Titus Mohan

Effects of stimulus intensity on the efficacy and safety of twice-weekly, bilateral electroconvulsive therapy (ECT) combined with antipsychotics in acute mania: a randomised controlled trial

OBJECTIVES To examine differences in speed of improvement and remission in people with mania undergoing bilateral, brief-pulse, twice-weekly electroconvulsive therapy (ECT) at stimulus intensities administered just above and 2.5 times their individually titrated seizure threshold. METHODS Consecutive, eligible subjects with mania, prescribed ECT, were randomised to receive treatments at stimulus doses either just above or 2.5 times their individually titrated seizure thresholds. Main outcomes were the speed of improvement and remission as measured by the Young Mania Rating Scale (YMRS) and the Clinical Global Impressions-Improvement scale (CGI-I) and cognitive side effects assessed by the Mini-Mental State Exam, the Wechsler Memory Scale, and a scale for autobiographical memory. RESULTS A total of 24/26 subjects (92.3%) given threshold ECT and 22/24 subjects (91.7%) given suprathreshold ECT were significantly improved [CGI = 2; odds ratio (OR) = 1.1, 95% confidence interval (CI): 0.1-8.4; p = 1.0] at the end of ECT. A total of 88% of the sample had remitted [YMRS < 10; threshold 23/26 (88.5%) versus suprathreshold 21/24 (87.5%)], with no significant differences between interventions (OR = 1.1, 95% CI: 0.2- 6.0; p = 1.0). The interventions did not differ significantly in the time or number of ECT treatments required for improvement or remission. Both interventions were equally safe. CONCLUSIONS Bilateral, twice-weekly ECT delivered at stimulus intensities just above individually titrated seizure threshold was as effective and safe as ECT administered at stimulus intensities 2.5 times seizure threshold in rapidly resolving the symptoms of acute mania.

Lessons from the 2004 Asian tsunami: Epidemiological and nosological debates in the diagnosis of post-traumatic stress disorder in non-Western post-disaster communities:

Background: The nosological validity of post-traumatic stress disorder (PTSD) remains controversial in non-Western communities. After natural disasters, epidemiological studies often overlook these conceptual debates and assess post-traumatic stress symptoms (PTSS) by short screening instruments. Such PTSS estimates are reported as inflated prevalence rates of PTSD in post-disaster settings. Aims: To discuss the prevalence and determinants of PTSS within the context of pertinent epidemiological and nosological debates. Methods: We assessed PTSS and grief symptoms of 643 survivors from five Indian villages struck by the Asian tsunami using the Impact of Events Scale – Revised and Complicated Grief Assessment Scale. We adopted a case control design and employed complex sample multiple logistic regression statistics to study the determinants of PTSS. Results: The prevalence of PTSS was 15.1% (95% CI 12.3%–17.9%). PTSS was significantly associated with traumatic grief, female gender, physical injury, death of children and financial losses, but not with functional disability (p = .91). Conclusions: Although PTSS were common in this population, elevating them to a psychiatric construct of PTSD is questionable, when functional impairment and avoidance behaviours were absent. Grief reactions, socio-economic burden, and poor support systems contribute towards PTSS. We highlight the important issues regarding the nosological validity and epidemiology of PTSD in non-Western communities.

Lessons from the 2004 Asian tsunami: Nature, prevalence and determinants of prolonged grief disorder among tsunami survivors in South Indian coastal villages

Background: Prolonged grief disorder (PGD), previously called complicated grief, is associated with significant distress and long-term disability, and it may complicate assessments for post-traumatic stress disorder (PTSD) after traumatic events. Methods: In order to distinguish PGD from PTSD, we conducted a cross-sectional survey among tsunami survivors in five tsunami-affected coastal villages in India, 9 months after the Asian tsunami. Results: Prevalence of PGD among 643 tsunami survivors was 14.2% (95% confidence interval (CI): 11.5%–16.9%) and among the 351 bereaved survivors was 25.9% (95% CI: 21.3%–30.5%). Spousal bereavement, extensive damage to homes, fewer years of education, and absence of tsunami-related physical injury differentiated those with PGD, after adjusting for potential confounders (p < .05). These factors were distinct from the factors associated with post-traumatic stress symptoms (PTSS) among these survivors. Scores on the avoidance, hyper-arousal and intrusion subscales of the Impact of Events Scale–Revised were significantly lower in those with PGD alone than in those with PTSS or with both disorders. Conclusion: Our findings support the validity of PGD in a non-Western post-disaster community and its distinctness from PTSD. They have important public health implications in planning responses to natural disasters and for future revisions of diagnostic classifications.

