Jacob Alexander

Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine

Objective To compare the effect of intramuscular olanzapine with intramuscular haloperidol plus promethazine on rapid tranquillisation of agitated or violent people with mental illness. Design Pragmatic, allocation concealed, randomised controlled trial. Setting Emergency services of a general hospital psychiatry department in Vellore, south India. Participants 300 adults with agitated or violent behaviour as a result of mental illness; 150 randomised to intramuscular olanzapine and 150 randomised to intramuscular haloperidol plus promethazine. Interventions Open treatment with intramuscular olanzapine or intramuscular haloperidol plus promethazine. Main outcome measures Primary outcome was proportion of patients who were tranquil or asleep at 15 minutes and 240 minutes. Secondary outcomes were proportion of patients who were tranquil, asleep, restrained, absconding, or clinically improved at 15, 30, 60, 120, and 240 minutes; additional medical interventions and adverse effects over four hours; and compliance with oral drugs and adverse effects over two weeks. Results Of 300 people randomised to receive either intramuscular olanzapine or intramuscular haloperidol plus promethazine, follow-up data were available for primary outcomes for 298 (99%). Both treatments resulted in similar proportions of people being tranquil or asleep at 15 minutes (olanzapine 131/150 (87%), haloperidol plus promethazine 136/150 (91%); relative risk 0.96, 95% confidence interval 0.34 to 1.47) and 240 minutes (olanzapine 144/150 (96%), haloperidol plus promethazine 145/150 (97%); relative risk 0.99, 0.95 to 1.03). However, more people given olanzapine than those given haloperidol plus promethazine required additional drugs over four hours (65/150 (43%) v 31/150 (21%); relative risk 2.07, 1.43 to 2.97). Adverse effects were uncommon with both treatments. Conclusions Intramuscular olanzapine and intramuscular haloperidol plus promethazine were effective at rapidly tranquillising or sedating agitated or violent patients with mental illness but the combination resulted in fewer additional medical interventions within four hours of intervention. Trial registration Clinical trials NCT00455234.

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.

Recreational use of naturally occurring dimethyltryptamine – contributing to psychosis?:

Australian & New Zealand Journal of Psychiatry, 47(4) diazepam and rapidly settled within 3 days. As the patient settled she reported the following longstanding complaints, which pre-dated her psychosis: ongoing severe arthritic pains in her hands, auditory hyperacusis, poor concentration, longstanding irritability and emotional lability, and profound fatigue with episodic sleep disturbances. Following peer review discussion, she was tested for Lyme disease, amongst other laboratory tests, with the following results: B. burgdorferi IgG titre = 80 and IgM titre = 10, indicating past Lyme disease. It is always a caveat of case reports that causal associations cannot be confirmed. Nevertheless, this report highlights the need to consider Lyme disease, in Australia, when reviewing the diagnosis of a patient presenting with longstanding complex neuropsychiatric symptoms, where people are from a rural background, especially where there is exposure to livestock (Mayne, 2011).

