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Background Some antipsychotic drugs elevate prolactin, and hyperprolactinaemia is associated with an increased risk of breast cancer. Women with schizophrenia have an increased incidence of breast cancer, but also multiple risk factors for the condition. Method This paper will critically review recent epidemiological studies concerning antipsychotics and breast cancer from a psychiatric perspective. Results Two recent epidemiological studies have found an association between use of prolactin-elevating antipsychotics and breast cancer in women with schizophrenia and other psychotic disorders. Prolactin-elevating drugs include paliperidone, risperidone, amisulpride and haloperidol, whilst prolactin-sparing antipsychotics included aripiprazole, brexpiprazole, cariprazine and quetiapine. In the two studies, estimated increased risks of breast cancer were disconcertingly high (up to 62%), but a third recent study found only a weak dose-response association. There are extensive methodological complications in this research, including the extent to which studies measure other risk factors for breast cancer and disagreement about the extent of prolactin elevation by some antipsychotics. Conclusion Although causation between prolactin elevating antipsychotics and breast cancer in women has not been demonstrated, recent epidemiological reports are worrying. For women on antipsychotics, informed consent should ideally include discussion of breast cancer concerns within the wider context of treatment benefits and risks.

Objective Cariprazine is the third partial dopamine agonist now available in Australia. This paper will review the properties, evidence and likely clinical place of cariprazine. Conclusion Cariprazine is a partial agonist with high affinity at dopamine D2 and D3 receptors, partial agonism at 5HT1a receptors, moderate 5HT2a and H1 antagonism and no anticholinergic activity. It is rapidly absorbed, is unaffected by food, achieves a peak plasma level in 4–8 hours and has high bioavailability. The half-life of cariprazine and its metabolites is long (7–8 days); steady state occurs in 4–8 weeks. It is hepatically metabolized via 3A4 cytochrome enzymes. Cariprazine is an effective antipsychotic in acute schizophrenia in both short and longer placebo-controlled studies. Cariprazine appears to have small advantages in negative symptoms of schizophrenia. While not approved for bipolar disorder, cariprazine is effective in mania and mixed states but requires doses higher than current maximums recommended. Cariprazine causes more akathisia than aripiprazole or brexpiprazole but is less prone to insomnia, weight gain and sedation. Risks for hyperprolactinaemia and QTc prolongation are low. Cariprazine is another ‘metabolically-friendly’ antipsychotic for schizophrenia, with advantages for those with negative symptoms, mood symptoms or problems with adherence.

Objective: The objective of this study was to perform a clinical and risk audit of private hospital inpatients who had been readmitted within 28 days of a preceding admission. Method: Of 118 readmissions within 28 days in 2017 (7% of all admissions), 50 were randomly selected for audit. Characteristics, illness severity and clinical risk profiles were ascertained at discharge from the index admission and at readmission. Results: Cases were 64% female, age 49.9 ± 18.2 years (range 19–89), 40% in relationships and 24% on disability support. At readmission, 88% posed danger to self due to effects of illness, 46% had high suicide risk and 40% had high physical risk. Illness was rated as severe in 58%, while 40% were rated markedly ill. Relapse or exacerbation of major depression was a cause of readmission in 78%, relapse of alcohol/substance use requiring readmission in 22% and relapse of psychosis in 20%. Index admission length of stay of cases did not differ from that of all hospital admissions. Conclusion: Most readmitted patients were suffering severe exacerbation of depression, were acutely suicidal and were otherwise at high risk of harm. If these patients had been denied readmission on the basis of insurer funding disincentives, catastrophic outcomes may well have occurred.

Objectives: To perform a clinical and risk audit of private hospital inpatients staying in hospital at least 21 days. Methods: Of 492 admissions for ≥21 days in 2016, 40 were randomly selected for audit. Characteristics, illness severity and course using the Clinical Global Impression severity (CGI-S) subscale and improvement (CGI-I) subscale, and clinical risk profiles were ascertained at admission, day 15 and discharge by two psychiatrists. Results: The cases were 65% female, age 50.0±16.2 years (range 24–86), 43% in relationships, and 28% on disability support. The length of stay was 29±7 days. On admission 88% were severely or markedly ill on the CGI-S subscale. Thirty-nine of 40 cases had ≥3 psychiatric diagnoses: 93% depression, 48% bipolar, 15% schizophrenia. High risk was present in suicide risk (48%), illness-induced dysfunction risk (78%) and physical risk (28%). By day 15, 63% were not improved or marginally worse. Suicide ratings were unimproved. By the time of discharge, illness severity and risk ratings were significantly reduced. Conclusion: Private hospital inpatients staying ≥21 days were predominantly female and had severe, diagnostically complex illnesses and high risk ratings. Most were still seriously unwell after 15 days. Patients improved significantly by the time of discharge (though were by no means recovered), indicating that the duration of hospitalisation was appropriate.

Objective: To compare inpatients who had been readmitted within 28 days of discharge with patients not readmitted within the same period in a private psychiatric hospital. Method: Of 118 readmissions within 28 days in 2017 (7% of admissions), 50 were randomly selected and matched by age and gender with control patients who had not been readmitted within 28 days. Differences in demographics, diagnosis, length of stay and number of admissions in the previous 12 months were examined. Results: Readmitted cases were 64% female, were aged 49.8 ± 18.2 years (range 19–89), 40% were in relationships and 24% were receiving disability support. Most patients were suffering an episode of depression. Cases had higher rates of multiple psychiatric diagnoses ( p < .001) and physical disorders ( p < .05). There were no significant differences between cases and controls on psychiatric diagnoses. Cases had a longer length of stay in their previous admission ( p < .01) and a higher number of admissions in the preceding 12 months ( p < .05) compared to controls. Conclusion: This study indicates that inpatients readmitted within 28 days of discharge were more likely to have multiple diagnoses, physical co-morbidity and relapsing conditions than patients who were not readmitted.