Managing clozapine discontinuation - acute and chronic maintenance strategies.

Clozapine is recommended for treatment resistant schizophrenia and its use has increased significantly in Australia over the last 10 years (Malalagama et al., 2011). However, clozapine non-adherence can limit its use and abrupt discontinuation has been documented to induce acute psychosis and rarely catatonia in certain patients, which is distinct from the underlying illness (Bastiampillai et al., 2009; Moncrieff, 2006). Traditionally, the term ‘supersensitivity psychosis’ refers to the phenomenon whereby chronic administration of dopamineblocking drugs increases sensitivity of dopamine receptors in the mesolimbic system and results in a withdrawal psychosis when dopamine receptor blockade ceases (Moncrieff, 2006). Clozapine, however, also has complex actions on other neurotransmitters including cholinergic, serotonergic, histaminergic, and alpha-adrenergic systems (Miller, 2009). Clozapine has particularly potent antimuscarinic effects and hence cholinergic rebound may contribute to the symptom profile when patient discontinue clozapine abruptly (Miller, 2009). We report the case of a 50-yearold man with a 25-year history of treatment-resistant schizophrenia. At the age of 39 he was commenced on clozapine 350 mg daily, which led to a marked improvement in mental state. However, he rapidly relapsed into severe psychotic episodes within 48 hours of non-adherence to clozapine. He had 10 such admissions during the 3-year period from 2006 to 2009 (mean 10.6 days, range 4–22 days). There were no admissions noted when he was compliant with clozapine. His relapses were characterised by florid delusions of a religious and grandiose nature, command auditory hallucination, and aggression. In September 2009 depot risperidone 37.5 mg was co-administered with the expectation that this strategy would protect against supersensitivity psychosis, due to dopaminergic hyperactivity. This combination was continued for 2 years. However, he experienced severe psychotic relapses within 48 hours of noncompliance to clozapine, resulting in three inpatient admissions (mean 15.3 days, range 12–21 days). His symptoms resolved with restitution of clozapine. While the period of non-compliance remained consistent across all admissions since 2006, we note that the length of hospital stay was markedly reduced when clozapine was recommenced at regular maintenance doses (six admissions, mean 7.6 days) rather than up-titrated from 12.5 mg (seven admissions, mean 15.1 days). In our patient, clozapine and depot risperidone co-administration proved ineffective in reducing the severity of symptoms and prolonging the time to relapse. This is consistent with the literature that clozapine withdrawal psychosis is not entirely due to the dopaminergic supersensitivity mechanism (Miller, 2009). Based on the observations on this case and literature review we suggest the following strategies to manage clozapine discontinuation both in the acute and maintenance phases. In the acute phase after clozapine discontinuation, clinicians should be aware of the potential for withdrawal psychosis and look specifically for signs of cholinergic rebound (agitation, headache, nausea and vomiting, insomnia, and diaphoresis). Clozapine levels should ideally be measured at the time of admission. Our case demonstrated that reinstating regular-dose clozapine promptly has the greatest impact on time to recovery. Hence if the patient has ceased clozapine within the last 48 hours, the regular dose should be resumed immediately. However, if a period greater than 48 hours has lapsed, clozapine should be resumed as 12.5–25 mg/day as per prescribing guidelines in order to prevent the risk of respiratory arrest and orthostatic hypotension (Novartis, 2010). If clozapine is titrated slowly, oral preparations with anticholinergic potency like chlorpromazine may better serve to control agitation and psychosis. Administrations of benztropine (4 mg) and atropine (1 mg) have been used in situations of cholinergic rebound (Dilsaver, 1983) and hence may also play a role in clozapine withdrawal. Patients and carers should be offered Letters

Clozapine-induced nephritis and monitoring implications.

