brain, mind and kep

Concurrent use of ECT and cholinesterase inhibitor medications

Bruce Boman, Rozelle Hospital, Sydney, Australia:

Three drugs are available in Australia for the treatmentof mild to moderate Alzheimer’s disease: donepezil,rivastigmine and galantamine. All act by increasingbrain acetylcholine levels via their blockade of acetyl-cholinesterase. I would like to raise three concerns abouttheir concurrent use with electroconvulsive therapy(ECT).

First, there is the synergistic enhancement of neuro-muscular blockade with suxamethonium, a muscle relax-ant which binds to the postsynaptic muscle receptorcausing initial depolarization followed by blockade. It ismetabolized by pseudocholinesterase. Hence any drugsthat reduce pseudocholinesterase activity will enhanceneuromuscular blockade leading to prolonged apnoeaand paralysis when used with suxamethonium. There arereports of both prolonged apnoea and death with theconcurrent use of suxamethonium and ecothiopate eyedrops, a cholinesterase inhibitor used for glaucoma [1].Of the cholinesterase inhibitors used for Alzheimer’sdisease, tacrine does reduce pseudocholinesterase activ-ity [1] and it is likely donepezil, rivastigmine and galan-tamine would have a similar effect [2,3]. Donepezilwould be particularly problematic because of its 70 hourhalf-life and washout period of 14 days leading to delaybefore ECT could be commenced without the risk ofprolonged apnoea.

Second, there is the synergistic potential for thecholinesterase inhibitors, ECT and suxamethonium toinduce significant bradycardia, cardiac arrhythmias andasystole. Administration of ECT is associated with twopowerful vagal parasympathetic surges, the first with thepassage of the electrical current, the second immediatelyfollowing ictal activity, and both sinus bradycardia andperiods of asystole lasting several seconds are notuncommon [4]. Suxamethonium also causes bradycardiaand asystole and caution is recommended in using itconcurrently with drugs of similar effect [1]. Thus,adding a cholinesterase inhibitor that has the potentialfor further increasing vagal parasympathetic activitymay carry the risk of causing serious cardiac events.

Third, because cholinomimetics are believed to havethe potential to cause generalized convulsions [2,3],there is the possibility of a reduced threshold when usedwith ECT, increasing the risk of prolonged seizures andstatus epilepticus.

While a

MEDLINE

search and a review conducted bythe three relevant pharmaceutical companies (Novartis,Pfizer and Janssen-Cilag) failed to find any reports ofadverse incidents involving concurrent use of ECT and

cholinesterase inhibitors, it would seem prudent to factorin what are potential dangers when considering the riskbenefit analysis of administering ECT to a patient on acholinesterase inhibitor, and to ensure the patient is fullyaware of such risks.

References

1. AstraZeneca, Suxamethonium chloride, full prescribing information.

MIMS Online

[Cited 27 August, 2002.] Available from URL: http://www.mims.hcn.net.au

2. Pfizer, Donepezil, full prescribing information.

MIMS Online


3. Novartis, Rivastigmine, full prescribing information.

MIMS Online


4. Beyer M, Weiner RD, Glenn MD.

Electroconvulsive therapy

. Washington, DC: American Psychiatric Press, 1998.

Methadone, morphine and PTSD

AD Macleod, Consultant Psychiatrist, PsychiatricConsultation Service, Christchurch Hospital, Christ-church, New Zealand; SG Duffy, Consultant Psychiatrist,Community Alcohol and Drug Service, Christchurch,New Zealand:

High rates of comorbidity suggests that posttraumaticstress disorder (PTSD) and substance use disorders arefunctionally related to one another [1]. There is emerg-ing consensus that PTSD encourages self-medicationand that substance withdrawal amplifies PTSD symp-toms [1,2]. Heroin and alcohol may dampen intrusiveand hyperarousal PTSD symptoms [2]. Opioid dys-regulation is a feature of PTSD [3]. Posttraumatic stressdisorder has been conceptualized as both opioid defi-cient and opioid excess states [3].

