Rohan Dhillon

Psychopathology in twins: ancient case study.

In a letter to this journal Pridmore provided an account of the Aboriginal myth ‘The Jealous Twins’ Perindi and Harrimiah, which Pridmore suggests is likely to be 5000 years old, followed by his psychiatric diagnostic speculations about the figures of the myth [1]. Pridmore treats the myth as an historical account, and the characters involved as if they were real people, to whom psychiatric diagnoses may be applied, as for example, ‘the information that is provided on symptoms is presented in ordinary, clear language rather than technical terms’, and ‘Perindi may have suffered a paranoid psychosis and Harrimiah a major depressive disorder’. When we consider the myth of Icarus and Daedalus we are unlikely to conclude that this father and son really fashioned wings with wax and feathers and really flew with them, or that the sun really did melt the wax of Icarus’ wings so that he fell to his death. We understand that the myth is a story of the imagination, a communication that represents something emotionally and culturally real, but not an account of real events or real people. Possibly it was not Pridmore’s explicit intention to convey the impression that Perindi and Harrimiah were real people, but if not then we are left with the conclusion that he has failed to grasp that psychiatric diagnosis is not applicable to the figures of myth. If one adopts the epistemological framework of psychiatric diagnosis, its potential validity must remain limited to real human beings; it cannot be logically or validly applied outside of this frame. It makes sense to suggest that the myth of Icarus and Daedalus deals with hubris, pride, and grandiosity, but it makes no sense to attribute a diagnosis of, say, narcissistic personality disorder to Icarus. Similarly it makes sense to consider, as Pridmore does, that the figures of Perindi and Harrimiah reflect elements of a split situation, and as reflecting psychotic and depressive aspects of the mind respectively, but this cannot be taken to support his conclusion ‘Perindi may have suffered from a paranoid psychosis and Harrimiah a major depressive disorder’. It would have made sense to consider the myth as an exploration of the nature of jealousy, as its name ‘The Jealous Twins’ suggests, but Pridmore makes no reference at all to this central theme. The second disturbing aspect of Pridmore’s analysis is the kind of psychiatric cultural imperialism that it conveys. I think it is unwise to simply superimpose a psychiatric perspective, which inevitably has significant cultural dimensions of its own, onto the imaginative creation of another culture. This is after all an Aboriginal myth, and in seeking to understand the meaning of this myth one might expect to begin by enquiring about the place of its origin, that is, in the Aboriginal culture and psyche. It is, of course, quite possible to argue that the scientific perspective has potential application that transcends cultural perspectives. Even if this possibility is allowed, however, Pridmore’s analysis remains invalid for the reasons outlined. It lies in the realm of pseudoscience rather than science. Pridmore suggests that his diagnostic conclusions may be ‘parsimonious and reasonable’; I would suggest they are parsimonious in every sense of the word, and quite unreasonable. Myths, like fairy tales and poetry, exist in what Winnicott has called the ‘transitional area’ of relating [2]. They are no one’s property and they defy reductionism.

Clozapine use in Australia

Clozapine is a well-recognized treatment for treatment-resistant schizophrenia. The Royal Australian New Zealand College of Psychiatrists (RAN ZCP) guidelines 1 and National Institute for Health and Clinical Excellence (NICE) guidelines 2 state that a trial of clozapine should be initiated in patients who do not respond adequately to trials of at least two different antipsychotics including one non-clozapine second generation antipsychotic. The guidelines have been supported by a number of studies, including the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) 3 and Cost Utility of The Latest Antipsychotic drugs in Schizophrenia Study (CUtLASS). 4

Exacerbation of tics secondary to clozapine therapy.

