the more important and clearer the frontal syndrome becomes. Since 1987 (not since only 1991, as suggested by Rodgers and Bland [1]), the neuropsychological profile was interpreted as an expression of a orbitofrontal syndrome and supported an additional argument in favour of organic interpretation of the psychiatric presentation of MS and characterological changes (6,7).

Patients with MS and bipolar disorder can respond favourably to sodium valproate without side effects after failure of other treatments. Since this drug is generally well tolerated and has a low incidence of adverse effects, it could be an interesting alternative to lithium. We reported successful results in 2 inpatients who presented mood disorders related to MS (8). These case reports suggest the necessity to perform controlled studies with valproate in patients with MS suffering from affective disorders.

References

1. Rodgers J, Bland R. Psychiatric manifestations of multiple sclerosis: a review. Can J Psychiatry 1996;41:441–5.

2. Carson HJ, Searle-White DJ. Occult multiple sclerosis presenting with psychosis [letter]. Can J Psychiatry 1996;41:486–7.

3. Huber SJ, Rammonhan KW, Bornstein RA, Christy JA. Depressive symptoms are not influenced by severity of multiple sclerosis. Neuropsychiatry, Neuro-psychology and Behavioral Neurology 1993;6:177–80.

4. Stip E, Truelle J-L. Syndrome de personnalité organique dans la sclérose en plaques et influence du stress sur les poussées. Can J Psychiatry 1994;39:27–33.

5. Bobon D. AMDP system. 2nd ed. Bruxelles: Mardaga; 1981.

6. Truelle JL, Pallisson P, Legall D, Stip E, Derouesne C. Troubles intellectuels et thymiques dans la sclérose en plaques. La Revue Neurologique 1987;143:595–601.

7. Stip E, Thibodeau M. Les manifestations psychiatriques dans la sclérose en plaques. Synapse 1994;109:21–8.

8. Stip E, Daoust L. Valproate in the treatment of mood disorder due to multiple sclerosis. Can J Psychiatry 1995;40:219–20.

Emmanuel Stip, MD, MSc, CSPQ
Mario Roy, MD
Montreal, Quebec

Zuclopenthixol Acetate in a Demented Elderly Patient with Agitation

Dear Sir:

Zuclopenthixol acetate (ZA), an injectable antipsychotic with a duration of action of approximately 3 days, is presently licenced in Canada exclusively for short-term use in acute schizophrenic exacerbation (1). Several studies suggest that ZA is a treatment option for management of acute psychoses and behaviour disturbance in the general adult population (2,3).

Oral zuclopenthixol has demonstrable efficacy in management of aggression, restlessness, and agitation in the elderly, with sedation being the major emergent adverse effect (4,5). To our knowledge, there has been no reported use of ZA in the treatment of agitation, psychosis, or behaviour disturbance in the demented elderly.

Mrs A was a 75-year-old woman with dementia admitted to the psychogeriatric unit on an urgent basis with several weeks’ history of refusing food and fluids. On admission, she was aggressive, dehydrated, and resistant of all attempts at care including feeding, investigations, and oral medications. She was given an intramuscular (im) injection of ZA 50 mg. Within several hours, she became much less resistant and became compliant with intravenous rehydratation and investigations. Moderate sedation was noted. Approximately 26 hours postinjection, she started to show increased aggression. It was necessary to repeat ZA administration about 48 hours following the initial dose. The dose was decreased to 25 mg ZA_im, in an attempt to reduce sedation. Within the next 60 hours, she required an additional dose of 25 mg ZA_im. During this interval, the patient was rehydrated and stabilized, and a diagnosis of psychotic depression was established. She was treated successfully with a course of electroconvulsive therapy and did not require any further ZA.

This case gives preliminary support to ZA being effective and well tolerated in the agitated, demented elderly patient. Sedation and behavioural control can potentially be achieved with a single, medium-acting injection that will permit necessary medical investigations and treatments to proceed. Given that hepatic microsomal enzyme activity falls with advancing age, administration of ZA to the elderly should be undertaken at reduced doses. Further study in this population will be necessary before widespread use can be advocated.

References

1. Marion Merrell Dow Canada. Product monograph: Clopixol, Clopixol-Acuphase, Clopixol Depot. Laval (PQ): Marion Merrell Dow Canada; 1996.

2. Chouinard G, Safadi G, Beauclair L. A double-blind controlled study of intramuscular zuclopenthixol acetate and liquid oral haloperidol in the treatment of schizophrenic patients with acute exacerbation. J Clin Psychopharmacol 1994;14:377–84.

