FULL PAGE VIEW

LETTERS TO THE EDITOR

Dear Sir:

A recent study reported that the incidence of delirium in psychiatric inpatients is approximately 2% (1). A possible explanation for this relatively low incidence is the introduction of new psychopharmacological agents in the past 10 to 15 years. Safer medications may be contributing to a diminishing rate of delirium. Conversely, reductions in the availability of psychiatric inpatient beds and administrative pressures for shorter lengths of stay may lead to more "aggressive" pharmacological treatment (such as more rapid dosage titration and a greater reliance on polypharmacy). Such changes could contribute to an increasing incidence of delirium.

Canadian hospital separation data provide an opportunity to examine secular trends in delirium frequency. Until recently, relevant data were compiled annually by Statistics Canada in a publication called Mental Health Statistics (2). In the future, these data will be compiled by the Canadian Institute for Health Information (3). Hospital separations refer to hospital discharges or deaths.

In this analysis, 2 diagnostic categories of delirium were evaluated in aggregate: acute confusional state (International Classification of Diseases [ICD-9] code 293.0) and subacute confusional state (ICD-9 code 293.1). When the rate of hospital separation for these conditions (the number of discharges for 1 of these conditions as primary diagnosis divided by the total number of hospital separations for all psychiatric patients) was examined over time, the rate increased progressively.

In 1985/1986, the hospital separation rate for delirium was 37.1 per 10 000. By 1993/1994 the rate had almost doubled to 76.53 per 10 000. A logistic regression model of the form (ln [odds of hospital separation with delirium] = ­5.65 + 0.097 [year since baseline]) provided a close-fitting description of the increasing rates over this interval. Here, the baseline year refers to the 1985/1986 year, and the associated logistic regression coefficient implies an increase of approximately 10% in the ln odds of hospital separation with delirium each year since that time. In the model, the coefficient for year since baseline was statistically significant (P < 0.001).

Since hospital separation data are compiled using health record abstracts prepared by technicians, it is possible that the increasing hospital separation rate is simply an artifact of an increasing awareness of delirium. Another possibility is that the frequency of delirium in psychiatric inpatients is increasing. This may be due to more frequent admissions of patients with delirium to psychiatric units or to an increasing incidence of delirium within those units. In either case, the implications for service delivery are considerable. If patients are becoming delirious more frequently as a result of psychiatric treatment, the inpatient psychopharmacological practices need to be reevaluated. If patients with delirium are being admitted more frequently to psychiatric units, then the implications of this practice, relative to the more traditional approach of managing such patients on medical units, need to be examined. Additional research in this area seems to be urgently needed.

References

1. Patten SB, Williams JVA, Haynes L, McCruden J, Arboleda-Flórez J. The incidence of delirium in psychiatric inpatient units. Can J Psychiatry 1997;42:858­63.

2. Statistics Canada. Mental Health Statistics. Mental Health Statistics Publication #83-245. Ottawa: Minister of Supply and Services, Canada; Annual.

3. Lalonde A. Canadian Institute for Health Information: founding members. Canadian Journal of Medical Technology 1994;56:79.

Scott B Patten, MD, FRCPC, PhD
Calgary, Alberta

Dear Sir:

Although antidepressants have been commonly associated with sexual dysfunction, several case reports highlight unusual or exaggerated sexual responses, including spontaneous orgasm (1,2), with antidepressants. Bupropion, unlike tricylic or serotonin reuptake inhibitor antidepressants which commonly cause sexual dysfunction, has minimal sexual side effects (3) and may even have prosexual effects (4,5). I report on a patient treated with bupropion SR who experienced increased libido and a spontaneous second orgasm during sexual intercourse.