Pathological jealousy has been associated with conditions such as schizophrenia, delusional disorder, paranoid personality, bipolar disorder, alcohol use and head injury [1]. Irresistible and repetitive jealous thoughts, found in patients with obsessive compulsive disorder (OCD), has often been termed ‘obsessional jealousy’ [2 5], but the term is yet to find official recognition in literature. Available data on this subject have shown that obsessional jealousy is limited to marital or committed relationships [2 5]. We report obsessional jealousy arising in a young man, focused on his elder brother’s wife, which has not been reported until now. The patient was a 19-year-old, unmarried, Muslim man who was brought to the clinic at G. B. Pant Hospital by his family members because he would not let his sister-in-law go out of the house and had threatened to kill her if she did not comply with his demands. The patient lived in a joint family household, as is customary in Indian society. Soon after the marriage of his elder brother, 5 years prior to consultation, the patient started touching his sisterin-law casually, to which she had no objection initially. Two years prior to consultation he saw her dancing with another man and reprimanded her. Since that time he did not allow her to talk to any man and followed her around when she went out. He would frequently make comments to her for wearing provocative clothes. This persisted despite objection from the woman herself as well as from other family members. The patient confessed that he was ashamed of his behaviour at home but was unable to control himself. He said that he experienced unwanted and irresistible sexual thoughts towards women and feared that other men might be viewing his sister-in-law in the same way. He experienced excessive concerns regarding contamination, symmetry, bodily symptoms and harm coming to him. The patient was aware of the absurdity of these thoughts, despite which they persisted. There was no previous history of substance use or head injury. Earlier he had received imipramine for 6 weeks and escitalopram for 7 weeks, without any response. A diagnosis of OCD was made on the basis of clinical presentation. His baseline Yale Brown Obsessive Compulsive Scale score was 30, which decreased to 3 after 6 weeks on clomipramine 75 mg day . This case is atypical in the sense that the patient’s jealousy was focused on his sister-in-law, who was not his romantic or married partner. He did not oppose his brother’s relationship with her, while at the same time restricting her from interacting with other men. It can be argued that the patient had been brought up in an orthodox household but the patient’s views were not endorsed by the rest of the family. That the patient’s jealousy responded to clomipramine supports the view that it was obsessional in nature. This report highlights the point that obsessional jealousy can emerge in people not connected by a romantic or married relationship. It also emphasizes the importance of the person’s sociocultural and ethnic background in the development of psychopathology.

Clozapine and associated QTc prolongation

QTc prolongation in the setting of antipsychotic use is well documented in the literature and antipsychotics have been withdrawn from the market due to their association with QTc prolongation and fatal arrhythmias [1]. Normal QTc is approximately 400 ms with upper limits of 440 ms (men), and 470 ms (women). QTc of 500 ms across both genders is identifi ed as a risk marker for fatal ventricular arrhythmias including Torsade de Pointes (TdP) [1 – 2]. Genetic, medical and medication-related factors have been implicated in QTc prolongation [2]. We present a rare case of QTc prolongation with clozapine. In the literature, only three case studies document a link between clozapine and QTc prolongation in 2.8 million patient years across 27 years [3]. A 61 year old single woman with a 40 year history of schizoaffective disorder and treatment resistant positive symptoms (hallucinations and delusions) despite several antipsychotic trials. In 1994, she commenced clozapine therapy and remained stable on 400 mg/day combined with sodium valproate 1500 mg/day. QTc on clozapine monotherapy was not known as no ECG reports were available in her community fi les. Ms A presented to hospital in November 2010 with agitation and confusion. This was attributed to hyperglycaemic encephalopathy and a urinary tract infection. She had been diagnosed with type-II diabetes mellitus several years previously. An ECG found incidental fi ndings of an inferior segment elevation myocardial infarction (STEMI) and prolonged QTc of 519 ms. Clozapine, together with medical factors aforementioned, was implicated in her QTc prolongation. In consultation with cardiology and psychiatry teams, clozapine and sodium valproate were ceased, and substituted with olanzapine 10 mg. She did not improve and developed clozapine-withdrawal catatonia (a rarely reported side-effect [4]) accompanied by acute positive symptoms. On olanzapine her QTc fl uctuated between 460 – 505 ms and then aripiprazole was added along with commencement of ECT, achieving partial response (catatonic component). Olanzapine was later stopped and her QTc normalized on aripiprazole 30 mg, ranging 434 – 453 ms. Given only partial response to aripiprazole and ECT, clozapine was reconsidered due. At the time of re-challenge, she was medically stable. Clozapine rechallenge, together with aripiprazole 30 mg, resulted in a gradual, dose-dependent increase in QTc. Over 10 days on clozapine 175 mg (50 mg mane, 125 mg nocte), the QT interval reached 488 – 505 ms. Interestingly, a morning ECG on day 10 showed a 505 ms QTc which decreased to 436 ms later in the day. Clozapine was subsequently ceased because of QTc prolongation and aripiprazole 30 mg monotherapy was continued with QTc ranging between 446 – 470 ms. However, continued non-improvement in her symptoms warranted cessation of aripiprazole and a switch to olanzapine. During the change-over period to olanzapine, she was on no antipsychotic medication except lorazepam pro re nata. The one ECG done during this time recorded her lowest QTc at 407 ms, essentially our only baseline ECG. Ms A scored 8 on the Naranjo algorithm [5] which suggests clozapine is a probable cause for QTc prolongation. Clozapine ’ s ability to increase the QTc interval in a dosedependent fashion has previously been reported in the literature [3]. Antipsychotics are thought to prolong QTc through blocking the human ether-a-go-gogene (HERG), thus preventing K infl ux through IKr channels. The affi nity of various antipsychotics for HERG is responsible for their variability and incidence in causing QTc prolongation. Clozapine acts on HERG in vitro , which suggests it has the potential to prolong QTc [6]. However, clinically, the association of clozapine with prolonged QTc is uncommon [3]. Given the rarity of this association, other factors including genetic predisposition and medical comorbidities may have compounded Ms A ’ s risk. In conclusion, this case suggests that clozapine is an antipsychotic that could increase the QTc interval in a dose-dependent manner. This report also shows a positive association between olanzapine monotherapy and QTc prolongation. Aripiprazole, however, is not implicated. Further research is required to confi rm the effects of clozapine on the HERG gene, explore the impact of dual antipsychotic use on QTc prolongation, and assess the effect of medical comorbidities on QTc. The fi nding of QTc variability on ECGs done within a 24 hour period, on a stable clozapine dose, may also warrant further research to standardize measurements of QTc interval