Opioid dependant persons recruited onto methadonemaintenance programmes frequently complain about thechoice of opioid.

A 28-year-old woman maintained on methadone70 mg/day (with high ‘therapeutic’ serum levels) com-plained of the exacerbation of previously quiescentintrusive and hyperarousal symptoms of chronic PTSD(childhood sexual and physical abuse). About one yearpreviously the perpetrator of her abuse had been diag-nosed with terminal malignancy and the patient hadresorted to re-using illicit morphine ‘to control my post-traumatic symptoms’. At relapse, affective symptomswere not prominent. Benzodiazepines failed to suppressher night terrors and hypervigilance. Medicinal main-tenance morphine (200 mg sustained release b.i.d.)resulted in a rapid clinical stabilization which has beensustained for nearly three years.

Methadone possesses antagonistic action of the gluta-mate receptor NMDA [4], whereas morphine does not.

Correspondence

CORRESPONDENCE 817

The glutamatergic system is a psycho-biological pathwayconceptually implicated in PTSD [3]. Methadone is apure mu receptor antagonist, devoid of morphine kappareceptor action. The endogenous opioids involved in thehuman stress response are active at the mu receptors.Therefore, methadone may not be the ideal maintenanceopioid for persons with PTSD and substance abuse.

References

1. Jacobsen LK, Southwick SM, Kosten TR. Substance use disorders in patients with post-traumatic stress disorder: a review of the literature.

American Journal of Psychiatry

2001; 158:1184–1190.

2. Bremner JD, Southwick SM, Darnell A, Charney DS. Chronic PTSD in Vietnam combat veterans – course of illness and substance abuse.


1996; 153:369–375.

3. Friedman MJ. What might the psychobiology of post-traumatic stress disorder teach us about future approaches to pharmacotherapy?

Journal of Clinical Psychiatry

2000; 61:44–47.

4. Gorman AC, Elliott KJ, Inturrisi CE. The d- and i- isomers of methadone bind to the non-competitive site of the N-methyl-D-asparate (NMDA) receptor in rat forebrain and spinal cord.

Neuroscience Letters

1997; 223:5–8.

Venlafaxine open-label treatment of patients with obsessive-compulsive disorder

Levent Sevincok, Associate Professor; Bulent Uygur,Research Assistant, Department of Psychiatry, AdnanMenderes University Faculty of Medicine, Aydin, Turkey:

Anecdotal evidence suggests that venlafaxine might beeffective in the treatment of patients with Obsessive–Compulsive Disorder (OCD) [1,2,3]. The purpose ofthis study was to assess the efficacy of moderate dosesof venlafaxine in an open-label study of 12 patientswith OCD.

Twelve patients (10 women, 2 men; mean

±

SD age =29.7

±

10.6 years; range, 18–48) who had a baselineYale-Brown Obsessive Compulsive Scale (YBOCS) [4]total score of 16 or greater, were treated with dailydoses of venlafaxine, ranging from 150 to 225 mg in an8-week, open-label trial. Target symptoms were rated atregular intervals with YBOCS; Hamilton Rating Scalefor Depression (HRSD) [5] and Clinical Global Impres-sion Scale (CGI) [6]. Symptom change was measuredusing an analysis of variance for repeated measures(

ANOVA

).The mean

±

SD duration of OCD was 6.0

±

4.9 years.The mean (

±

SD) daily dose of medication was 210.0

±

31.6. There were no dropouts. Nine patients (75%) werejudged responders based on

≥

35% decrease in YBOCS,whereas six patients (50%) were judged respondersbased on CGI scale scores of 1 or 2. The mean OCDscores declined for the group between baseline andweek eight, with statistically significant changes seen

in the YBOCS (26.18

±

3.37 vs 15.45

±

6.1, F = 35.34,p = 0.000). Statistically significant differences werefirst observed by week four (baseline vs week four,F-test:10.49, p = 0.009) and increased until the end oftreatment. Hamilton Rating Scale for Depression ratingsshowed a significant change at the end of the study,declining from 13.54

±

7.34 to 3.0

±

2.19 (F = 30.53,p = 0.000).