Aripiprazole, brexpiprazole and cariprazine differ from all other second-generation antipsychotics due to partial agonism at the dopamine D2 and D3 receptors. In contrast to aripiprazole, brexpiprazole has lower intrinsic dopamine D2 activity and higher affinity for the serotonin 5-HT1A and 5-HT2A receptors, while cariprazine has the highest affinity for the dopamine D3 receptor, and the longest half-life. The main adverse effect of dopamine receptor partial agonists (DRPAs) is akathisia of low-to-moderate severity, which occurs in a small proportion of patients, usually in the first few weeks of treatment. While definitive conclusions concerning differences between the DRPAs require head-to-head comparison studies, on the available evidence, akathisia is probably least likely to occur with brexpiprazole and most likely with cariprazine; the risk of akathisia with aripiprazole lies in between. Weight-gain risk is low with aripiprazole and cariprazine, but moderate with brexpiprazole. Risk of sedation is low with DRPAs, as is risk of insomnia and nausea. Partial dopamine agonism leads to a low risk for hyperprolactinaemia (and probably a low risk of sexual dysfunction). Prolactin concentrations fall in some patients (particularly those with elevated levels prior to initiating the drugs). Rates of discontinuation due to adverse effects in pivotal studies were low, and on the whole, DRPAs are well tolerated. Aripiprazole has been implicated in pathological gambling and other impulse control behaviours, likely due to partial dopamine agonist activity (there have been no reports with brexpiprazole and cariprazine). The risks for diabetes and tardive dyskinesia with DRPAs are unknown, but are likely to be low. On the basis of tolerability, DRPAs should be considered as first-line treatment options, particularly in patients with early schizophrenia.

Objective: Milnacipran is a serotonin noradrenaline reuptake inhibitor (SNRI) approved for treatment of fibromyalgia in Australia, but is used for depression in Europe and elsewhere. This paper will briefly review milnacipran and its utility in psychiatry for the treatment of depression. Conclusion: Milnacipran is a dual reuptake inhibitor of noradrenaline and serotonin, with greater effect on noradrenaline than serotonin, in contrast to the related drugs venlafaxine, desvenlafaxine and duloxetine. Rapidly absorbed irrespective of food, milnacipran has a half-life of approximately 8 hours, reaches steady state in 2 days and is excreted renally. Milnacipran helps a minority of patients with fibromyalgia by reducing pain and fatigue. It is also an effective antidepressant with efficacy comparable to venlafaxine and duloxetine, and a side effect profile characteristic of SNRIs. The dose range is 50–200 mg, in divided doses. Milnacipran may be useful for patients with depression and pain, and endogenous depression characterised by anergia, psychomotor retardation and hypersomnia. Caution is necessary in the presence of heart disease, hypertension, renal impairment, epilepsy, glaucoma, bipolar disorder, and bleeding tendency. Milnacipran is likely to be a useful late antidepressant option in treatment-resistant patients, as well as those with chronic pain, anergia and hypersomnia.

Objectives: This paper reviews the major findings of the Victorian Psychiatry Attraction, Recruitment and Retention Needs Analysis Project and considers some of the implications for the psychiatrist workforce working in public sector psychiatry. Conclusions: The report provides a snapshot of the issues that are impairing the ability of Victorian psychiatrists to comprehensively treat those in our community who have severe mental illness. As the report shows, the issues impacting the profession are multi-faceted and complex, yet surmountable.

Objectives: Brexpiprazole is a new dopamine partial agonist antipsychotic in the same class as aripiprazole. This paper will briefly review brexpiprazole and compare it with aripiprazole. Conclusions: Brexpiprazole and aripiprazole are both partial agonists at dopamine D2, and serotonin 5-HT1A and antagonists at serotonin 5-HT2A and noradrenergic α1B receptors. However, the two drugs are significantly different in potencies at various receptors; neurochemical profiles predict that brexpiprazole may be comparable with aripiprazole in its antipsychotic efficacy but may cause less akathisia, extrapyramidal side effects (EPS) and activation. In pivotal trials brexpiprazole demonstrated antipsychotic efficacy in short and long-term studies; it was also found to be an effective adjunct in patients with major depression resistant to antidepressants. Akathisia can occur early in treatment with brexpiprazole, as can minor weight gain and prolactin elevation. Indirect data extrapolations from pivotal studies suggest that brexpiprazole and aripiprazole have comparable efficacy but brexpiprazole may cause less akathisia. Like aripiprazole, brexpiprazole has been approved in the USA for use in schizophrenia and antidepressant-resistant depression. Although much more clinical experience is needed, brexpiprazole appears to be distinct from aripiprazole and a promising new ‘metabolically-friendly’ antipsychotic option for treatment of psychoses and mood disorders.

