A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis.

NMDA autoantibody encephalitis presenting as schizophrenia suggests the possible role of adaptive cell-mediated immunity in idiopathic schizophrenia. However, to our knowledge there have been no trials of the immune-suppressant methotrexate in schizophrenia. We tested if low-dose methotrexate as used in the treatment of systemic autoimmune disorders would be tolerable and effective in people with schizophrenia in a feasibility study. Ninety-two participants within 5 years of schizophrenia diagnosis were recruited from inpatient and outpatient facilities in Karachi, Pakistan. They were randomised to receive once weekly 10-mg oral methotrexate (n = 45) or matching placebo (n = 47) both with daily 5-mg folic acid, in addition to treatment as usual for 12 weeks. There were eight dropouts per group. Side effects were non-significantly more common in those on methotrexate and were not severe. One person developed leukopenia. Positive symptom scores improved more in those receiving methotrexate than placebo (ß = -2.5; [95% CI -4.7 to -0.4]), whereas negative symptoms were unaffected by treatment (ß = -0.39; [95% CI -2.01 to 1.23]). There were no immune biomarkers but methotrexate did not affect group mean leucocyte counts or C-reactive protein. We conclude that further studies are feasible but should be focussed on subgroups identified by advances in neuroimmune profiling. Methotrexate is thought to work in autoimmune disorders by resetting systemic regulatory T-cell control of immune signalling; we show that a similar action in the CNS would account for otherwise puzzling features of the immuno-pathogenesis of schizophrenia.

Antipsychotic drug use and pneumonia: Systematic review and meta-analysis.

OBJECTIVES: The purpose of this study was to investigate the association of antipsychotic exposure to the incidence and mortality of pneumonia. METHODS: The design of this study involved meta-analysis of observational studies identified from electronic databases. RESULTS: In total, 19 studies were included in the systematic review and 14 in the meta-analysis. Risk of pneumonia was increased by first-generation antipsychotics (risk ratio 1.69, 95% confidence interval 1.34-2.15; five studies), second-generation antipsychotics (risk ratio 1.93, 95% confidence interval 1.55-2.41; six studies) and all antipsychotics (risk ratio 1.83, 95% confidence interval 1.60-2.10; seven studies) compared with no antipsychotic use. Pneumonia risk did not differ in seven studies comparing first-generation antipsychotics with second-generation antipsychotics (risk ratio 1.07, 95% confidence interval 0.85-1.35). Case fatality rate was not different in pneumonia cases associated with antipsychotic exposure versus cases without exposure (risk ratio 1.50; 95% confidence interval 0.76-2.96; two studies). All antipsychotics with data from ⩾2 studies allowing meta-analysis, were associated with a significantly increased pneumonia risk (i.e. haloperidol, olanzapine, clozapine, risperidone, quetiapine, zotepine). CONCLUSION: Exposure to both first-generation antipsychotics and second-generation antipsychotics is associated with an increased pneumonia risk. Clinicians need to be vigilant for the occurrence of pneumonia in patients commencing antipsychotics, especially those with other risk factors for pneumonia including older age, chronic respiratory disease, cerebrovascular disease, dysphagia and smoking.

BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment.

Excess deaths from cardiovascular disease are a major contributor to the significant reduction in life expectancy experienced by people with schizophrenia. Important risk factors in this are smoking, alcohol misuse, excessive weight gain and diabetes. Weight gain also reinforces service users' negative views of themselves and is a factor in poor adherence with treatment. Monitoring of relevant physical health risk factors is frequently inadequate, as is provision of interventions to modify these. These guidelines review issues surrounding monitoring of physical health risk factors and make recommendations about an appropriate approach. Overweight and obesity, partly driven by antipsychotic drug treatment, are important factors contributing to the development of diabetes and cardiovascular disease in people with schizophrenia. There have been clinical trials of many interventions for people experiencing weight gain when taking antipsychotic medications but there is a lack of clear consensus regarding which may be appropriate in usual clinical practice. These guidelines review these trials and make recommendations regarding appropriate interventions. Interventions for smoking and alcohol misuse are reviewed, but more briefly as these are similar to those recommended for the general population. The management of impaired fasting glycaemia and impaired glucose tolerance ('pre-diabetes'), diabetes and other cardiovascular risks, such as dyslipidaemia, are also reviewed with respect to other currently available guidelines.These guidelines were compiled following a consensus meeting of experts involved in various aspects of these problems. They reviewed key areas of evidence and their clinical implications. Wider issues relating to primary care/secondary care interfaces are discussed but cannot be resolved within guidelines such as these.

Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology.