Antidepressants are effective in the acute treatment ofOCD at higher doses than those used to treat depression.We found that antidepressant doses of venlafaxinemight be effective in acute treatment of OCD. In ourstudy, the improvement observed was significant by thefourth week of treatment and increased until the endof the trial. However, double-blind placebo-controlledtrials with different doses of at least 12 week’s dura-tion, are required before a clear judgement of efficacycan be made.

References

1. Ananth J, Burgoyne K, Smith M, Swartz R. Venlafaxine for OCD.


1995; 152:1832.2. Rausch SL, O’Sullivan RL, Jenike MA. Open treatment of OCD

with venlafaxine: a series of ten cases.

Journal of Clinical Psychopharmacology

1996; 16:81–84.3. Grossmann R, Hollander E. Treatment of OCD with venlafaxine.


1996; 153:576–577.4. Goodman WK, Price LH, Rasmussen SA

et al

. The Yale–Brown Obsessive–Compulsive Scale, II: validity.

Archives of General Psychiatry

1989; 46:1012–1016.5. Hamilton M. A rating scale for depression.

Journal of Neurology, Neurosurgery and Psychiatry

1960; 23:56–62.6. Guy W, ed. Clinical Global Impressions (CGI). In:

ECDU assessment manual for psychopharmacology.

Washington, DC: US Department of Health and Human Services, Public Health Service, Alcohol Drug Abuse and Mental Health Administration, NIMT Psychopharmacology Research branch, 1976; 218–222.

Clinical research and scientific creativity

Leo Sher, Riverdale, New York, US:

Creativity and innovations are important for everyfield of medicine, including psychiatry [1,2]. Charltonsuggests that the ‘deceleration in major innovation hasrecently been documented for the field of psychiatryand psychopharmacology’ [1]. In his recent article [2],Horrobin states that ‘a person who develops nearly anytype of cancer, common skin disease, asthma, or psychi-atric or neurological illness is unlikely to be much betteroff than if they were receiving the best available treat-ment 30–40 years ago.’ No doubts, the psychiatric researchroad is long and difficult one with many problems to beovercome. However, effective clinical innovation is anethical imperative.

Boxenbaum [3] suggests that once a researcher hastaken a position within an organization, there are both

818 CORRESPONDENCE

positive and negative conditions that promote and dis-courage creativity, respectively. The following actionstend to promote creativity:– Provide an atmosphere of psychological safety. The

atmosphere should emphasize encouragement, empa-thetic understanding, etc;

– Make creativity part of the culture in an organizationor department;

– Stop converting talented and creative researchers intomediocre managers;

– Provide resources for productive and creative work.Individual creativity may be suppressed by the follow-

ing:– A military or command-mode management structure;– An environment in which the organization does not

recognize creative or innovative ideas;– Discouragement of deviant views and radical innova-

tions. Truly creative scientists, by their very nature,are persons dissatisfied with the status quo. Creativeindividuals need to find their niche within an organi-zation;

– An overemphasis on extrinsic (organizational) moti-vation. Intrinsic motivation is very important forthe self-actualizing process of individual scientificcreativity.

The story of James Lind, a creative and astute clini-cian, is an interesting example. In 1747, Lind, a youngphysician from Scotland, conducted a study on the pre-vention and treatment of scurvy [4]. He chose 12 sailorswith scurvy and divided them into six groups of twopatients each. All 12 sailors received an identical diet butthe six groups differed from one another in what theyreceived as a supplement to the standard diet: cider;elixir of vitriol; vinegar; sea water; oranges and lemons;and a folk remedy that consisted of garlic, mustardseeds, horseradish, balsam of peru, and gum myrrh.After one week of treatment patients who were givenoranges and lemon improved dramatically. None of theother groups improved. Lind concluded that citrus fruitcould treat or prevent scurvy. This discovery saved manylives. However, it would be extremely difficult for Lindto publish his report nowadays. The number of casesinvolved in his experiment is very small. He made adiscovery on the basis of statistically non-significantdata.