In general, specialist advice should be sought when stopping or switching antipsychotics While antipsychotics are often needed long term, there are circumstances when clinicians, patients and families should reconsider the benefits versus the harms of continuing treatment Withdrawal syndromes, relapse and rebound can occur if antipsychotics are discontinued, especially if they are stopped abruptly. Generally, they should be reduced and stopped slowly, ideally over weeks to months Relapse of psychosis and exacerbation occur in most patients with psychotic disorders, occasionally with drastic consequences. Sometimes this occurs many months after stopping antipsychotics Switching from one antipsychotic to another is frequently indicated due to an inadequate treatment response or unacceptable adverse effects. It should be carried out cautiously and under close observation

Objective: Paliperidone palmitate is now available as a three-month depot injection. This paper will review the pharmacokinetics, pharmacodynamics, efficacy and tolerability, as well as practical issues and pitfalls for clinicians with this innovative treatment for schizophrenia. Conclusion: The three-month depot formulation of paliperidone for the treatment of schizophrenia is not a new compound. The nanocrystalline structure of the three-month formulation is larger and takes longer to disperse than the one-month formulation, hence its extended depot action. As expected, it is non-inferior to one-month depot paliperidone, and superior to placebo, for the treatment of schizophrenia. The side effect profile of three-month paliperidone is identical to the one-month formulation. The relapse rate on treatment is low, and the median time to relapse after ceasing the drug is 395 days. An understanding of half-life and kinetics is crucial for clinicians using this compound, and the loading strategy is important to ensure effectiveness. There are significant challenges: ensuring timely administration and switching a three-month depot treatment to another antipsychotic may be problematic. Paliperidone palmitate three-month depot injection represents an advance for both convenience and effectiveness in the long term psychopharmacological treatment of schizophrenia.

Objective: Suvorexant, a new hypnotic, is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance, and is used long-term. This paper will briefly review suvorexant. Results: Orexin is a hypothalamic peptide which promotes wakefulness. By blocking orexin receptors, suvorexant induces sleep. Peaking 2 h after ingestion, it has a half-life of 12 h and is hepatically metabolized mainly by CYP3A. Kinetics are not affected by age but concentrations are higher in females and obese patients. There may be interactions with benzodiazepines, antidepressants and antipsychotics. Suvorexant is available in 15 mg and 20 mg doses at which benefits are moderate: after three months’ treatment users fell asleep 6 min faster and slept 16 min longer than those on placebo. Studies with 40 mg showed greater benefits but more side effects: next day somnolence, fatigue, xerostomia and peripheral oedema. Hallucinations, sleep paralysis and somnambulism occur rarely. Tolerance, withdrawal and rebound do not generally occur at recommended doses. Conclusion: Suvorexant has not been trialled against other hypnotics, is expensive and its utility for insomnia in patients with psychiatric disorders is unknown. Currently, use of suvorexant could be considered where more established treatments are inappropriate.

Objective: Antidepressant-induced sexual dysfunction is a common, troublesome complication of antidepressant treatment that patients often fail to report, which can have major consequences, including non-adherence to treatment with resultant relapse of depressive illness. The aim of this paper is to review the extent, causation and evidence-based management of antidepressant-induced sexual dysfunction to inform clinical practice. Conclusions: The preponderance of evidence suggests that antidepressant s can be divided into high risk (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors) and low risk (agomelatine, bupropion, moclobemide and reboxetine) categories with regard to propensity for antidepressant-induced sexual dysfunction, although there is disagreement, particularly about mirtazapine, and methodological issues militate against definitive findings. Antidepressant-induced sexual dysfunction is dose-dependent to an extent, but patient vulnerability factors are also relevant. There are significant differences in antidepressant-induced sexual dysfunction between men and women. It is important to ask antidepressant -treated patients about sexual dysfunction as few self-report; this may well contribute to antidepressant non-adherence. Consider using an antidepressant with low risk of antidepressant-induced sexual dysfunction for initial treatment. When antidepressant-induced sexual dysfunction has developed, try to persuade the patient to wait in case tolerance develops. Then consider changing to a lower risk or use of high/low risk antidepressant combinations but pharmacological expertise is required. Adjunctive sildenafil can help in both sexes.

Switching from one antidepressant to another is frequently indicated due to an inadequate treatment response or unacceptable adverse effects. All antidepressant switches must be carried out cautiously and under close observation. Conservative switching strategies involve gradually tapering the first antidepressant followed by an adequate washout period before the new antidepressant is started. This can take a long time and include periods of no treatment with the risk of potentially life-threatening exacerbations of illness. Clinical expertise is needed for more rapid or cross-taper switching as drug toxicity, including serotonin syndrome, may result from inappropriate co-administration of antidepressants. Some antidepressants must not be combined. Antidepressants can cause withdrawal syndromes if discontinued abruptly after prolonged use. Relapse and exacerbation of depression can also occur. Gradual dose reduction over days to weeks reduces the risk and severity of complications.

Objective: Aripiprazole long acting injection (ALAI) is now available, and this paper aims to assist clinicians in deciding when to use ALAI. Conclusion: Aripiprazole is a partial dopamine agonist with low sedation, relatively favourable metabolic profile and a tendency to lower, rather than raise, prolactin. Available for over a decade, aripiprazole has been increasingly recognised by many clinicians as a useful option in the treatment of psychoses. ALAI is a suspension of crystalline aripiprazole in water which takes 5–7 days to reach steady state after an initial intramuscular injection. Monthly injections achieve steady state in four months. Studies have demonstrated that ALAI is effective in aripiprazole-responsive patients. ALAI was generally well tolerated, but more prone to cause extrapyramidal side-effects than the oral form. ALAI has not been compared with other depots. Although the recommended starting dose is 400 mg, it is likely that there will be significant inter-individual dose variation. Dose optimisation in each patient will be necessary for best effectiveness and tolerability. ALAI is currently appropriate for aripiprazole-responsive patients who need a depot, but clinicians are likely to try ALAI in patients who have been on other depots, particularly in whom weight gain and hyperprolactinaemia have been problematic.