3. Baastrup PC, Alhfors UG, Bjerkenstedt L, Dencker SJ, Fensbo C, Gravem A, and others. A controlled Nordic multicentre study of zuclopenthixol acetate in oil solution, haloperidol and zuclopenthixol in the treatment of acute psychosis. Acta Psychiatr Scand 1993;87:48–58.

4. Nygaard HA, Bakke K, Brudvik E, Elgen K, Lien GK. Dosing of neuroleptics in elderly demented patients with aggressive and agitated behaviour: a double-blind study with zuclopenthixol. Curr Med Res Opin 1994;13:222–32.

5. Nygaard HA, Fulgum E, Elgen K. Zuclopenthixol, melperone and haloperidol/levomepromazine in the elderly. Meta-analysis of two double-blind trials at 15 nursing homes in Norway. Curr Med Res Opin 1992;12:615–22.

Lonn Myronuk, BSc, MD
Maria Geizer, MD
RJ Ancill, MA, MB
Vancouver, British Columbia

Extrapyramidal Side Effects with Low-Dose Risperidone

Dear Sir:

I would like to report a case of severe extrapyramidal symptoms and possible laryngospasm in a patient receiving low-dose risperidone.

Mr A, a 26-year-old man, presented with a complaint of pain in his teeth “like biting a lemon.” He had been evaluated by a dentist, neurologist, and an otolaryngologist, who started amitriptyline 25 mg/day and suggested a psychiatric evaluation. In addition to the mouth pain, Mr A had occasional looseness of association, possible delusions (“I’m condemned by God”), and symptoms of depression, including the wish to die if the mouth pain continued. He was started on risperidone 2 mg at bedtime and increased to 4 mg at bedtime after one week. At his next appointment, Mr A described difficulty breathing, beginning the day after the risperidone dosage was increased, which he said progressed over 12 to 16 hours then gradually resolved after discontinuing risperidone. His only medications at the time were risperidone and amitriptyline.

Three weeks later, Mr A was started on a course of fluoxetine 20 mg/day with little improvement in depressive symptoms or mouth preoccupation. Mr A reported improvement in the mouth pain during risperidone therapy and asked to restart this medication. After careful discussion of side effects, risperidone 2 mg at bedtime was added to the regimen of fluoxetine and amitriptyline. Mr A was instructed to take diphenhydramine 50 mg as needed for muscle stiffness. Eight days later, Mr A reported painful and very distressing tongue movements, which began 2 days after restarting risperidone, but he denied any breathing difficulties. He had not taken the diphenhydramine. The dose of risperidone was decreased to 1 mg at bedtime, and these symptoms subsided after 2 days and have not returned.

Risperidone is an atypical antipsychotic that binds to both serotonergic and dopaminergic receptors (1). Two large studies have suggested that risperidone is associated with no more extrapyramidal symptoms than placebo at doses less than 10 mg daily (2,3). A search of the MEDLINE database revealed only 3 reports of dystonic reactions during risperidone therapy. Two occurred during clozapine discontinuation (4,5) and the third after rapid titration from 1 to 3 mg twice daily over a period of 3 days (6). Mr A developed extrapyramidal symptoms during both courses of therapy with low doses of risperidone. His symptoms during the first course were consistent with mild laryngospasm (7). He had no history of pulmonary disease, panic attacks, or other etiology for his shortness of breath, and the symptoms developed shortly after increasing the dose of risperidone. During the second course of risperidone, this time given along with fluoxetine, he developed tongue dysfunction and akathisia at an even lower dosage. Risperidone is reportedly metabolized by the P450 2D6 system, which is inhibited by fluoxetine (8). Thus fluoxetine may have contributed to the extrapyramidal side effects through a pharmacokinetic interaction with risperidone. The case illustrates that severe extrapyramidal symptoms can develop at even low doses of risperidone, particularly if combined with medications that inhibit the P450 2D6 enzyme system. Careful monitoring for these symptoms by both the patient and clinician is warranted when starting or increasing the dosage of risperidone.

References

1. Leysen JE, Gommeren W, Eens A, deChaffoy deCourcelles D, Stoof JC, Janssen PAJ. Biochemical profile of risperidone, a new antipsychotic. J Pharmacol Exp Ther 1988;47:661–70.

2. Marder SR, Meilbach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994;151:825–35.

3. Chouinard G, Jones B, Remington G, Bloom D, Addington D, MacEwan GW, and others. A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993;13:25–40.

4. Dickson R, Williams R, Dalby JT. Dystonic reaction and relapse with clozapine discontinuation and risperidone initiation [letter]. Can J Psychiatry 1994;39:184.

5. Radford JM, Brown TM, Borison RL. Unexpected dystonia while changing from clozapine to risperidone [letter]. J Clin Psychopharmacol 1995;15:225–6.