Modern research instruments and statistical analysisare important for the development of medical sciences.The progressive development of increasingly sophisti-cated and precise neuroscience research techniques pro-vides new opportunities to unravel the mysteries of brainfunction. However, neither powerful research instrumentsnor contemporary statistical analysis can replace the sharp-ness of mind of a clinical researcher. As Schopenhauer

noted, the task of the creative mind is ‘not so much to seewhat no one has seen yet; but to think what nobody hasthought yet, about what everyone sees’ [5].

References

1. Charlton BG. Natural kinds, natural history, and the clinician-researcher.

Quarterly Journal of Medicine

1997; 90:707–709.

2. Horrobin DF. Effective clinical innovation: an ethical imperative.

Lancet

2002; 359:1857–1858.3. Boxenbaum H. Scientific creativity: a review.

Drug Metabolism Reviews

1991; 23:473–492.4. Wynder EL. A corner of history. James Lind’s discovery of the

causes of scurvy.

Preventive Medicine

1974; 3:300–305.5. Von Bertalanffy L.

Problems of life

. New York: Harper, 1960; 1.

Brain, mind and kep

Michelle Gill, Hazel Samilowitz, Saxby Pridmore,Department of Psychiatry, Royal Hobart Hospital,Hobart, Australia:

Cartesian dualism, the separation of body (brain) andmind, is now considered by many psychiatrists andphilosophers to be a flawed concept. Critics argue thatit has delayed progress in our understanding. Kendler [1]points out that useful ways of conceptualizing theseissues include considering mind to be the process of thebrain, or to consider some aspects of mind as emergentproperties. It has long been clear that structure can influ-ence mind. More recently, in the study of facilitated geneexpression, as occurs for example through learning, wehave come to know that mind can influence structure.

While a definitive understanding has not been reached,two points are starting to be accepted (i) that mind andbrain are not the same, and (ii) that mind and brain areinseparable. However, full acceptance has not beenachieved by all members of the medical profession,much less the general public. How can understanding beadvanced?

We believe that this advancement cannot occur whilethe words brain and mind are still in use. A new wordcould be invented which could mean ‘all the thingswhich were once meant by the words brain and mind’.This word might be ‘kep’.

Under this arrangement students would be taught thatthe kep includes neurones, supportive tissue, thoughts,emotions, nuclei, etc., that it was previously called boththe brain and the mind, but that a new word had tobe invented so that they would avoid a conceptual culde sac.

References

1. Kendler KS. A psychiatric dialogue on the mind-body problem.


2001; 158:989–1000.

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Low rates of monitoring of mood stabilizing drugs for bipolar disorder in community psychiatric clinics

Geoffrey Schrader, Senior Lecturer; Rima Al Atrash-Najar, Research Assistant, Department of Psychiatry,Adelaide University, Adelaide, Australia; Rohan Dhillon,Consultant Psychiatrist; Tarun Bastiampillai, Psychi-atric Registrar North-West Adelaide Mental HealthService, Adelaide, Australia:

Therapeutic drug monitoring has been widely cited asa method to evaluate the adequacy and ensure the safetyof treatment with mood stabilizing drugs. However, anumber of reports have described less than adequatemonitoring of these drugs [1,2]. We set out to determinerates of monitoring of mood stabilizing drugs in patientswith bipolar disorder in two community mental healthclinics in metropolitan Adelaide and to determine whetherseverity of symptoms or presence of substance abuse,affected monitoring.

After obtaining informed consent, patients with bipolardisorder at the clinics were interviewed by a researchassistant to determine symptom severity using the BriefPsychiatric Rating Scale [3] (BPRS), substance abuseusing the substance abuse section of the CompositeInternational Diagnostic Interview [4] and how frequentlythey visited the clinic. After approximately six months,adherence to established guidelines for the monitoring ofmood stabilizing drugs was ascertained by checking casenotes and by reviewing records of tests ordered at thetwo laboratories servicing the clinics.