Clozapine-induced interstitial nephritis has been increasingly recognised as a potential serious complication of clozapine therapy. A recent report (Kanofsky et al., 2011) has summarised eight cases of clozapine-induced acute interstitial nephritis (AIN). In all except one case onset of AIN occurred within 2 weeks of clozapine initiation. We report a delayed onset of AIN in a 53-year-old woman with chronic schizophrenia and discuss the clinical implications with regards to monitoring renal function. Ms W had a 19-year history of schizophrenia characterised by treatment-resistant positive symptoms. Clozapine was started in May 2012, during an admission to hospital for an acute on chronic relapse of psychosis. Relevant baseline investigations were done as per protocol (Novartis, 2008) and were unremarkable. Ms W had commenced sodium valproate 3 weeks prior to starting clozapine. Within a fortnight, clozapine was ceased for 12 days after Ms W experienced fever, vague abdominal pain and diarrhoea. Urinalysis revealed proteinuria and she received trimethoprim for a possible Escherichia coli infection. Eosinophilia was first noted on day 6 since clozapine initiation and persisted for 2 months (mean 0.93 ×109/L). Ms W was recommenced on clozapine by slow titration when her abdominal symptoms subsided. The maximum clozapine dose achievable was 200 mg/day. After 60 days of recommencing clozapine Ms W was referred to the medical team owing to hypotension (90/70 mmHg), pyrexia (38.6oC), tachycardia (148 bpm), tremors and an unsteady gait. She was clinically suspected to have pneumonia but the chest X-ray was unremarkable. She was empirically treated with azithromycin 500 mg and ceftriaxone 1 g for 2 days. At the time of admission there was renal dysfunction, with creatinine 149 μmol/L (reference range 50–100 μmol/L) and urea 7.9 mmol/L (reference range 2.7–8 mmol/L). Septic screens were negative and autoimmune markers were inconclusive. The nephrology team suspected an acute kidney injury due to clozapine-induced AIN. Clozapine and sodium valproate were ceased. Renal function continued to worsen, with elevated creatinine and urea (rising to 252 μmol/L and 15 mmol/L, respectively, 23 days after presentation). Apart from brief episodes of diarrhoea Ms W did not report any major physical symptoms. She underwent a renal biopsy for a definitive diagnosis. Histology confirmed the clinical suspicion of AIN, with interstitial scarring noted to be developing in 50% of the cortical area. She was given prednisolone 25 mg daily with rapid taper to avoid further deterioration. Ms W’s renal parameters slowly improved after the course of steroids. Aripiprazole 15 mg was commenced to prevent an exacerbation of psychosis. She was eventually transferred to a psychiatric unit when her renal parameters were near baseline (creatinine 135 μmol/L, urea 5.9 mmol/L). Our patient developed AIN 90 days after clozapine was initiated. The diagnosis was confirmed by biopsy and other potential contributory factors were eliminated. The Naranjo scores were clozapine, 5; sodium valproate, 4; and azithromycin and ceftriaxone, 0; thus implicating clozapine as the probable cause for the AIN (Naranjo et al., 1981). Antibiotics administered with the presumption of infection could potentially worsen the course of AIN (Rossert, 2001). Clozapine-induced AIN raises important issues for clinicians and on the current clozapine monitoring protocol. In our case, and in other reported cases of AIN, the diagnosis was not readily considered owing to a lack of pathognomonic markers to warrant early intervention. Eosinophilia or fever may be sensitive early warning signs of AIN (Kanofsky et al., 2011), but may not be specific markers given that > 50% of patients develop eosinophilia or fever within 6 weeks of clozapine initiation (Roge et al., 2012). Recent literature suggests clozapine’s immunomodulatory effects play a role in clinically significant adverse effects such as benign hyperthermia, myocarditis, agranulocytosis, and eosinophilia (Roge et al., 2012). AIN possibly falls under this umbrella of immune-mediated effects, but has received less attention in psychiatric literature. Existing protocols (Novartis, 2008) do not include monitoring for the possibility of AIN. In the absence of specific symptoms or signs that would raise clinical suspicion of AIN, and with the emerging literature that this adverse effect is not uncommon, we propose that renal parameters are incorporated into existing clozapine monitoring protocols for up to 6 months given the possibility of delayed AIN.