6. Faulk RS, Gilmore JH, Jensen EW, Perkins DO. Risperidone-induced dystonic reaction [letter]. Am J Psychiatry 1996;153:577.

7. Garcia MM, Mercer PR. A case of neuroleptic-induced laryngospasm. West J Med 1990;153:438–9.

8. Pollock BG. Recent developments in drug metabolism of relevance to psychiatrists. Harvard Review of Psychiatry 1994;2:204–13.

E Sherwood Brown, PhD, MD
Dallas, Texas

Risperidone, Weight Gain, and Bulimia Nervosa

Dear Sir:

We would like to report on a patient with childhood-onset schizophrenia who developed significant weight gain and bulimia nervosa with the use of risperidone.

Ms S was a 12-year-old girl with a one-year history of a schizophrenic illness characterized by persistent paranoid delusions, hallucinations, and marked psychosocial deterioration in the absence of any concurrent mood symptomatology or substance use. She had no history suggestive of a pervasive developmental disorder, and workup (including computed tomography, magnetic resonance imaging, electroencephalogram, and blood work) had not revealed the presence of an underlying medical disorder. Familial loading was present for bipolar disorder and/or schizophrenia on the paternal side and bulimia nervosa on the maternal side.

Initial treatments with haloperidol, chlorpromazine, and thioridazine were discontinued because of ineffectiveness or adverse effects, prompting the use of risperidone. Over a 3-month period, the dosage was gradually titrated upwards to 5 mg/day, with only some symptomatic improvement in the psychosis seen at the higher doses. Unfortunately, a weight gain of 20 kg also occurred, which vastly exceeded the patient’s growth over the same 3-month period. Parallelling the weight gain was a preoccupation with her weight and body shape, prompting binge eating at least 5 times a week and purging at least twice a week (meeting criteria for bulimia nervosa). The bulimic symptoms progressively worsened as the dose of risperidone was titrated higher, which eventually led to its discontinuation because the improvement in her psychosis was limited. Of note, a trial of a selective serotonin reuptake inhibitor (SSRI) was not tolerated in combination with risperidone because of increased agitation and the development of a rash.

The clinical impression was that the initiation of the risperidone was associated with Ms S’s marked weight gain and the emergence of the bulimia nervosa. This impression was based upon previous reports associating significant weight gain with the use risperidone (1,2), the acuity of symptom development in relation to the initiation of the drug therapy, the progression of symptoms with the increase in dosage, and the lack of previous similar symptoms seen when typical antipsychotics were used.

This last point is of particular importance in that it suggests that risperidone’s selective antagonism of central serotonergic activity (the basis of its atypicality) may be responsible for the observed association. Previous research supports this hypothesis, suggesting that deficient central serotonin may represent an underlying neurobiological factor in the pathogenesis of bulimia nervosa based on serotonergic abnormalities found in the cerebrospinal fluid and platelets of bulimic patients, the potential role of serotonin in satiety, and the beneficial response seen in some bulimic patients with the use of the SSRIs (3–5). A recent case report of an exacerbation of bulimia nervosa with the use of another atypical antipsychotic, clozapine, furthers this hypothesis because it also concluded (based on similar reasoning) that the antagonism of central serotonergic activity may have been responsible (6). We suggest, therefore, that caution in the use of atypical antipsychotics with serotonergic activity may be warranted in patients with or predisposed to bulimia nervosa.

References

1. Penn JV, Martini J, Radka D. Weight gain associated with risperidone. J Clin Psychopharmacol 1996;16:259–60.

2. Umbricht D, Kane JM. Medical complications of new antipsychotic drugs. Schizophr Bull 1996;22:475–83.

3. Garfinkel PE. Eating disorders. In: Kaplan HI, Saddock BJ, editors. Comprehensive textbook of psychiatry. 6th ed. Baltimore: Williams & Wilkins; 1995. p 1361–71.

4. Goldbloom DS, Kennedy SH, Kaplan AS, Woodside DB. Anorexia nervosa and bulimia nervosa. Can Med Assoc J 1989;140:1149–54.

5. Weltzin TE, Fernstrom MH, Kaye WH. Serotonin and bulimia nervosa. Nutr Rev 1994;52:399–408.

6. Brewerton TD, Shannon M. Possible clozapine exacerbation of bulimia nervosa. Am J Psychiatry 1992;149:1408–9.

David N Crockford, MD
Geoff Fisher, MB, BS, FRCPC, MRCPsych
Phillip Barker, MB, BS, FRCP(Ed), FRCPsych, FRCPC
Calgary, Alberta