Seventy-seven patients with a diagnosis of bipolardisorder were interviewed for the study. During a 12-month period, of patients prescribed lithium, 62% had noserum levels performed, only 11% had a thyroid functiontest performed and 17% had a creatinine level performed.Of patients prescribed sodium valproate, 38% had noserum levels performed, only 27% had a complete bloodexamination, and 17% had liver function tests performed.Of patients taking carbamazepine, 87% had no serumlevels performed, only 38% had a complete blood exam-ination, and 63% had liver function tests performed.

More younger than older patients were monitored,although this did not reach significance (

χ

2

= 3.25,df = 1, p = 0.06). Mean BPRS scores (t = 0.09, df = 75,p = 0.9) did not differ significantly between those whohad some form of monitoring and those who had none.Frequency of visits to the clinic did not differ sig-nificantly between those who were and who were notmonitored (t = – 0.17, df = 75, p = 0.8). There was nosignificant difference in rates of monitoring betweenpatients who were or who were not dependent or abusingeither alcohol or cannabis (

χ

2

= 0.052, df = 1, p = 0.52).

We found even fewer patients received some sort ofmonitoring than previously reported in the US and UK.We similarly found that comorbid substance abuse ordependence and frequency of clinic visits, presumablymarkers of higher risk patients, were not associated withmore frequent monitoring. An examination of the practicestyle, routine and custom at the two clinics may providesome insight into the low rates of monitoring we dis-covered. Both clinics had taken on substantially greatercase loads following the closing of a mental hospital andthe opening of a new mainstreamed psychiatric unit at alocal general hospital some years prior to the study [5].Services were provided on a generic basis, in the main byregistrars rotating from the local hospital, with neitherclinic having a mood disorders clinic. There were nospecific case note forms to facilitate review of monitoringof drugs and neither clinic had access to computer soft-ware to aid monitoring. Interaction with local generalpractitioners was in the form of occasional written lettersand there was little use of case conferencing or shared careplans. A survey of local general practitioners’ understand-ing of the need for monitoring of mood stabilizing drugs[6] indicated that a substantial number were unaware as towhether they or the mental health team should monitoringpatients’ levels. In view of these findings, the clinics areconsidering the establishment of a mood disorders’ clinic,the introduction of alerting software and greater use ofshared care arrangements with local general practitioners.

The study was supported by a grant from the QualityUse of Medicines Program, grant SG512.

References

1. Marcus SC, Olfson M, Pincus HA

et al.

Therapeutic drug monitoring of mood stabilizers in patients with bipolar disorder.


1999; 156:1014–1101.2. Eagles JM, McCann I, MacLeod TNM, Paterson N. Lithium

monitoring before and after the distribution of clinical practice guidelines.

Acta Psychiatrica Scandinavica

2000; 101:349–353.3. Overall JE, Gorham DR. The brief psychiatric rating scale.

Psychological Reports

1962; 10:799–812.4. World Health Organization.

Composite International Diagnostic Interview (CIDI).

Geneva: World Health Organization, 1996.5. Schrader GD. The impact of mental health reform on general

hospital psychiatry: unintended consequences.

Australasian Psychiatry

1998; 6:287–288.6. Schrader GD, Dhillon R, Bastiampillai T, Al Atrash-Najar R.

Monitoring of mood stabilising drugs for bipolar disorder in Australian general practice.

Australasian Psychiatry

2002; 10:265–267.

Cardiac risk of psychotropic drugs

David Ames, John Camm, Peter Cook, Peter Falkai,Charles Gury, Rod Hurley, Gordon Johnson, RobertPiepho and Victor Vieweg; members of the CardiacSafety in Schizophrenia Group:

Andrew Firestone’s recent letter to the journal [1]raises a number of points on which we, the members of

820 CORRESPONDENCE

the Cardiac Safety in Schizophrenia Group (CSISG),would like to comment.

