Clozapine rechallenge after myocarditis

Philip Reid, Milford McArthur and Saxby Pridmore,Department of Psychological Medicine, Royal HobartHospital, Hobart, Australia:

We present a case of clozapine rechallenge aftermyocarditis. Recently, the frequency of the side-effect ofmyocarditis from clozapine has been reported at a higherlevel than was once thought; Australian data suggests anincidence of one in five hundred in the first month [1].This has prompted recommendations for further monitor-ing in the form of regular electrocardiograms (ECG), echo-cardiograms and blood tests. This monitoring is likely todetect subclinical cases. Clinicians will increasingly facethe difficult decision of discontinuation when interpretingthe significance of more subtle ECG changes.

In June 1994, a 23-year-old former university studentwith deteriorating, treatment-resistant schizophrenia wasstarted on clozapine. He had no history of cardiac diseaseor alcoholism and was physically fit. Clozapine was begunat 12.5 mg and increased slowly to 200 mg over 3 weeks.Initially, he exhibited the side-effects of hypersalivation,mild sedation and some dizziness from hypotension butthese passed with time. His mental state improved signif-icantly with a reduction of his positive symptoms. He wasdischarged on clozapine only and attended an outpatientclinic with regular blood testing.

Five weeks after starting clozapine, he complained ofshortness of breath and non-specific aches and pains inhis legs and body. On examination, he had a regularpulse of 120 beats/min, but no signs of heart failure. AnECG was taken which revealed marked ST-depressionand T-wave inversion in the lateral and inferior leads.Eosinophilia was absent and creatine kinase was notelevated. Echocardiogram showed a hyperdynamic heartwith left ventricular chamber size at the upper limit ofnormal. Heart valves and function were reported asnormal. A consultant cardiologist diagnosed myocarditissecondary to clozapine as no other confounding comor-bidity was identified.

The clozapine was ceased, but a deterioration in his mental state with thought-blocking and grimacingensued 2 weeks after ceasing the medication. Hestarted on resperidone which was later augmented withlithium. However, he continued to deteriorate, withmarked anhedonia, alogia, amotivation and blunting ofaffect. A trial of haloperidol did not lead to any obviousimprovement.

In 1996 clozapine was resumed. This decision wasmade after consultation with the patient, his family and the cardiologist who had made the diagnosis ofmyocarditis in 1994. Because of his steady decline inmental state and poor quality of life, another trial of

clozapine was attempted with weekly ECG and eosinophilcounts. Repeat echocardiogram prior to the commence-ment of clozapine was normal, apart from the trivialmitral regurgitation. His ECG had improved but still hadevidence of T-wave flattening and ST depression.

The dose of clozapine was built up to a dose of 225 mgat night, his ECG remained unchanged and there was norise in eosinophils. Again, his symptoms and functioningimproved significantly over the initial 2 months withfurther subtle but significant positive change over years.He remains well and free of cardiac side-effects.

Myocarditis is a difficult condition to define anddiagnose even with endocardial biopsy [2]. The patho-physiology of clozapine myocarditis is not known andcomplicated by the high likelihood of previous anti-psychotic exposure. However IgE-mediated hyper-sensitivity, type 3 allergic reaction and direct toxiceffects have been postulated in its aetiology [1].

Australian figures suggest clozapine-associated myo-carditis is most likely to occur within the first 3 weeks oftherapy. In the present case, symptoms developed in thesixth week. There are reports of numerous organ systemsincluding the cardiovascular system being involved inclozapine-induced allergy which is invariably associatedwith eosinophilia [3]. The lack of eosinophilia and the latertiming of the episode may suggest a toxic rather that aller-gic response in this patient. Some suggest that the ultimatetest for causality of a drug reaction is dechallenge followedby rechallenge [4], thereby ruling out clozapine in thiscase. However, the timing and ECG findings, together withcardiology opinion, suggested this to be clozapine-inducedmyocarditis at the time of discontinuation.

This case highlights the significant and unique con-tribution that clozapine can make to some individualswith treatment-resistant schizophrenia. For this patientquality of life improvement outweighed the risk offurther clozapine therapy. This is the first reported caseof rechallenge of clozapine after myocarditis. It wasachieved after considering the risk benefit, receivingthe informed consent of the patient and with closecardiac monitoring.

References1. Kilan JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and

cardiomyopathy associated with clozapine. Lancet 1999;354:1841–1845.