Mr A was a 37-year-old lawyer with a long history of attention-deficit disorder. There was no significant medical, neurological, or surgical history and no family or personal history of other mental illness or substance misuse. His mental status exam was unremarkable except for complaints of sustained attention problems. The attention-deficit disorder had been treated with methylphenidate and d-amphetamine with partial success, though these treatments were stopped because of medication-induced anxiety. There were no adverse sexual effects from the psychostimulants. He was then treated with bupropion SR, 150 mg 3 times daily, for his attention problems. He took no other medications. Over several weeks he noted improved concentration and attention but also noted bothersome increased libido, increased feeling on orgasm, and rare spontaneous partial erections during the day. There were no other signs or symptoms of hypomania. Six weeks after starting bupropion he experienced a surprise second orgasm during sexual intercourse. He reported that the initial ejaculation and orgasm were normal, but they were followed 5 seconds later by a spontaneous and pleasurable second ejaculation and orgasm. This had never happened previously. He stopped the medication out of concern for the increased libido. His libido returned to normal several days after stopping bupropion. Several months later he resumed bupropion SR, 150 mg twice daily, again experienced increased libido, and once more experienced an unexpected second orgasm during intercourse. He again stopped the bupropion. Libido returned to normal and he experienced no further altered orgasm.

This case highlights that, like other antidepressants, bupropion SR may have unusual sexual side effects. The patient's experience of increased libido and alteration in orgasm with 2 trials of the drug suggests that the effects were caused by bupropion SR and were not a coincidence. The sexual experience did not otherwise seem part of drug-induced hypomania. The sexual side effects may be uncommon adverse effects, and it is unclear if they are dose-dependent. The mechanism of this possible adverse effect is unknown, though bupropion's central effects on norepinephrine or dopamine transmission may contribute. With the increased use of bupropion SR in the treatment of nicotine cessation, more cases of sexual adverse effects may come to light.

References

1. Garcia-Campayo J, Sanz-Carillo C, Lobo A. Orgasmic sexual experiences as a side effect of fluoxetine: a case report. Acta Psychiatr Scand 1995;91:69­70.

2. McLean JD, Forsythe RG, Kapkin IA. Unusual side effects of clomipramine associated with yawning. Can J Psychiatry 1983;28:569­70.

3. Gardner EA, Johnston JA. Bupropion: an antidepressant without sexual pathophysiological action. J Clin Psychopharmacol 1985;5:24­9.

4. Labbate LA, Pollack MH. Treatment of fluoxetine induced sexual dysfunction with bupropion. Ann Clin Psychiatry 1994;6:13­5.

5. Rowland DL, Myers L, Culver A, Davidson JM. Bupropion and sexual function: a placebo controlled prospective study on diabetic men with erectile dysfunction. J Clin Psychopharmacol 1997;17:350­7.

Lawrence A Labbate, MD
Charleston, South Carolina

Dear Sir:

The patient was a 35-year-old female with a 16-year history of major depression with psychotic features, borderline personality, and bulimia. During a 2-year episode of depression she had been resistant to electroconvulsive therapy, antidepressants, and augmentation with haloperidol or lithium but partly responded to fluvoxamine 200 mg daily with loxapine 25 to 35 mg daily. After decreasing the loxapine, because of akathisia, she was admitted to hospital with depression, suicidal ideation, and paranoid delusions. Loxapine was stopped, and she started olanzapine 5mg daily, which was increased to 10 mg daily after 5 days. After 2 more days she reported fears of germs, compulsive handwashing (20 to 30 times daily), and extensive roomcleaning activity. Her hands were red and abraded, and she had developed a coarse tremor that did not respond to benzotropine 4 mg daily. Her affective disorder had improved, but olanzapine was stopped because of these side effects, which remitted 10 days later. She relapsed after 4 weeks and was rechallenged with olanzapine 5 mg daily after fluvoxamine had been tapered. Her symptoms recurred within 48 hours. She could resist compulsions with effort but had continued contamination obsessions. These gradually decreased after the introduction of venlafaxine, up to 150 mg twice daily, despite the subsequent increase of olanzapine to 10 mg daily. The tremor remitted on propranolol 30 mg daily, showing a temporary relapse when pass medication was omitted.