The CSISG was formed to address issues associatedwith cardiac safety in schizophrenia, raise awarenessof cardiac issues related to drugs used to treat schizo-phrenia (with a specific focus on the currently topicalissue of clinically significant QTc prolongation), helppsychiatrists minimize potential cardiac risks associatedwith treating schizophrenia and to produce educationalmaterials on cardiac safety in schizophrenia. CardiacSafety in Schizophrenia Group is supported by anunrestricted educational grant from the Eli LillyCompany and is administered through the companyCohn & Wolfe Ltd. The nine members of CSISG listedabove represent an international cross section of psychi-atrists, cardiologists, pharmacists and pharmacologistsworking with patients who have schizophrenia. We haveprepared and published a consensus statement ‘Minimiz-ing the risks associated with significant QTc prolonga-tion in people with schizophrenia’ [2].

The publication by Eli Lilly Australia of a single tableextracted from the first edition of the Consensus State-ment [2] as an advertisement was unfortunate, occurredwithout prior knowledge of the members of CSISG,and did not meet with our approval. In our opinion theConsensus Statement [2] should be read as a whole andshould not be used in advertising. Shortly after theadvertisement appeared Cohn & Wolfe communicatedwith Eli Lilly and were assured that the ConsensusStatement [2] would not be used again in a promotionalor advertising context for Eli Lilly products.

We agree with Dr Firestone that precipitate regulatoryaction (as occurred when the Australian Drug EvaluationCommittee restricted the availability of thioridazine)may not always be in the best interests of all patients.This is one of the reasons why we agreed to produce aConsensus Statement [2] to try and give guidance in thisarea for practitioners around the world, because the regu-latory response to the emerging knowledge that certain

antipsychotic drugs can produce QTc prolongation hasvaried very widely in different jurisdictions.

Unfortunately, a simple annual electrocardiogram(ECG) examination as suggested by Dr Firestone, maymiss state dependent alterations in ECG traces and couldlull prescribers into a false sense of security with respectto drugs that have the potential to prolong QTc [2].

There is now an emerging body of evidence to indicatethat the potential dangers of thioridazine [2–4] mayindeed be excessive compared to those posed by otherantipsychotics. We agree with Dr Firestone that the posi-tioning of trifluoperazine within our table has the poten-tial to cause controversy, but we note that the report ofthe Royal College of Psychiatrists PsychopharmacologyWorking Group on the association between antipsychoticdrugs and sudden death (1997) [5] also listed triflu-operazine on page 16 of the report as a drug known toprolong the QT interval of the ECG. The associationbetween trifluoperazine use and ECG abnormality hasbeen documented since 1964 [6].

The Consensus Statement [2] makes reference to otherissues of cardiac safety in schizophrenia including smok-ing, weight gain, diet and hyperglycaemia, all of whichwarrant guidelines in their own right.

References

1. Firestone A. Cardiac risk of psychotropic drugs.

Australian and New Zealand Journal of Psychiatry

2002; 36:703–704.2. Cardiac Safety in Schizophrenia Group.

Minimising the risks associated with significant QTc prolongation in people with schizophrenia

. London: Cohn Wolfe, 2001.3. Reilly J, Thomas H, Ferner I. Recent studies on ECG changes,

antipsychotic use and sudden death in psychiatric patients.

Psychiatric Bulletin

2002; 26:110–112.4. Reilly J, Ayis S, Ferrier I, Jones S, Thomas S. Thioridazine and

sudden unexplained death in psychiatric inpatients.

British Journal of Psychiatry

2002; 180:515–522.5. Royal College of Psychiatrists.

The association between antipsychotic drug use and sudden death

. London: Royal College of Psychiatrists, 1997.

6. Ban TA, St-Jean A. The effects of phenothiazines on the ECG.

Canadian Medical Association Journal

1964; 91:537–540.

brain, mind and kep

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