2. Peters NS, Poole-Wilson PA. Myocarditis – a controversialdisease. Journal of the Royal Society of Medicine 1991;84:1–2.

3. Benning TB. Clozapine-induced extrinsic allergic alveolitis.British Journal of Psychiatry 1998; 173: 440–441.

4. Po AL, Kendall MJ, Pinto YM, van Gelder IC, Crijns HJ,Heeringa M. Causality assessment of adverse drug effects:when is rechallenge ethically acceptable? Lancet 1999; 354: 683.

Correspondence

Weight gain with antipsychotic medication

Stephen Arthur, Maroubra, Sydney, Australia:Surely people must have noticed the extreme weight

gain in many patients who are taking the newer anti-psychotic medications.

It is always a shame when unwanted problems arefound with new ‘wonder drugs’, and it is especially ashame with these drugs as their beneficial effects are soobvious. But the problem needs to be raised and strate-gies adopted to help these patients lose weight.

Instead of the ‘average’ 10 kg weight gain over severalmonths that the drug companies claim, anecdotally I haveseen several patients gain double that in just 3 months andcontinue putting it on there after.

If we do not do something fast, in a few years time‘control and restraint’ courses for staff working in acutepsychiatric settings might be a thing of the past. Insteadthey will be undertaking a lot more training in lifting!

But seriously, how long before patients begin to takelegal action? Are the drug companies and the medicalprofession confident that the concept of ‘informed con-sent’ will protect them against a sharp lawyer?

Neuroleptic malignant syndrome precipitatedby promethazine and lorazepam

Harpreet S. Duggal, S. Haque Nizamie, Central Institute ofPsychiatry, Ranchi, India:

Neuroleptic malignant syndrome (NMS) has anecdo-tally been associated with neuroleptic withdrawal [1]. A case of NMS precipitated by a combination of pro-methazine and lorazepam while the patient was off neu-roleptics for a week is described. To our knowledge, thisis the first report of NMS following such a drug regimenin a neuroleptic-withdrawn patient.

An 18-year-old man was diagnosed in the outpatientclinic as having a first episode of mania and started onhaloperidol 15 mg/day, trihexyphenidyl 4 mg/day andchlorpromazine 100 mg/day. He returned for follow up12 days later with severe extrapyramidal symptoms(EPS), including rigidity, sialorrhoea, tremors and brady-kinesia. The patient had developed these symptoms withina week of starting treatment and had stopped all medi-cations. On admission he was treated with parenteralpromethazine 100/mg day to treat the EPS and lorazepam6 mg/day to control his agitation. The same evening (dayone), the patient became febrile with the body tem-perature peaking at 40 °C. In addition, he developedtachycardia (150 beats/min) and labile blood pressure(110/70–130/84 mmHg). On day two, patient becamestuporose, diaphoretic and doubly incontinent, and onday three, he had a respiratory rate of 45 breaths/min.

Laboratory tests indicated elevated levels of erythro-cyte sedimentation rate (80 mm/hr), creatine phospho-kinase (630 IU/L), alanine aminotransferase (57 IU/L),aspartate aminotransferase (85 IU/L) and blood urea nitro-gen (55 mg/dL), although the blood cell counts, creati-nine, sugar and electrolyte values were normal. ChestX-ray revealed a bilateral lower zone consolidationindicative of aspiration pneumonia. Computed tomog-raphy scan of the brain and cerebrospinal fluid examina-tion were within normal limits.

The patient was treated with antibiotics for his chestinfection while all other drugs were stopped. He wasmanaged symptomatically and from day five to day 13,he gradually improved and was discharged on increasingdoses of thioridazine with an uneventful follow up.

Our patient met the DSM-IV research criteria forNMS. The peculiarities of this case are two-fold. First,the patient developed NMS after neuroleptic withdrawal,an uncommon, although previously reported, presenta-tion [1]. Second, the more interesting of the two obser-vations, he developed NMS after being treated with acombination of promethazine and lorazepam. To ourknowledge, NMS being precipitated by promethazine isan extremely rare presentation [2], and no report of itbeing precipitated by a combination of promethazine andlorazepam is documented.