Clozapine prescription patterns in Australia over the last 10 years

Clozapine is a clinically effective and well accepted therapy for patients with treatment-resistant schizophrenia. Both NICE guidelines and RANZCP guidelines recommend a trial of clozapine therapy if more conventional anti psychotic therapy is ineffective in the management of symptoms [1,2]. Our previous study was based on analysing the current use of clozapine in Australia (2009) and any interstate variations that were present [3]. The aim of this correspondence is to examine how the rates of clozapine use in Australia have changed over the last 10 years (2000 – 2009) and consider the possible reasons behind any variations. Through personal communication and access to the Hospira database we were able to ascertain the amount of clozapine that had been imported into Australia from 2000 – 2009 [Hospira, personal communication]. This allowed us to calculate the amount of clozapine being imported into Australia, per 1000 people over the age of 16 (Australian Bureau of Statistics) [4], per year (Table 1). As can be seen below, clozapine importation has signifi cantly increased over the last 10 years from 134 mg/1000 population in 2000 to 238 mg/1000 population in 2009. Since this data is comparing the amount of clozapine imported to the number of people in Australia (over age 16), an increase

The long-term effectiveness of clozapine and lamotrigine in a patient with treatment-resistant rapid-cycling bipolar disorder

The challenges in the management of treatment-resistant rapid-cycling bipolar disorder are multifaceted and represent a significant burden to the patient. There is a need for more exploration into the potential utility of various combination therapies in the setting of severe affective states. A 52-year-old woman with a history of severe treatment-resistant rapid-cycling bipolar affective disorder (BPAD) was hospitalized for the treatment of a severe mixed episode. The introduction of lamotrigine and clozapine in combination proved remarkably effective and well tolerated in both the acute management and in subsequent maintenance. The patient has remained asymptomatic during the 5-year follow-up without any further mood disturbance. Lamotrigine and clozapine are among the less-prescribed agents for BPAD and there is as yet little research into their use in combination. It is possible that these agents have complementary modes of action on various facets of the affective pathology, resulting in superior mood stabilization in this patient.