This case provides evidence for the de novo provocation of obsessive­compulsive symptoms (OCS) by olanzapine. The OCS started with treatment, remitted after discontinuation, and recurred on rechallenge. OCS have also been reported with clozapine (1) and risperidone (2), which are potent 5-HT₂ antagonists, like olanzapine (3). The nonselective 5-HT₂ antagonist metergoline exacerbated symptoms in obsessive­compulsive disorder, although similar studies have been negative (4). Fluvoxamine, like olanzapine, is metabolized via cytochrome P450 1A2 and 3A3/4 but is a more potent inhibitor (Eli Lilly data sheet, 5). At rechallenge, fluvoxamine was discontinued in case it had increased the olanzapine levels. The patient found the compulsions easier to resist, and they gradually resolved after the introduction of venlafaxine, which is a less potent inhibitor. In the absence of plasma levels, these findings are not definitely attributable to a drug interaction. Tremor occurs in 4% of olanzapine-treated patients (Eli Lilly data sheet). In view of the lack of response to benzotropine 4 mg daily, the sustained improvement with propranolol 30 mg daily is of clinical note.

References

1. Baker RW, Chengappa KNR, Baird JW, Steingard S, Christ MAG, Schooler NR. Emergence of obsessive compulsive symptoms during treatment with clozapine. J Clin Psychiatry 1992;53:439­42.

2. Remington G, Adams M. Risperidone and obsessive compulsive symptoms [letter]. J Clin Psychopharmacol 1994;14:358­9.

3. Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, and others. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacol 1996;14:87­96.

4. Price LH, Goddard AW, Barr LC, Goodman WK. Pharmacological challenges in anxiety disorders. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: the fourth generation of progress. New York: Raven Press; 1995. p 1311­23.

5. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 1997;32:1­21.

Abdul Al-Mulhim, MBBS
Sanita Atwal BA, BSc
Nick J Coupland MBChB, MRCPsych
Edmonton, Alberta

Dear Sir:

The serotonin syndrome, relatively recently identified as a potential drug­drug interaction between 2 or more agents known to increase the activity of serotonin at the 5-HT_1A receptor, remains rarely diagnosed. The following case history is a presentation of the syndrome with some unusual features.

Ms C, aged 34 years, had been a member of an outpatient psychotherapy group for about 11 months. The group was conducted by 2 experienced psychiatry residents and supervised by the writer through a 1-way mirror.

During her history of 8 years of intermittent involvement with mental health services, Ms C received a number of different diagnoses, among which were posttraumatic stress disorder (PTSD); personality disorder not otherwise specified, with histrionic, borderline, and dependent traits; somatisation disorder; and subsequently, bulimia nervosa. Around the time of her referral to the group, she was started on fluoxetine 20 mg daily to treat the symptoms of PTSD.

About 2 months before the serotonin syndrome appeared, Ms C visited her family doctor and described to him several symptoms suggestive of obsessive­compulsive disorder. He started her on clomipramine and rapidly increased the dose to 75 mg daily. He was also prescribing fluoxetine, and these additions to her medication regimen were not communicated to the writer or to the residents running the group.

Some 5 weeks after the medication change, Ms C began complaining during group meetings of increasingly severe headaches, nausea, and flushing. These complaints were not dealt with on an individual basis and were lost in the vague and fluctuating symptom picture that Ms C presented to the group.

After a further 2 weeks, Ms C presented to the emergency room complaining of tremors and describing postural hypotension. She was seen in the emergency room by the physician and the psychiatrist on duty and was told to reduce her clomipramine to 50 mg daily because "it is probably causing your symptoms." I was asked to see her individually to review her medication.

When seen individually, 2 months after starting clomipramine, Ms C complained of a 1-month history of appetite loss and weight loss with tremulousness and postural hypotension. She had developed a dull, constant headache bilaterally in the fronto-temporal region. She frequently felt nauseated, was hot and flushed, and was sweating more than was normal for her.

I felt it likely that these symptoms were manifestations of the serotonin syndrome and advised the patient to discontinue the clomipramine. In response to this course of action the above symptoms rapidly abated. The fluoxetine was not discontinued.