Panhypopituitarism and psychosis in a male patient.

Jacob Alexander , Queen Elizabeth Hospital – Psychiatry, Adelaide, South Australia, Australia, Peak Mann Mah, Lyell McEwin Hospital Endocrinology, Division of Medicine, Elizabeth Vale, South Australia, Australia, Narsing Laddipeerla, Queen Elizabeth Hospital, Endocrinology, Adelaide, South Australia, Australia, Titus Mohan The Queen Elizabeth Hospital, Cramond Clinic, Adelaide, South Australia, Australia :

Lithium-associated silent thyroiditis: clinical implications.

Australian & New Zealand Journal of Psychiatry, 47(10) Beck Depression Inventory scores even after the first intravenous dose of infliximab itself. A significant decline in high-sensitivity C-reactive protein is seen in depressed patients who responded to intravenous therapy with infliximab. Similarly, patients with Crohn’s disease who are administered infliximab show significant improvements in the social as well as the emotional dimensions of the Inflammatory Bowel Disease Questionnaire. Infliximab also improves symptoms in patients with anxiety. For instance, Ertenli et al. (2012) in a recent study have reported a significant reduction in the Hospital Anxiety and Depres sion Scale anxiety scores following infliximab infusions. A simultaneous improve ment in quality of life is seen. Similarly, infliximab infusions significantly improve fatigue especially in cancer patients. Patients with bipolar disorder typically demonstrate higher TNF-alpha levels. Hence, TNF-alpha antagonism may have a significant affect in ameliorating the symptoms of bipolar disorder. These results have been corroborated in recent case reports by Bassukas et al. (2008). Similarly, elevated TNF-alpha and reduced interleukin 4 levels are seen in schizophrenic patients during psychotic exacerbations. Infliximab may very well play a major role on attenuating TNF-alpha levels and resolving these exacerbations. In fact, Reimer et al. (2009) have reported a patient with Crohn’s disease and coexisting psychosis. They have reported the successful treatment of the psychotic manifestations in this patient with infliximab. As is clear from the above, there is good evidence that infliximab is of benefit in psychiatric illness associated with inflammation. There is a plausible theoretical basis for its clinical application in other psychiatric illnesses, given the demonstration of increased inflammatory markers in these populations. The above examples clearly illustrate the important role that infliximab may have to play in the management of psychiatric disorders. Funding