Impact of a psychiatric unit’s daily discharge rates on emergency department flow:

Objective: To investigate relationships between time spent in the emergency department (ED) in patients requiring admission to the psychiatric ward, the day of the week of presentation and the daily number of discharges from the psychiatric ward. Method: Retrospective analysis of patient flow as a function of day of week, time of day (a.m., p.m.), number of patients requiring admission and number of ward discharges over a one-year period, for all mental health related presentations to the ED of the Queen Elizabeth Hospital in Adelaide, South Australia, before their admission to the psychiatric inpatient facility. Results: The time spent by patients in the ED waiting for admission to the psychiatric ward was significantly greater on weekends. There were significantly fewer discharges from the psychiatric ward during weekends compared with weekdays. The average time spent by patients in the ED requiring admission to the psychiatric ward for those days when there were vacant beds was 17.9 hours (SD=14.5). More people presented to the ED with a psychiatric diagnosis in the afternoons. There was a significant inverse correlation between the time spent by patients in the ED requiring admission to the psychiatric ward per day and the number of discharges from the psychiatric ward per day. Conclusion: These findings demonstrate that patient flow is significantly slower on weekends because of fewer discharges from the ward, leading to longer times spent in the ED before ward transfer. Waiting times in the ED were very substantially greater than the proposed 4-hour target even when vacant beds were available, raising considerable doubt about that target being realistic for psychiatric patients.

Could modafinil be a drug of dependence

Modafinil is a novel, nonamphetaminebased wake promoting medication approved for narcolepsy and obstructive sleep apnoea. Owing to its activating and cognitive enhancing effects, there is an expanding list of off-label use, including the treatment of methamphetamine and cocaine withdrawal. Although modafinil was previously thought to be nonaddictive (Jasinski, 2000),we present a possible case of modafinil dependence. Mr A is a 23-year old man prescribed modafinil 200 mg for 6 weeks as an adjunctive treatment for daytime hypersomnolence and fatigue following methamphetamine withdrawal. The patient was admitted 6 months later with a methamphetamineinduced psychosis. It was discovered Mr A had also been abusing modafinil at a self-increased dose of 400 mg daily. His psychosis resolved and modafinil was to be ceased owing to lack of evidence in the long-term treatment of methamphetamine withdrawal. Mr A became extremely agitated regarding the planned cessation. He stated that since commencing modafinil, his chronic methamphetamine use had decreased significantly from daily to episodic use. He spoke positively about modafinil helping him concentrate, feeling energised and becoming more productive. Mr A’s accounts were contrary to the history provided by his parents, who attributed his daily modafinil use as the cause for his recent difficulties in social and occupational functioning. Following protracted discussions, Mr A reluctantly agreed to cease modafinil and did not experience any withdrawal symptoms. In our opinion, Mr A satisfied the DSM 5 criteria for substance abuse disorder as highlighted by his psychological craving, unwillingness to cease use, social and occupational impairment, risky use, self-initiated increase in dose and continued attempts to source modafinil. Our literature search identified only one report of modafinil dependence in a patient with schizophrenia taking supratherapeutic doses of 2000 mg daily for 12 months (Kate et al., 2012). At a neurobiological level Volkow et al. (2009) demonstrated that modafinil exhibited a dose-dependent inhibition of dopamine transporters. This action reduces reuptake of dopamine and increases synaptic dopamine concentrations, particularly within the nucleus accumbens, an essential component in the biological pathway of addiction. This case highlights the potential of modafinil to be a drug of dependence. On this basis, clinicians should adopt a cautious approach when prescribing modafinil, especially in patients with a known history of substance abuse problems. Further clinical and basic science research is warranted focusing on its potential for abuse and dependence.