Objective: There has been widespread interest from the public and media in the potential of ketamine as a novel treatment for depression. This paper reviews whether current evidence supports the use of ketamine for the clinical treatment of depression. Conclusions: Clinical trials have investigated the use of intravenous ketamine for the treatment of depressive symptoms over the past 15 years. However, there remain many unanswered questions regarding its effectiveness, safety, and the route, dose and regimen for repeated administration. Experts have also raised concerns regarding ketamine’s adverse effects, abuse potential and the risk of addiction. At this stage, the use of ketamine in the treatment of depression remains in the realm of research settings.

BackgroundThe efficacy and safety of long-acting injectable risperidone have not been compared with those of an oral atypical antipsychotic.AimsTo compare long-acting risperidone and oral olanzapine in 377 patients with DSM–IV schizophrenia or schizoaffective disorder.MethodPatients were randomised to receive long-acting risperidone (25 mg or 50 mg every 14 days) or olanzapine (5–20 mg/day).ResultsIn the 13-week phase, long-acting risperidone was at least as effective as (not inferior to) oral olanzapine. In the 12-month phase, significant improvements in the Positive and Negative Syndrome Scale (PANSS) total and factor scores from baseline to month 12 and end-point were seen in both groups of patients. Few patients discontinued treatment because of an adverse event.ConclusionsBoth treatments were efficacious and well tolerated.

Objective: The treatment of depressive disorders remains unsatisfactory for many patients with regard to efficacy and tolerability. Vortioxetine has been registered by regulatory authorities for the treatment of major depressive disorder. This paper aims to provide clinicians with a brief overview of vortioxetine and its place in treatment. Conclusions: Vortioxetine is a serotonin reuptake inhibitor with additional serotonergic receptor effects of uncertain significance; hence, its classification as ‘multimodal’. The half-life is about 2.75 days and steady state requires about 14 days. Metabolism is hepatic and involves cytochromes 2D6 and 3A4/5. Antidepressant efficacy in major depressive disorder has been established in registration studies, but the effectiveness of vortioxetine in ‘real world’ patients and in comparison to other antidepressants needs further investigation. The recommended dose range is 5–20 mg. Nausea, constipation and vomiting are the most common side effects. Sexual dysfunction may occur at higher doses but there appears to be low risk of weight gain and sedation. There is still much to learn about this drug, particularly whether it has unique characteristics in comparison to existing antidepressants. At present, vortioxetine can be considered as an antidepressant option in patients with established major depressive disorder who have not responded adequately to other antidepressants.

Objectives: To investigate the efficacy and tolerability of transdermal estrogen patches for the adjunctive treatment of aggressive behavior in male patients with advanced dementia.Methods: The study was designed as an 8-week, randomized, controlled trial in acute aged psychiatry inpatient units and specialized nursing homes in Melbourne, Australia, between 1998 and 1999. The participants were 27 men with established dementia, identified as displaying aggressive behavior not responding to treatment for at least 2 weeks prior to referral. The instruments used to measure aggressive behavior were the Rating Scale for Aggressive Behavior in the Elderly (RAGE), the Cornell Scale for Depression in Dementia (CSDD) and the Mini-mental State Examination (MMSE). Physical examination was performed and biochemistry and serum hormone concentrations were measured at baseline and at 8 weeks. Concomitant psychotropic medication use was recorded and analyzed.Results: There was no significant difference in aggressive behavior at 8 weeks, but significant “rebound” in aggressive behavior (change in scores between week 8 and week 10, ppp=0.031). The use of patches was associated with a significant rise in serum estrogen (pp=0.077). There were no adverse effects associated with their use.Conclusions: The use of transdermal estrogen yielding up to 100μg per day was not associated with discernable improvement in aggressive behavior in men with advanced dementia. Small subject numbers, multiple variables and a lack of statistical power impair interpretation of these results. However, the tolerability and apparent rebound effect on removal of patches indicate the need for larger studies in this area.

Atypical antipsychotics are a diverse group of drugs. Their widespread use has significantly

Over the last decade there has been escalating debate regarding the competency of patients with psychoses to give informed consent to participate in research. This debate has been made evermore complex by variations in the definition and evaluation of competency. Importantly, competency must meet both medical and legal standards, although the criteria for each of these are not always consistent and may be mediated by contextual factors. The matter of competency to give informed consent is further complicated in the case of patients with psychoses. As a result of their disorder, patients with psychoses develop a mental state where there is impairment of reality appreciation. The impact on competency however, is highly variable and can frequently be accommodated in the consent process. Establishing associations between particular psychotic symptoms and their severity, with competency to consent at different levels of risk is the central theme of research currently being conducted.

The measurement of the quality of life of patients diagnosed with psychiatric disorders has become central to evaluating the effectiveness of treatments offered by Australian mental health services. The importance of quality of life as an indicator of the outcomes of interventions has been reflected by a large body of research seeking to measure the impact of variables such as gender, ethnicity and duration of illness on the measurable quality of life of an individual diagnosed with schizophrenia. This study aims to review and synthesize the recent literature in which quality of life has been measured by the use of at least one quality of life instrument. It is concludes that while the measurement of quality of life is valuable as a measure of outcomes, it should be treated as only one means of doing so.