Venlafaxine-Induced Delirium

The serotonin and norepinephrine re-uptake inhibitor (SNRI) venlafaxine is one of the most commonly used antidepressant medications in Australia, with 2.8 million PBS/RPBS scripts for this medication in 2008 [1]. It is a potent inhibitor of serotonin reuptake, a weak inhibitor of dopamine reuptake, and at higher doses ( 150 mg/day) it is also a potent inhibitor of norepinephrine reuptake [2] by pre-synaptic neurons. Venlafaxine has been linked to delirium in the context of serotonin syndrome. In addition, venlafaxine may induce hyponatraemia, which can also cause delirium. Venlafaxine-induced hyponatraemia develops secondary to inappropriately high release or non-suppression of anti-diuretic hormone (ADH) [3]. Venlafaxine-induced delirium in the absence of either serotonin syndrome or hyponatraemia appears to be rare. A literature review by the authors produced only two previously documented cases of delirium under these circumstances [4,5] (the latter in the context of a drug interaction). We report a third case of venlafaxine-induced delirium in the absence of serotonergic syndrome or hyponatraemia. A 53-year-old male patient, suffering from a depressive illness reported a 24 h period of confusion, disorientation, agitation and partial recollection of events soon after his dose of venlafaxine was increased from 150 mg/day to 225 mg/day. The onset of symptoms was acute and satisfi ed criteria for a DSM-IV diagnosis of delirium [6]. The delirium resolved with the reduction of medication dose to 150 mg of venlafaxine a day. He was subsequently put on escitalopram 20 mg a day without event. The patient was concomitantly on esomeprazole for the management of gastritis. He had used this for many years without event. A thorough physical examination and laboratory investigations were unremarkable. Laboratory tests included complete blood examination, electrolytes, urea/ creatinine, troponin T, C-reactive protein, and a CT head scan. Serum venlafaxine levels were not undertaken. Esomeprazole and other proton pump inhibitors have been implicated in the causation of delirium [7]. However, the patient had been on this drug for years without event and he continued to be on this medication post-discharge without a recurrence of delirium, suggesting that esomeprazole was unlikely to have been the cause of delirium. Venlafaxine is known to undergo extensive fi rst-pass hepatic metabolism, being converted by the CYP2D6 enzyme to its active metabolite, desvenlafaxine ( O -desmethylvenlafaxine), via demethylation. This patient may have had an impaired ability to metabolize venlafaxine due to a past diagnosis of non-alcoholic steatohepatitis (NASH). However, his current liver function tests were normal, with no suggestion of impaired hepatic function. An increase in the dose of venlafaxine with enhanced effects of serotonin and norepinephrine reuptake appear to be the most likely culprits in the induction of delirium. The exact mechanism by which delirium is induced has not been clarifi ed, although an excess activation of the serotonin system and increased noradrenergic activity have both been implicated in the pathogenesis of delirium [8]. Given the popularity of venlafaxine use in outpatient situations, this uncommon but potentially life threatening adverse effect should receive more attention. In addition, clinicians need to be aware of potential drug interactions and physical conditions that may increase patient vulnerability to this side effect.

SSRIs as a Treatment Alternative for Monosymptomatic Delusional Disorders

Delusional halitosis has been well documented as a monosymptomatic delusional disorder [1,2]. Its treatment, however, has been less well documented. Given its classifi cation under the psychotic spectrum, it follows logically that the treatment should primarily involve antipsychotic medication and/or adjunctive cognitive behavioural therapy (CBT) [3]. The evidence currently appears to favour the typical agent pimozide [4,5] and the atypical antipsychotics olanzapine and risperidone [4–6]. There is sparse information on the role of selective serotonin re-uptake inhibitors (SSRIs) in the treatment of delusional halitosis. This case report describes a patient’s response to a combination of the SSRI sertraline and CBT. It explores possible explanations for why a delusional disorder may have responded to a non-antipsychotic intervention. The patient was a 29-year-old software engineer who presented with a 2 year history of delusional halitosis that satisfi ed DSM-IV-TR criteria for the diagnosis of a delusional disorder–somatic type. Distress emanating from this delusional belief had signifi cantly impacted on his lifestyle, occupational functioning and mood state. Treatment over a 2 year period with olanzapine, risperidone and CBT yielded partial results. Disabling side-effects with the atypical antipsychotics (weight gain with risperidone, sedation and weight gain with olanzapine) interfered with compliance. Distress was severe enough to lead to two suicide attempts. This led to his general practitioner prescribing sertraline (50 mg) as an antidepressant. Additionally, he had been prescribed benzodiazepines for short periods of time to control agitation. He reported little improvement with previous interventions at fi rst contact. The patient was taken off the olanzapine, the sertraline was titrated up to 200 mg po mane and a programme of CBT was initiated to work through his delusions 3 weeks after the increased SSRI dosage. He reported signifi cant resolution of these delusional beliefs over an 8 week period. This was refl ected in increased social interaction without accompanying distress that had

Aripiprazole induced tardive dyskinesia--accruing evidence.