Transgender late onset psychosis: the role of sex hormones

Gender identity disorder (GID) affects around 1 in 11 900 males and 1 in 30 400 females [1]. An increasing number seek hormone therapy with or without gender reassignment surgery. With increasing evidence emerging in the literature of the role of oestrogen as a psychoprotective agent [2], the potential psychiatric adverse effects of hormone manipulation with, or without gender reassignment surgery has not been well studied, or reported in the literature. We report a case of a 48 year old transgender female to male who was diagnosed with GID 12 years previously. Since the age of 38, he has received exogenous testosterone 250 mg IMI three-weekly. He underwent a bilateral mastectomy at age 45 without a hysterectomy or bilateral salpingo-oophrectomy. Prior to his initial presentation to hospital with a schizophreniform psychosis at age 47, he was generally stable. Organic factors to explain the psychosis were excluded and there was no noted genetic predisposition. The patient ’ s psychosis progressed to a treatment resistant state after several antipsychotic trials within a short time frame of several months after the initial diagnosis. His psychosis is in partial remission on 30 mg of olanzapine. It is thought that oestrogen has a protective effect against the onset of schizophrenia based on epidemiological and clinical studies. The epidemiological evidence shows that young women are less likely to develop schizophrenia than men at an early age. Women are more likely to develop late onset schizophrenia after menopause due to diminishing oestrogen concentrations. Clinical studies have also demonstrated higher rates of psychotic symptoms in peri-menopausal women [2,3]. This psycho-protective effect of oestrogen is hypothesized to be due to its ability to reduce dopamine levels, receptor quantity and receptor sensitivity in the striatum [4]. There are no reports in the literature of exogenous testosterone causing psychosis. In the case of our patient, the psychosis emerged in later life, age 47 around the time of onset of peri-menopausal symptoms (irregular menstruation). Therefore, based on a review of the literature we hypothesize that diminishing oestrogen levels in the patient and not the effects of exogenous testosterone was a signifi cant aetiological factor in the onset of his psychosis. Several clinical trials have shown the antipsychotic benefi t of oestrogen therapy in addition to antipsychotic medications in psychotic female patients with physiolo gically low oestrogen levels [4,5]. Using oestrogen in such cases can lead to lower required doses of antipsychotics [3,4]. Our patient declined an empirical trial of oestrogen because of its potential feminizing effects. In a transgender female to male, the consideration of adding oestrogen with potential feminizing effects raised ethical questions. The option of reducing testosterone had limited antipsychotic evidence and potential negative psychological effects for the patient. This case could also be approached as a generic treatment-resistant psychosis where clozapine was indicated. This case of late onset treatment resistant psychosis with the potential clinical and psychological considerations highlights the ethical and management challenges potentially facing clinicians working in the transgender area.

'I saw the words right from your mouth': An unusual case of synaesthesia.

Australian & New Zealand Journal of Psychiatry, 48(2) infarction in November 2010. Hence, we decided to rechallenge Ms A on clozapine in closely monitored settings with adjusted serial ECG readings. Ms A had an anti-psychotic-free period and behavioural disturbances were treated solely with benzodiazepines. Her baseline QTc interval was demonstrated to be consistently in the normal range of 400–420 ms. The cardiology team cleared her for clozapine rechallenge. We performed twiceweekly morning ECG readings, weekly clozapine levels and daily physical observations in addition to the requirements stipulated by the local clozapine protocol (Novartis, 2008). At doses of 200 mg daily, Ms A’s highest clozapine level attained was 189. Her physical observations and laboratory investigations were unremarkable. Apart from one isolated borderline reading of 483 ms, the remaining QTc readings were less than 470 ms after correction with the Fridericia formula. The mean QTc value was 428 ms over 13 readings. There was no linear relationship between plasma clozapine levels and QTc prolongation. The isolated borderline QTc occurred at a dose of 175 mg daily that normalised even when the dose was further increased. Receiving 200 mg of clozapine daily, Ms A showed considerable improvement in her mental state. She returned to her previous residence and has been receiving regular community management. This case demonstrates a successful rechallenge of clozapine if QTc values are scrutinised within an appropriate theoretical framework. We encourage clinicians to revisit cases where clozapine may have been discontinued due to QTc prolongation. Given that clozapine may be the only choice in the setting of treatment-resistant schizophrenia, issues pertaining to QTc prolongation should promote further rigorous inquiry using the principles outlined by Nielsen rather than immediate cessation of clozapine.