Are we mindful of psychosis

We intend to offer the readership a general understanding of the neuropsychological processes involved in contemporary approaches such as Mindfulness-Based Cognitive Behaviour Therapy (MBCT) and MindfulnessBased Stress Reduction (MBSR) by using the subject–object paradigm. We conducted a literature review using Medline, with search terms ‘attention’, ‘mindfulness’, and ‘meditation’ in October 2011, which yielded 591 results. We focused on articles discussing the neuroscience of meditative states and, in particular, the effectiveness of meditation-based approaches in people suffering from psychosis. We came across an informative article by Allen et al. (2006) that provides an overview of mindfulness-based therapies and practical considerations when applied in clinical situations. Mindfulness has been described as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally” (Kabat-Zinn, 1994). When a person is mindful they have an expanded awareness of internal (originating from the self) and external (arising from the environment) events, and accept them as they are, without attempting automatically to alter associated thoughts and behaviours. Mindfulness-based therapies therefore differ from traditional cognitive-behavioural approaches in that there is no attempt to dispute dysfunctional cognitions, but to accept them non-judgmentally (Allen et al., 2006). When a person meditates, there are experiences of general well-being, enhanced attention and positive effect. Neuroimaging and electrophysiological testing correlate these findings with increased cortical activation, specifically in the anterior cingulate and prefrontal cortex. These functional cortical changes are evident even after short periods of meditative therapy (Rubia, 2009). Mindfulnessbased cognitive therapies are effective in improving attentional focus and quality of life in patients with clinical depression, anxiety, eating disorders and chronic pain syndromes (Allen et al., 2006). We observe that the clinical benefits in the above conditions are due to a common denominator; a metacognitive consciousness cultivated through meditative practice. Raffone and Srinivasan (2009) suggest that this metacognitive consciousness encompasses any form of awareness based on the subject–object cognitive duality. That is, when a person (the subject) attends to an internal or external ‘object’ (for example, a bodily sensation or a flower), there is a subjective phenomenal experience (cognition) of that object based on past experiences and ingrained patterns of thinking. A metacognition would go beyond the cognitive subject–object duality, as the ‘awareness of being aware’. Clinically, if the subject is the depressed person and the object is a self-critical thought then the phenomenal experience of such a thought would be a depressive cognition. Rather than challenging this cognition, a metacognitive awareness cultivated through mindfulness would allow a non-judgmental appraisal of the present moment without succumbing to repetitive detrimental patterns of cognitions that worsen the depressed state. In practice we see patients (the subject) who suffer psychotic phenomena like auditory hallucinations (the object), often find these symptoms to be greatly distressing. If they are trained to have a non-judgmental awareness of the phenomena, the automatic catastrophic emotional res ponses to derogatory hallucinations can then be modified. This has been substantiated in recent studies of mindfulness in patients with psychosis when used in controlled, clinical settings (Chadwick et al., 2009; Jacobsen et al., 2011). Whilst these preliminary studies have highlighted the effectiveness of mindfulness-based approaches in psychosis, there are some hypothesized challenges and risks. Pinto (2007) suggests that patients require a sufficient level of insight into their condition, and adequate trust of the therapist before such treatments could be considered. The greatest barrier, however, may be the skeptical attitudes of mental health professionals in regard to alternative therapies potentially Commentaries

The role of Transcranial Magnetic Stimulation in treatment resistant depression

Electro-Convulsive Therapy (ECT) is an effective intervention for treatment resistant depression (TRD) (Pagnin et al., 2004). However, therapeutic alternatives are limited if ECT is deemed medically unsafe. Repetitive Transcranial Magnetic Stimulation (rTMS) has gained evidence (Slotema et al., 2010) in the management of depression. We describe a complex scenario in which we used rTMS to manage TRD. Mr T is a 56-year-old man who presented with depression, nihilistic delusions, and progressive deterioration in functioning over two years. Over three prolonged admissions in a 13-month period his symptoms were refractory to pharmacological trials of citalopram, sertraline, venlafaxine, aripiprazole, and risperidone. Comprehensive screening revealed no organic aetiology and neuropsychological assessment revealed mild impairment in attention related tasks. MRI-Brain revealed an incidental right cortical telangiectasia. Mr T’s presentation was formulated as TRD and five sessions of brief pulse-width (1ms) bifrontal ECT were performed. Mr T showed a marked improvement following ECT but developed lower limb deep vein thrombosis necessitating anticoagulation. Anticoagulation and cerebral telangiectasia in combination potentially increased the risk of intracerebral haemorrhage with ECT, and therefore ECT was ceased. Given inadequate response to medication trials we administered adjunctive low frequency rTMS (1Hz) to the right dorsolateral prefrontal cortex thrice weekly for six weeks. Mr T’s mental state improved partially with emerging reactivity of affect and improvements in self-care. His Hamilton depression scale score improved from 13 to 5 points, Hamilton anxiety scale score improved from 17 to 7 points and MADRS improved from 24 to 16 points. However, Mr T’s symptoms recurred objectively and subjectively within a fortnight of ceasing rTMS. He required further ECT following the 6-month course of anticoagulation and this resulted in complete remission of his depression. Mr T had partial remission on combination rTMS (with antidepressants) when compared to antidepressants alone. While literature suggests that ECT is superior to rTMS in severe depression, the effect size for rTMS (0.55) in depression is higher when compared to antidepressants (0.17 to 0.46) (Slotema et al., 2010). Moreover combining rTMS with antidepressants has been shown to accelerate the antidepressant response (Huang et al., 2012). Our case while confirming the effectiveness of ECT, also demonstrates that combination rTMS is superior to antidepressant monotherapy, particularly when ECT is medically contraindicated. Hence rTMS is a potentially valuable intervention to be considered earlier in TRD, rather than sequential extended medication trials.