Objective. To evaluate dosing and time to efficacy of atypical antipsychotics in an acute inpatient unit. Methods. Admissions during 2001 were reviewed. Patients primarily treated with an atypical antipsychotic (including those simultaneously commenced on a mood stabiliser and/or antidepressant or receiving benzodiazepines) were evaluated. Non-acute patients, those without medical records or transferred to other hospitals were excluded. Medication details were noted. Results. A total of 137 patients were evaluated; 56 (41%) had received risperidone, 38 (28%) olanzapine, and 37 (27%) quetiapine. Mean doses (mg/day) at discharge were risperidone 4.1±2.3, olanzapine 22.5±10.2, quetiapine 576±472. Dose ranges (mg/day) were risperidone 0.5-12, olanzapine 5-40, quetiapine 50-1800. No differences between atypicals in time to efficacy/concomitant anticholinergics/mood stabilisers were observed. Benzodiazepine use was more frequent with risperidone and olanzapine than quetiapine. No serious side effects with any drug were noted. Quetiapine was rapidly titrated in 20 patients (up to 400 mg on Day 1). In 18 of these, acute disturbance was controlled. Two patients were switched for lack of efficacy, one due to persistent tachycardia, and five for concern about early postural hypotension. Conclusion. These data provide further evidence concerning dose and dose range of atypicals required for optimal clinical outcome. More rapid initiation with quetiapine may be of benefit to some patients in the acute inpatient setting.

We have considered published work and clinical experience focusing on the atypical antipsychotic quetiapine in order to form a consensus on the most appropriate treatment strategies for hospitalised patients with acute schizophrenia or bipolar disorder. It is important to consider the specific treatment needs of these patients and these are discussed in the context of current treatment guidelines. We will review the efficacy and tolerability of atypical antipsychotics versus conventional antipsychotics and/or benzodiazepines as a first-line treatment, and examine the suitability of oral versus intramuscular formulations in the acute setting. The potentially beneficial properties of specific atypical agents are also considered. Appropriate dosing is particularly important in acutely ill patients as it can help achieve rapid improvement. We will discuss emerging data which show that rapid initiation of quetiapine in patients with acute psychosis or mania is not only as effective as standard initiation, but is also well tolerated. This may be important for treatment in the long term as a positive initial treatment experience can determine patient compliance and treatment adherence. In conclusion, this review recommends that oral atypical antipsychotics should be a first-choice medication for acutely ill cooperative patients in the hospital setting.

What to do when clozapine therapy (or other medications) does not work … or, more often, doesn’t work well enough? This is a real clinical conundrum. Moreover, clinicians struggle daily with the dilemma of distilling information on appropriate augmentation strategies from studies of groups of patients and thereupon extrapolating that information to the individual patient in their practice. This is a complicated equation at the time when the clinician and/or the patient conclude that clozapine therapy has reached its plateau and other options are called for. This chapter will detail the range of options as well as some considerations for selecting one choice over another for given patient scenarios.

Risperidone (Risperdal) is a benzisoxazole derivative with a high affinity for serotonin 5-HT2 and dopamine D2 receptors, and some affinity for alpha- adrenergic, histamine H1 and dopamine D1 receptors. It has no anticholinergic effects. Early studies demonstrated risperidone to be an effective medication for psychotic symptoms, probably more so than the older neuroleptics for both positive and negative symptoms. At clinically effective doses, risperidone causes no more extrapyramidal side-effects (EPS) than placebo; at higher doses EPS frequency increases in a dose-dependent manner. Since it became available in 1994, extensive experience with the drug supports favourable early impressions of efficacy and tolerability. Minimal sedation, relatively little weight gain and absence of anticholinergic manifestations contribute to the relative tolerability of risperidone as compared to older neuroleptics. However, risperidone is associated with hyperprolactinaemia which can result in amenorrhoea and sexual dysfunction. Compared to older neuroleptics, pharmacoeconomic studies have shown that use of risperidone is associated with reduced hospitalisation and direct cost savings. A recent study found equivalent efficacy between risperidone and clozapine for treatment-resistant patients. Two studies comparing risperidone and olanzapine have yielded positive but conflicting findings. The overall positive experience with risperidone has resulted in the drug being widely recommended as a first line treatment option for psychoses.

Changes in serotonin receptors and the serotonin transporter have been reported in the dorsolateral prefrontal cortex from subjects with schizophrenia, an area of the brain thought to be important in the pathology of the illness. To further our understanding on how such changes could play a role in the pathology of the illness, in situ radioligand binding with autoradiography was used to measure the density of the serotonin 1A receptor, the serotonin 4 receptor and the serotonin transporter in the dorsolateral prefrontal cortex, obtained at autopsy, from 10 schizophrenic and 10 control subjects. The binding of [ 3 H]8-OH-DPAT to serotonin 1A receptor, [ 3 H]GR113808 to the 5HT 4 receptor and [ 3 H]citalopram to serotonin transporter was not altered in subjects with schizophrenia. Significantly, only in tissue from the control subjects was there a relationship between age and the density of the serotonin 4 receptor in Brodmanns areas 8 ( r = 0.71, P = 0.02) and 10 ( r = −0.67, P = 0.03). Importantly, this confounding factor did not influence the comparison of the density of serotonin 4 receptor in the tissue from the schizophrenic and control subjects. This study has failed to show a difference in the density of serotonin 1A receptor, the serotonin 4 receptor or the serotonin transporter in the dorsolateral prefrontal cortex (Brodmanns areas 8, 9 and 10) from subjects with schizophrenia. These data suggest that not all serotonergic markers are altered in the dorsolateral prefrontal cortex from schizophrenic subjects.

Psychoses affect up to 4% of the population.These conditions usually require long-term treatment with antipsychotic drugs, mood stabilisers or both.