The proposed hypothesis of cholinergic reboundleading to NMS in cases of abrupt neuroleptic with-drawal may not hold true in this patient [1]. This isbecause the patient was not treated with neurolepticsover a sufficiently long period of time so as to developcholinergic receptor supersensitivity. Moreover, theadministration of promethazine, which has a potent anti-cholinergic effect, is likely to have prevented such arebound. This led us to explore the role of promethazineand lorazepam in precipitating NMS. A possible hypoth-esis explaining this presentation could be of an alreadyexisting imbalance between dopaminergic and choline-gric activity that was exacerbated by these two drugs.Evidence supporting this hypothesis exists. Muscariniccholinergic activation produces increased dopaminerelease [3], with drugs having anticholinergic activity,such as promethazine, blocking this effect. Thus,promethazine may have further decreased the dopamin-ergic transmission in this case creating a more severehypodopaminergic state, which is thought to manifest asNMS [1]. Furthermore, the role of lorazepam in this sce-nario cannot be ignored. Benzodiazepines in low dosesreduce cholinergic activity in the basal ganglia and athigher doses reduce both dopaminergic and cholinergicactivity [4]. While the former effect would have potenti-ated the role of promethazine in precipitating NMS, thelatter could have only exacerbated the condition. Support

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for the involvement of reduced cholinergic activity inNMS comes from a post-mortem study showing reducedcholine acetyltransferase in the striatum of a patientdying of NMS [3].

In conclusion, this report calls for exercising cautionwhen starting drugs with potent anticholinergic activityin combination with high doses of benzodiazepines inpatients with an existent hypodopaminergic state mani-festing as EPS. Moreover, the polemical position of ben-zodiazapines in the treatment of NMS needs elucidationas benzodiazapines have been reported to complicateNMS [5].

References1. Corrigan FM, Coulter F. Neuroleptic malignant syndrome,

amitriptyline, and thioridazine. Biological Psychiatry 1988;23:320–321.

2. Chan-Tack KM. Neuroleptic malignant syndrome due topromethazine. Southern Medical Journal 1999; 92:1017–1018.

3. Kish SJ, Kleinert R, Minauf M et al. Brain neurotransmitterchanges in three patients who had a fatal hyperthermiasyndrome. American Journal of Psychiatry 1990;147:1358–1363.

4. Menza MA, Harris D. Benzodiazepines and catatonia: anoverview. Biological Psychiatry 1989; 26:842–846.

5. Velamoor VR. NMS complicated by diazepam. British Journalof Psychiatry 1992; 160:135–136.

A dose–response relationship of imitationalsuicides with newspaper distribution

Elmar Etzersdorfer, Furtbachkrankenhaus, Hospital forPsychiatry and Psychotherapy, Stuttgart, Germany; MartinVoracek, Department of Psychoanalysis and Psychotherapy,University of Vienna Medical School, Vienna, Austria; andGernot Sonneck, Department of Medical Psychology,University of Vienna Medical School, Vienna, Austria:

Sensational newspaper reports about suicides maytrigger additional suicides (the ‘Werther effect’ [1,2]).However, until now, a ‘dose–response’ relationshipbetween regional newspaper distribution and magnitudeof imitational effects has not been revealed [3,4].

In late October 1990, the owner of a famous Viennesehotel, Hotel Sacher, committed suicide by firearm.Mass-media coverage of this celebrity suicide was exten-sive, although mostly in a moderate way, which hasbecome common practice among the media following anincrease in subway suicides in Vienna [5]. The onlynewspaper that reported the Sacher suicide in a verydramatic way, including headline coverage and photo-graphs, was Austria’s leading tabloid newspaper, theNeue Kronenzeitung (NKZ). It ran a very detailed andsensationalized serial about the ‘life and death’ of thesuicide victim, covering two pages per issue for five con-secutive days.

The NKZ is read by almost 50% of the population,although there is substantial regional variation. Thisreporting, in conjunction with the distribution of theNKZ, provided the opportunity for a natural experiment.We obtained Austrian suicide data, including method andregion, within a time-frame aligned ± 3 weeks aroundthis celebrity suicide for 1990 (n = 223) and for a controlperiod (1981–1989, n = 2051), and regional NKZ distri-bution data.