There are 4 aspects of concern in this case:

1)

The serotonin syndrome developed in response to the combination of a selective serotonin reuptake inhibitor (SSRI) with clomipramine. Warnings about the serotonin syndrome continue to focus on the combination of SSRIs with the much less commonly used monoamine oxidase inhibitors (MAOIs) or with tryptophan. However, clomipramine may be particularly likely to cause the syndrome (1).

2) The onset of the syndrome seems to have been gradual over a period of at least 4 weeks. It is generally believed that the syndrome most often has a rapid onset within hours of beginning the second medication.

3) Ms C sat in front of a psychiatrist and 2 psychiatry residents on at least 2 occasions, complaining of the symptoms of the syndrome. Because of expectations relating to the diagnoses of somatisation disorder and eating disorder, and because of the context in which these complaints were uttered, they were not initially heard for what they were. It was, so to speak, difficult to separate the signal from the noise. Even the physician and the psychiatrist at the emergency room failed to make the diagnosis, perhaps in part because of personal unfamiliarity with the syndrome, in part because of the unusual presentation.

4) In this era of increasing cooperation between family physicians and psychiatrists in the management of psychiatric disorders, good communication, especially about medications, is vital.

We need to be constantly alert if we are to identify the unusual but hazardous events that can occur when we believe we have full knowledge of a situation.

Reference

1. LoCorto MJ. The serotonin syndrome. Emerg Med Clin North Am 1997; 15:665­75.

Simon A Brooks, MB, FRCPC
Halifax, Nova Scotia

Dear Sir:

Improvement in drug-induced parkinsonism has been observed with the use of low dose L-dopa in intravenous (1) and oral (2) form. Two studies (3,4) failed to show an improvement in drug-induced parkinsonism treated with high-dose L-dopa. Chouinard and associates (5) found a beneficial effect of low-dose L-dopa in a subgroup of patients with drug-induced parkinsonism, in a long-term, double-blind study comparing L-dopa, procyclidine, and placebo.

Mrs R is a 60-year-old woman with chronic paranoid schizophrenia. The first episode of psychosis occurred at age 28 years. She was maintained on uninterrupted treatments of low to moderate doses of perphenazine, trifluoperazine, fluphenazine, and fluspirilene. She was referred to our clinic in 1992 with minimal psychotic symptoms but severe drug-induced parkinsonism and tardive dystonia. She was receiving fluspirilene 4 mg daily intramuscular weekly, procyclidine 10 mg 3 times daily, and diazepam 2.5 mg twice daily. The movement disorder as measured by the Extrapyramidal Symptom Rating Scale (ESRS) (6) scored 4/6 for rigidity, bradykinesia, and facial mask; 5/6 for tremor; 6/6 for gait and postural stability; and 5/6 for tardive dystonia of the left lower limb. Investigations, including magnetic resonance imaging, were normal. The neuroleptic was changed to risperidone, resulting in ESRS improvements in tremor, rigidity, and facial mask to 2/6, and bradykinesia to 3/6, but the disturbed gait, postural reflexes, and tardive dystonia persisted. When L-dopa/benserazide 50/12.5 mg 3 times daily was added, the improvements in ESRS ratings of gait to 2/6 and postural stability to 3/6 allowed her to walk safely without a cane. She experienced a mild exacerbation of psychotic symptoms which subsided with an increase in risperidone to 2 mg daily. Her movement disorder has remained stable, although she has required increasing doses of L-dopa. Her current pharmacotherapy includes risperidone 2 mg daily, clonazepam 0.5 mg 3 times daily, procyclidine 10 mg 4 times daily, L-dopa/benserazide 100/25 4 times daily, and L-dopa/carbidopa 100/50 4 times daily.