Australian & New Zealand Journal of Psychiatry, 47(3) RS in our case. Vulnerability for druginduced EPS, the earlier onset of RS (i.e. 2 months), and the rapid improvement which occurred with the reduction in levosulpiride dosage (and the addition of benzhexol) implicates the role of a low-dose mechanistic blockade of dopamine receptors in the genesis of RS. A similar mechanism has been reported in the genesis of resting orolingual tremors with levosulpiride (Kim et al., 2009), but future neurophysiological research of the basal ganglia holds the key to better understanding and improved treatment of this syndrome. Funding

Nitrous oxide induced manic relapse

Nitrous oxide (N2O) is a widely used and readily available drug of abuse [1], as well as being commonly used as a dissociative anaesthetic in medicine and dentistry. The negative effects of chronic nitrous oxide inhalation, such as cognitive and neurological deficit secondary to disrupted vitamin B12 metabolism, are well documented [2,3]. Psychiatric manifestations of acute inhalation have not received as much attention. We describe a case of nitrous oxide precipitated mania with psychosis and discuss implications for psychiatric practice. A 31 year old teacher with a 10 year history of bipolar affective disorder (BPAD) presented with a fifth episode of mania with psychosis 10 days after the birth of her first child. She had been compliant with amisulpride that had replaced the mood stabilizer sodium valproate at conception. There was a family history of affective illness and a past history of substance abuse but she had been abstinent for several years. Pain relief prior to labour was discussed and N2O offered as an option. The patient had been aware of the abuse potential for N2O and discussed her reservations at length with her midwife who assured her of the safety of use. Four hours into the use of N2O the patient reported a heady rush, experiencing auditory hallucinations, a feeling of well-being and thought processes becoming abstract and philosophical. She and her partner were clearly able to temporally correlate the onset of the current relapse with the use of nitrous oxide. Her initial symptoms were predominantly those of increased energy and neurovegetative difficulties. She continued to experience auditory hallucinations from the time of N2O use to the time of admission. Her levels of agitation required a period of closed ward management and her symptoms responded to treatment with a combination of olanzapine and benzodiazepines. She was discharged on amisulpride alone and continues to maintain improvement at three month follow up. While many of these symptoms can be attributed to nitrous oxide intoxication [4], auditory hallucinations are a rare symptom and are better explained by the presence of a psychotic state or delirium. It could also be argued that perinatal stress and sleep pattern disruption could precipitate a manic episode in susceptible individuals; however, the close temporal correlation between the onset of N2O use and the onset of symptoms would suggest otherwise. The persistence of the perceptual abnormalities over a period of weeks after the use of N2O in the absence of altered sensorium would rule out intoxication or delirium. While the neuropathic effects of chronic N2O inhalation and consequent vitamin B12 deficiency have been established, the time course of this episode necessitates an alternative explanation. A recently proposed mechanism for N2O analgesia suggests that it stimulates the uptake of L-arginine at pre-synaptic nerve terminals where the nitric oxide synthase (NOS) enzyme converts it to nitric oxide (NO) [5]. Animal studies have demonstrated increased NOS activity throughout the brain after N2O exposure [5]. NO reacts with superoxide free radicals generating peroxynitrite (ONOO-), which in turn reacts with thiol groups in amino acids, interfering with normal protein function and making it highly neurotoxic. Researchers have measured NO activity in bipolar patients and found it to be elevated [6]. Anaesthetic use of nitrous oxide is widespread in both medicine and dentistry. In light of the current case it is our hypothesis that in the setting of affective illness N2O is capable of triggering a manic episode. With a plenitude of anaesthetic alternatives available it may be prudent to advocate the use of other agents that circumvent this risk in patients with a history of affective illness.

Phentermine (Duromine) precipitated psychosis

Jacob Alexander , Yi Han Cheng , Juthika Choudhary and Anthony Dinesh , Rural and Remote ward, Glen side Campus, Country Health SA, Eastwood, South Australia, Australia: The results of the 2007 – 2008 National Health Survey reveal that more than 61.4% of Australians are either overweight or obese [1]. This has led to a renewed focus on strategies to control body weight with signifi cant government investment in such ventures. Patients with psychiatric illnesses warranting antipsychotic medication appear doubly disadvantaged. A recent study showed that 78.8% of patients receiving such medication increased their body weight by 7% [2]. Obesity is a known harbinger of adverse health outcomes. People with severe mental illness die up to three decades earlier than the general population. A recent survey suggests that obesity-related problems cost Australia an estimated

Aripiprazole associated hyponatraemia

58.2 billion annually in direct and indirect costs [3]. While the mainstay of obesity treatment was centred on diet modifi cation and exercise, diet pills have gained popularity in recent years. The diet pill industry in Australia is estimated to be worth

Panhypopituitarism and psychosis in a male patient.

208 million per annum, out of which