In the control period (1981–1989), use of firearm assuicide method declined slightly for regions both of ‘low’and ‘high’ distribution of NKZ (from 10.8% before to7.9% after that day for ‘low’ regions, and from 16.0% to 15.8% for ‘high’ regions, respectively). In 1990 in ‘low’regions the proportion of suicide by firearm was 15.8% ofall suicides prior to the celebrity suicide, whereas no caseoccurred during the 3 weeks thereafter. For the ‘high’regions a statistically significant increase from 13.2% to 34.1% was found (OR = 3.41, 95% CI = 1.11–10.56)during this period, which represents a tripling of thenumbers (from five to 15 suicides). Total suicides byfirearm in Austria increased from 17 to 28 cases; how-ever, the total number of suicides increased only slightlyfrom 107 to 116 cases.

Further regional-level analysis revealed a strong associ-ation between NKZ distribution and an increase of sui-cides by firearm (log OR) after the NKZ serial (Pearson’sr = 0.62, n = 9 regions, one-tailed p = 0.04). In otherwords, nearly 40% of the variance in changes in suicideby firearm was attributable to differential NKZ dis-tribution. There was no such association for the con-trol period.

This finding of a ‘dose–response’ relationship providesfurther evidence of the influence of media reports on sui-cidal behaviour from a new perspective, lending supportto efforts to achieve more moderate reporting in massmedia [1–5].

References1. Phillips DP. The influence of suggestion on suicide: substantive

and theoretical implications of the Werther effect. AmericanSociological Review 1974; 39:240–253.

2. Hassan R. Effects of newspaper stories on the incidence ofsuicide in Australia: a research note. Australian and NewZealand Journal of Psychiatry 1995; 29:480–483.

3. Goldney RD. Suicide: the role of the media. Australian and NewZealand Journal of Psychiatry 1989; 23:30–34.

4. Phillips DP, Lesyna K. Suicide and the media research andpolicy implications. In: Diekstra RFW, Gulbinat W, DeKienhorst I, Leo D, eds. Preventive strategies on suicide.Leiden: EJ Brill, 1995:231–261.

5. Etzersdorfer E, Sonneck G, Nagel-Kuess S. Newspaper reportsand suicide. New England Journal of Medicine 1992;327:502–503.

Improvement in chronic pain with transcranialmagnetic stimulation

Philip Reid and Saxby Pridmore, Department of Psycho-logical Medicine, Royal Hobart Hospital, Hobart, Australia:

A 22-year-old science masters student with a 4-yearhistory of bilateral facial pain was referred for a courseof transcranial magnetic stimulation (TMS) for a con-current major depressive episode.

She had a strong family history of facial pain. Her painwas triggered by the removal of impacted teeth in 1996.Since then, debilitating pain had persisted despite gan-gliotomy and the use of numerous medications includingmethadone, morphinesulphate, gabapentin, tramadol andamitriptyline. Her mood state was also difficult to treatwith past use of venlafaxine, nefazadone and, morerecently, fluoxetine. Current medication included mor-phine 50 mg nocte, fluoxetine 60 mg daily, gabapentin1200 mg daily, propranolol 40 mg q.i.d. and tramadol100 mg q.i.d., which was unchanged throughout thetreatment course.

The course of TMS consisted of 14 sessions over 3 weeks and was well tolerated. Each session comprised30 trains of 2 s at 20 Hz to the left prefrontal cortex.Stimulation was given at 100% of motor threshold. Painintensity was monitored with the aid of a visual analogue

scale, and the Montgomery and Asberg DepressionRating Scale (MADRS) and Beck Depression Inventory(BDI) measured depression at entry and exit.

In the first week of treatment, little change was notedin either her pain or depression. However, in the secondweek, she reported a decrease in her pain of 42%.Reduced pain reporting and behaviour was also con-sidered clinically significant by her regular treating phys-icians. Her pain response had plateaued by the third weekbut was maintained at the 4-week follow up. In contrast,her mood did not show significant improvement over her treatment course. The MADRS moved from 27 to 19,while the BDI was static moving from 47 to 48 at exit.

Transcranial magnetic stimulation is a relatively newtechnology which employs the principles of electromag-netism to create electric currents in the cortex. Plasticchanges have been observed in the central nervous sys-tem following administration [1]. Such change may becapable of influencing the pattern-generating mechanismof chronic pain. The present case suggests a possibletherapeutic potential for TMS in chronic pain whichwarrants further investigation.

Reference1. Pascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M.

Responses to rapid-rate transcranial magnetic stimulation of thehuman motor cortex. Brain 1994; 117:847–858.

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