Australia and Canada are currently the only Western nations with government guidelines for analyzing the cost-effectiveness of drugs. We used guidelines issued by the Australian Pharmaceutical Benefits Advisory Committee to construct a model for comparing the cost-effectiveness of risperidone and haloperidol over a 2-year period in patients with chronic schizophrenia. Use of clozapine was also included in the analysis as an alternative treatment given to patients who proved unresponsive to therapy with haloperidol or risperidone. Results are expressed in Australian dollars. Cost-effectiveness was determined by using decision-analytic modeling to compare clinical outcomes and costs. The analytic model contained a decision tree for each of the compared agents that tracked the distribution of patients between treatment outcome pathways (ie, scenarios). Distributions were based on probabilities derived from our meta-analysis results reported elsewhere and from other sources. Each scenario had an associated monetary cost that included all significant direct costs (ie, hospital costs; outpatient costs; and the cost of drugs, the services of health care professionals, and government-subsidized hostel accommodation). The cost for a given outcome was the sum of costs for all scenarios leading to that outcome. Cost-effectiveness was expressed as the total cost per favorable outcome. The definition of a favorable outcome was one in which the patient was in a response phase at the end of the 2-year period. The probability of a patient experiencing a favorable outcome at the end of 2 years was 78.9% for risperidone versus 58.9% for haloperidol. The total cost of treatment for 2 years was $15,549.00 for risperidone versus $18,332.00 for haloperidol. The expected cost per favorable outcome was $19,709.00 for risperidone and $31,104.00 for haloperidol. Risperidone was more cost-effective than haloperidol and therefore was “dominant” in pharmacoeconomic terms because it produced a higher proportion of favorable outcomes at lower cost. Sensitivity analysis showed that the difference in clinical response rate was a key determinant of cost-effectiveness.

Changes in G-protein linked neurotransmitter receptors have been reported in a number of regions of the brain of schizophrenic subjects. These changes, if functional, could cause a change in proteins such as protein kinase C (PKC) and adenylate cyclase (AC) which are important components of the G-protein linked second messenger cascades. We therefore used autoradiography to measure the distribution and density of [3H]phorbol ester binding to PKC and [3H]forskolin binding to AC in tissue obtained at autopsy from schizophrenic and non-schizophrenic subjects (Controls). There were significant decreases in the density of PKC in the parahippocampal gyrus (687 +/- 60 vs. 885 +/- 51 fmol/mg TE; mean +/- SEM; p0.01) and in AC in the dentate gyrus (75 +/- 4.9 vs. 92 +/- 6.5, p0.05) from the schizophrenic subjects. These data could indicate that changes in neurotransmitter receptors in the hippocampus from subjects with schizophrenia could have resulted in a change in their associated second messenger systems.

We describe a model of cognitive-existential group therapy designed to be integrated over 6 months with regimens of adjuvant chemotherapy given as conventional medical treatment to breast cancer patients with stage 1 and 2 disease. Our broad therapy goals are for members to develop a supportive network, work through grief over losses, improve problem solving and develop cognitive strategies to maximise coping, enhance a sense of mastery over life and re-evaluate priorities for the future. Specific group themes include death anxiety, fear of recurrence, living with uncertainty, understanding treatment with chemotherapy, radiotherapy and hormone regimens, the collaborative doctor-patient relationship, body and self image, sexuality, relationships with partner, friends and family, surgical reconstruction, life style effects and future goals. Active coping skills are developed through teaching formal problem solving and cognitive restructuring of automatic negative thoughts. Technical aspects of the therapy are discussed.

Functional status in schizophrenia depends in part on cognitive function. Newer antipsychotics, such as risperidone, produce better cognitive function in patients with schizophrenia than do conventional neuroleptics, which implies that the indirect costs of the illness will be less in patients treated with risperidone. A robust decision-analytic model of schizophrenia suggests that the overall cost of treating a patient with risperidone is $11,772.00 per year compared with $13,622.00 per year for haloperidol and that the cost per response is even more favorable toward risperidone—$14,599.00 versus $23,040.00. This model supports the results of naturalistic trials in which risperidone produced better outcomes than did conventional neuroleptics. Overall, the use of the more effective, better tolerated newer antipsychotics should reduce the cost to society of schizophrenia and improve patients' quality of life.

Objective: To review the contemporary landscape regarding pharmacological treatments for schizophrenia. Method: Selective literature review. Results: Newer antipsychotic agents include aripiprazole, asenapine, paliperidone, sertindole and ziprasidone. Each has some particular benefits and some shortcomings. Overall treatment efficacy (for positive symptoms at least) has not advanced substantially but some newer agents might have a better profile than older typical agents for negative and cognitive symptoms. Metabolic side effects and hyperprolactinaemia remain a problem with some of the newer agents and appropriate monitoring is required. Conclusions: Whilst newer antipsychotics have been welcome additions to our pharmacological armamentarium, mostly in terms of tolerability, we have still not seen a ‘quantum leap’ agent brought to market. Mechanisms of action apart from post-synaptic dopamine blockade appear worthy of further investigation in this regard.

Dopamine (DA) D2 receptors which act by modulating second messenger pathways that include protein kinase C (PKC) and adenylate cyclase (AC) have been repeatedly shown to be increased in striatum from subjects with schizophrenia. Therefore it seemed possible that chronic up-regulation of DA-D2 receptors in the schizophrenic brain could result in a change in either of these two proteins. Hence we measured PKC and AC in striatum from 20 schizophrenic subjects and 20 non-schizophrenic subjects by quantitative autoradiography and could show no difference in the density of either PKC (436 +/- 35 vs. 485 +/- 29 fmol/mg tissue equivalents (TE), mean +/- SEM) or AC (77 +/- 9 vs. 80 +/- 7 fmol/mg TE) in the tissue from schizophrenic compared to the non-schizophrenic subjects. Thus, these data do not support the hypothesis that PKC or AC are changed in the schizophrenic brain.