The use of L-dopa in drug-induced parkinsonism remains unclear. L-dopa has the potential to aggravate psychosis. In our patient, we did not observe an increase in psychosis with low-dose L-dopa. We observed the same on­off and wearing-off phenomena as seen in the treatment of idiopathic parkinsonism. However, the use of low-dose L-dopa, in combination with central anticholinergics, appears to be an efficacious treatment strategy for pateints with intractable, severe drug-induced parkinsonism and/or tardive dystonia.

References

1. Bruno A, Cumer BS. Effects of l-dopa on pharmacological parkinsonism. Acta Psychiatrica Scandinavia 1966;42:264­71.

2. Shoulson I. Carbidopa/levodopa therapy of coexistent drug-induce parkinsonism and tardive dyskinesia. Adv Neurol 1983;37:253­8.

3. Fleming P, Makar H, Hunter KR. Levodopa in drug-induced extrapyramidal disorder [letter]. Lancet 1970;2:1186.

4. Yaryura-Tobias JA, Wolpert A, Sana L, Merlis S. Action of L-dopa in drug induce extrapyramidalism. Diseases of the Nervous System 1970;31:60­3.

5. Chouinard G, Annable L, Mercier P, Turnier L. Long-term effects of l-dopa and procyclidine on neuroleptic-induced extrapyramidal and schizophrenic symptoms. Psychopharmacol Bull 1987;23:221­6.

6. Chouinard G, Ross-Chouinard A, Gauthier S, Annable L, Mercier P. An extrapyramidal rating scale for idiopathic and neuroleptic-induce parkinsonism and dyskinesia (abstract F-13). 14th Collegium Internionale Neuro-Psychopharmacologicum (CINP) Congress Abstracts, 1984.

Karl J Looper, MD
Guy Chouinard, MD, MSc(Pharmacol)
Montreal, Quebec

Dear Sir:

The present study compares the durations of major depressive episode (MDE) before the first visit in bipolar II and unipolar outpatients. A Medline search did not find similar reports. The same sample was the object of different reports (1,2).

Consecutive bipolar II (n = 92) and unipolar (n = 103) outpatients presenting for treatment of an MDE according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) in a private practice (a setting representative of mood disorder patients in Italy, whereas the public setting deals mainly with severe cases) were interviewed with the Comprehensive Assessment of Symptoms and History (3), the Montgomery-Asberg Depression Rating Scale (4), and the Global Assessment of Functioning Scale (5). As reported (1), bipolar II and unipolar patients were similar on many variables (gender, recurrence, chronicity, psychosis, comorbidity, duration of illness, severity). They differed in age at baseline and onset of the first depression, which was significantly lower in bipolar II patients, and atypical features, which were more common in bipolar II patients. Duration of the present MDE was calculated in weeks, from onset of its minimum symptom criteria to the time of the first visit. Since durations of MDEs were not normally distributed (Kolmogorov-Smirnov test, KS distance 0.3247 and 0.3025, P < 0.0001), medians were compared with the nonparametric 2-tailed Mann-Whitney U test.

Median bipolar II MDE duration (8 weeks) was significantly shorter than median unipolar MDE duration (12 weeks) (U = 3231, P = 0.0271). Shorter MDE duration from onset to the first visit in bipolar II patients than in unipolar patients suggests that bipolar II patients seek treatment more quickly. Quicker treatment-seeking by bipolar II patients was not related to baseline severity or to recurrences, since these variables were not significantly different (1). The reason is unclear.

References

1. Benazzi F. Prevalence of bipolar II disorder in outpatient depression: a 203-case study in private practice. J Affect Disord 1997;43:163­6.

2. Benazzi F. Antidpressant-associated hypomania in outpatient depression: a 203-case study in private practice. J Affect Disord 1997;46:73­7.

3. Andreasen NC, Flaum M, Arndt S. The comprehensive assessment of symptoms and history (CASH). Arch Gen Psychiatry 1992;49:615­23.

4. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382­9.

5. American Psychiatric Association. Diagnostic and statistical manual of mental disorder. 4th ed. Washington (DC): American Psychiatric Press; 1994.

Franco Benazzi, MD
Forlì, Italy