Movement Disorder as Prodrome of Schizophrenia

Movement disorders are well recognized as a potential complication of antipsychotic therapy but less well known is its reported presence in antipsychotic na ï ve psychotic patients without organicity in the prodromal period [1]. Studies in the literature on movement disorders found its prevalence to be 23% in psychotic patients, versus 7% in the non-psychotic population [2]. The conceptualization of schizophrenia as a disorder of cortico-basal ganglia-thalamo-cortical/cerebellar network disconnectivity suggests that the basal ganglia may play a role in its pathogenesis, with mesolimbic dopaminergic hyperactivity as the cause of positive psychotic symptoms [2]. It has been hypothesized that there may be a primary or an adaptive striatal dopaminergic hypoactivity, resulting in negative symptoms and movement disorders [3]. We report a 38-year-old man who developed a movement disorder three months before the onset of positive psychotic symptoms. The movement disorder occurred on the background of a 2-year history of apathy, social withdrawal and functional decline as part of a prodrome. Three weeks before his fi rst psychiatric admission, he experienced visual and auditory hallucinations with accompanying hostility. There was also a noted worsening of his movement disorder with the onset of psychosis. This patient ’ s movement disorder consisted of spontaneous, involuntary movements of the left upper limb and left facial muscles. They were the result of non-sustained muscular contractions, each lasting less than 3 s and worsened by stress. The limb movements were purposeless, jerky but not choreiform. Facial movements resembled grimacing. There were no tremors or fasciculation. Neurological with cranial nerve examinations were normal. The patient has no relevant past medical and psychiatric history. There was no history of substance use. His maternal grandfather was diagnosed with Parkinson ’ s disease. Organic causes of his movement disorder were investigated and excluded. These included Huntington ’ s disease, tic disorders, epilepsy, Wilson ’ s disease, haemochromatosis, autoimmune diseases, vitamin defi ciencies, heavy metal poisoning and infections. After a neurological review, baclofen was empirically trialled for his movement disorder without benefi t. The patient fulfi lled the DSM-IV criteria for schizophrenia, and hence olanzapine was prescribed. There was no response after 1 month and his medication was changed to risperidone 6 mg/day. His psychosis improved and his involuntary movements decreased in frequency. He was discharged after a 2-month admission. He remained on risperidone for 4 months post discharge. Due to the persistence of both psychotic symptoms and his movement disorder, risperidone was ceased and quetiapine commenced. His psychotic symptoms worsened on quetiapine and his movement disorder was unchanged. Risperidone was reinstated in the interim with an elective admission planned in the future to initiate clozapine. On assessment 6 months after discharge, the patient still showed moderate psychiatric illness (Brief Psychiatric Rating Scale: 44). His movement disorder was rated using the Simpson-Angus Scale (score: 3), Abnormal Involuntary Movement Scale (score: 3) and Barnes Akathisia Rating Scale (score: 3). Clozapine was considered in the setting of treatment resistance, negative symptoms and the persistence of his movement disorder [4]. This case highlights how the presence of a movement disorder can be part of a psychotic prodrome and that its persistence with negative symptoms can predict a poorer prognosis and a greater likelihood of treatment resistance [5]. The presence of a movement disorder without organicity in schizophrenia can be an integral part of the illness process, and its poorer prognosis suggests that clinicians should consider clozapine early rather than later [1,5].