Standard neuroleptic medications have been augmented by the introduction of risperidone and clozapine into clinical practice. A great deal of attention has also been focused on efficacy and the lower propensity to extrapyramidal side-effects associated with the new agents. However, antipsychotic medication, both old and new, can cause a range of other adverse effects, some of which are serious, and many of which have the potential greatly to diminish the quality of life of patients who need to take medication in the long term. Of particular significance are postural hypotension, cardiotoxicity, peripheral and central anticholinergic effects, sedation, weight gain, and endocrine and haematological effects. Various antipsychotic compounds differ substantially with regard to propensity to adverse effects. Side-effects can be minimized by optimization of clinical strategies, including choice of appropriate drug, slow titration and dosage reduction. It is also vital to explain carefully to both patients and carers the nature of the side-effects which can be anticipated. The choice of antipsychotic is often determined by evaluation of the potential impact of the various adverse effects on a particular patient. New drugs, such as risperidone, are well tolerated, with fewer side-effects, and should now be considered as a first-line option.

This study was a preliminary open clinical trial aimed at exploring the hypothesis that estrogen may provide protection against schizophrenia in women. Eleven women with acute psychotic symptoms, as scored on the BPRS, SAPS and SANS, had 0.02 mg estradiol added to neuroleptic treatment for eight weeks. Their response was compared to seven women with similar symptom severity receiving neuroleptic treatment alone. Both groups had baseline hormonal assays of estrogen, progesterone, LH and FSH and underwent regular psychopathology ratings during the eight weeks. The group receiving the estradiol adjunct showed more rapid improvement in psychotic symptoms compared with the group receiving neuroleptics only. This difference was not sustained for the entirety of the trial. Both groups reached similar levels of recovery by the eighth week. These results suggest that estradiol may have antipsychotic properties and/or act as a catalyst for neuroleptic responsiveness in women with schizophrenia.

Obiective : The purpose of this study was to determine 1) the reliability of diagnoses of schizophrenia at coronal autopsy and 2) the degree to which the use of different diagnostic instruments for schizophrenia would affect postmortem brain research. Method : Eighty-three subjects, recorded at coronal autopsy as having had schizophrenia, were referred for neuro-chemistry studies. The diagnoses reported to the state coroner's office were reevaluated by a review of psychiatric case histories by clinicians using semistructured assessment and diagnostic criteria. Results : The application of DSM-III-R, Research Diagnostic Criteria (RDC), ICD-10, Schneiderian, and Feighner criteria to the diagnosis of the 83 subjects revealed that 63.9%, 48.2%, 48.2%, 43.4%, and 42.2%, respectively, met the criteria for schizophrenia. Highest concordance was between the RDC and ICD-10 systems, while lowest concordance was between the RDC and Schneider systems. Conclusions : These data suggest that unless carefully reviewed, diagnosis may be a major confounding factor in postmortem studies ofbrain tissue from subjects with schizophrenia.

The binding of [ 3 H]paroxetine and [ 3 H]ketanserin to particulate membranes from frontal cortex of subjects who had or did not have schizophrenia was measured as was [ 3 H]paroxetine binding to particulate membranes from the hippocampus and caudate nucleus. There was no change in either the affinity or density of [ 3 H]ketanserin binding to membranes from the frontal cortex of subjects who had schizophrenia. Similarly, there was no difference in the density of [ 3 H]paroxetine binding to membranes from subjects who had or did not have schizophrenia. The affinity of [ 3 H]paroxetine binding in the frontal cortex and putamen did not differ in subjects who had schizophrenia. By contrast, there was a significant decrease in the affinity of [ 3 H]paroxetine binding to the hippocampal membrane from subjects who had schizophrenia (0.40 ± 0.06 nM vs 0.26 ± 0.02 nM ; p < 0.05). Furthermore, this difference was more apparent in the subjects who had schizophrenia and committed suicide (0.49 ± 0.09 nM) than it was in those who had schizophrenia but did not commit suicide (0.32 ± 0.09 nM). As [ 3 H]ketanserin binds to the serotonin 2 receptor our data suggest that this receptor is not changed in the Brodmann's area 9 of the frontal cortex. By contrast, [ 3 H]paroxetine binds to the serotonin transporter and therefore our data suggest that the serotonin transporter is altered in the hippocampus of subjects with schizophrenia.

Antipsychotics, both the long established typical drugs and the recently introduced atypical drugs clozapine and risperidone, are highly effective in acute and maintenance treatment of schizophrenia. However, typical antipsychotics are associated with tardive dyskinesia after long term use, and many other clinical situations arise for which discontinuation of therapy may be appropriate. For patients who have recovered from a first episode of psychosis, it is recommended that antipsychotics are continued for 1 to 2 years before withdrawal is considered. Patients who have experienced recurrent psychotic episodes need long term maintenance treatment and there is no simple guide as to when discontinuation might be attempted. The risk of potentially dangerous psychotic relapse is high in most circumstances. Long term prognosis may also be worsened by the occurrence of repeated psychotic relapses. Additionally, there can be withdrawal reactions, which are mostly attributable to cholinergic rebound. The problems of discontinuation are minimised by very gradual dosage reduction and, occasionally, the temporary addition of anticholinergic medications. A key principle for maintenance treatment is the use of the lowest effective dose of antipsychotic, established by trial and error. If discontinuation of typical antipsychotic medication is essential, an option is to switch to risperidone or clozapine. Because of the problems associated with both continuation and withdrawal of antipsychotics, the decision to discontinue should be made with the informed consent of the patient and their carers.

Remoxipride, a substituted benzamide, is a selective D-2 antagonist with an atypical neuroleptic profile. Previous studies have demonstrated its antipsychotic efficacy against haloperidol and, more recently, thioridazine. Of the 144 patients enrolled in the Australian remoxipride-thioridazine comparative trial, 28 presented for their first episode of schizophrenia and/or had no previous neuroleptic treatment. These patients form the subject of this paper.

It remains a matter of conjecture as to whether a schizophrenia-like syndrome commencing in old age differs from the early-onset disorder in any substantial way. This article reviews both the historical background to the concept of defining paraphrenia as a distinct entity, as well as the current controversies concerning whether it should remain a separate entity: the latter is important as paraphrenia has not been included in the DSM Ill-R and ICD 10 classification systems. Clinical parameters and aetiological factors relevant to an understanding of the syndrome are discussed under the rubrics of descriptive and construct validity. Of particular importance are the role of cerebral organic factors and the pathoplastic effect of the ageing process and how both interface with the development of psychotic symptoms. Whilst the course of this syndrome has been considered relatively benign, outcome studies have yet to establish consistent features that provide a basis to determine predictive validity.

Objective: The aim of the present study was to evaluate clinical factors relevant to suicide prevention (including treatment) in cases of bipolar suicide with available therapeutic histories. Method: Victorian Coroner's Office data enabled identification of suicides that occurred between March 1993 and December 2001. Cases involving sufficient clinical notes to enable diagnosis of DSM-IV bipolar disorder and review of treatment were de-identified and assessed by an expert clinical panel. Results: From 3752 suicides, 35 eligible bipolar subjects (22 men, 13 women) aged 40.3±1.8 years were identified. Duration of illness was 11.9±1.1 years. A total of 86% had made at least one previous suicide attempt, and 83% were in the depressed phase of illness. A total of 63% manifested psychosis at some time during lifetime illness. Fourteen per cent were inpatients, and 26% suicided within 6weeks of hospital discharge. The panel's retrospective risk assessment concluded that only 48% of cases could have been assessed as high risk. In the 4 weeks prior to suicide, treatment was rated as not reaching benchmark standards in 60% of cases. Electroconvulsive therapy had been given to 11%, lithium to 43% (but definitely therapeutic in only 11%), 31% had never been treated with lithium, and psychosocial interventions did not reach adequate standards in 57% during the previous year. Conclusions: In the majority of bipolar suicide cases in the present case series the subjects did not receive treatment at or above a benchmark standard, often due to illness and situational factors, but also possibly due to inadequate clinical interventions. Strategies to improve treatment may reduce suicide in bipolar disorder.

Background Clozapine is an atypical antipsychotic drug indicated for patients with schizophrenia in whom traditional antipsychotic drugs (such as haloperidol or the phenothiazines) are ineffective, or in those who experience intolerable adverse effects. Clozapine treatment may be complicated by the development of life-threatening agranulocytosis, so regular haematological monitoring is required. Objectives To determine the incidence of clozapine-induced agranulocytosis in Australia and the importance of monitoring white blood cell counts in patients treated with clozapine. Design Review of haematological monitoring for the first three years (June 1993-July 1996) of operation of the Australian Clozaril (clozapine; Novartis Australia) Patient Monitoring System (CPMS) central database. Results In the 4061 patients prospectively monitored by the CPMS, the incidence of agranulocytosis, neutropenia and leukopenia combined was 2.6% (n = 104); the incidence of agranulocytosis was 0.9% (n = 37). So far there have been no deaths in Australia from the complications of clozapine-induced agranulocytosis. Conclusion The incidence of agranulocytosis and neutropenia associated with clozapine use in Australia is similar to that in the rest of the world. Monitoring the white blood cell counts of patients being treated with clozapine ensures minimal risk to patients who develop agranulocytosis.

Up to 45% of patients with debilitating and potentially lethal depressive illness do not achieve remission with initial drug treatment. Using combinations of antidepressants as an early option for treatment-resistant depression has become increasingly common. Before trying combination therapy, it is essential first to ensure diagnosis is correct, and then to optimise antidepressant monotherapy, using an effective dose for an adequate period. Subsequently, augmentation of antidepressants with lithium and triiodothyronine should be considered, as these strategies are strongly supported by numerous clinical trials. Electroconvulsive therapy is the most effective treatment for severe depression. There is little evidence to support use of antidepressant combinations. Risk of toxicity and drug interactions mandate that combinations be used as a last resort, and only in specialist settings.

Research on the cognitive capacity of heart failure patients is limited, with a paucity of benchmark information available for this population. It is highly likely that cognitive deficits affect patients' understanding of disease and treatment requirements, as well as limiting their functional capacity and ability to implement treatment plans, and undertake self-care.The purpose of this study was to establish a comprehensive neurocognitive profile of the heart failure patient through systematic neurocognitive assessment and to determine whether an association existed between severity of heart failure and cognitive abilities.Thirty-eight patients were recruited from the heart failure patient databases of two metropolitan hospitals in Melbourne, Australia. Participants were individually assessed using four standardised, internationally recognised neuropsychological tests that examined current and premorbid intelligence, memory and executive functioning.Although there was no significant decline from premorbid general intellectual function, other specific areas of deficit, including impaired memory and executive functioning, were identified. There were no significant correlations between heart failure severity and the neurocognitive measures used.The results support the need to recognise cognitive impairment in people with heart failure and to develop an abbreviated method of assessing cognitive function that can be easily implemented in the clinical setting. Identifying cognitive deficits in this population will be useful in guiding the content and nature of treatment plans to maximise adherence and minimise worsening of heart failure symptoms.