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines.

A revision of the 2008 British Association for Psychopharmacology evidence-based guidelines for treating depressive disorders with antidepressants was undertaken in order to incorporate new evidence and to update the recommendations where appropriate. A consensus meeting involving experts in depressive disorders and their management was held in September 2012. Key areas in treating depression were reviewed and the strength of evidence and clinical implications were considered. The guidelines were then revised after extensive feedback from participants and interested parties. A literature review is provided which identifies the quality of evidence upon which the recommendations are made. These guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing and management, next-step treatment, relapse prevention, treatment of relapse and stopping treatment. Significant changes since the last guidelines were published in 2008 include the availability of new antidepressant treatment options, improved evidence supporting certain augmentation strategies (drug and non-drug), management of potential long-term side effects, updated guidance for prescribing in elderly and adolescent populations and updated guidance for optimal prescribing. Suggestions for future research priorities are also made.

A naturalistic evaluation and audit database of agomelatine: clinical outcome at 12 weeks.

OBJECTIVE: To determine the effectiveness of agomelatine in routine clinical practice and explore factors associated with response and continuation. METHOD: Consecutive patients prescribed agomelatine in participating psychiatric services were included. Patient demographic and outcome data were collected at treatment initiation and then at weeks 4, 8 and 12. Outcomes were analysed with respect to clinical and demographic factors. RESULTS: A total of 110 patients from nine NHS trusts were followed through 12 weeks of treatment. Agomelatine was largely used in difficult-to-treat or refractory patients: 83 (75%) had failed to respond to, or relapsed on, prior antidepressants. There were high rates of physical (54.5%) and psychiatric (50.0%) comorbidity. At 12 weeks of treatment, 68 (62%) continued agomelatine treatment. Overall, 69 subjects (62.7%) improved by at least one point of the Clinical Global Impression (severity) scale. Of 42 who discontinued, 23 (56%) discontinued because of lack of efficacy and 10 (24%) due to an adverse event. Of all variables examined, only a history of more than five episodes of depression significantly predicted discontinuation of treatment (OR continuation - 0.36, 95% CI 0.14, 0.95). CONCLUSION: Agomelatine was effective and generally well tolerated in a cohort of difficult-to-treat patients in clinical practice.

The use of antidepressants in clinical practice: focus on agomelatine.

OBJECTIVE: Agomelatine (Valdoxan) is licensed by the European Medicines Agency for the treatment of major depressive episodes in adults. The objective of this review was to consider how the drug should be used in clinical practice in particular starting, stopping and switching to and from the drug. METHODS: The existing clinical evidence was reviewed. RESULTS: Data suggest that when switching to agomelatine from other antidepressants consideration should be given to tapering the previous antidepressant in order to minimize the risk of the original drug causing discontinuation/withdrawal symptoms. The risk of pharmacological interactions between most antidepressants and agomelatine is low and so tapering the previous antidepressant can usually be done after agomelatine has been started. An exception is fluvoxamine which should not be concurrently prescribed with agomelatine. As agomelatine appears to cause no significant discontinuation symptoms, it can probably be stopped abruptly when treatment is completed or when switching to another antidepressant. CONCLUSIONS: While this guidance may change as clinical evidence and experience grows, currently agomelatine appears to have a good tolerability profile and is relatively easy to use, though prescribers should note the requirement to conduct liver function tests (LFTs) in accordance with the Summary of Product Characteristics (SPC).

Psychiatrists' use, knowledge and attitudes to first- and second-generation antipsychotic long-acting injections: comparisons over 5 years.

Psychiatrists' attitudes and knowledge about antipsychotic long-acting injections (LAIs) are important given the increasing emphasis on patient choice in treatment and the availability of second-generation antipsychotic (SGA) LAIs. A cross-sectional study of consultant psychiatrists' attitudes and knowledge in North West England was carried out. A pre-existing questionnaire on clinicians' attitudes and knowledge regarding LAIs was updated. Of 102 participants, 50% reported a decrease in their use of LAIs. LAI prescribing was evenly split between first-generation antipsychotic (FGA) and SGA-LAIs. Most regarded LAIs as associated with better adherence (89%) than tablets. A substantial proportion believed that LAIs could not be used in first-episode psychosis (38%) and that patients always preferred tablets (33%). Compared with a previous sample, the current participants scored more favourably on a patient-centred attitude subscale (60.4% vs 63.5%, P = 0.034) and significantly fewer regarded LAIs as being stigmatising and old-fashioned. Reported LAI prescribing rates have decreased in the last 5 years despite an SGA-LAI becoming available and most clinicians regarding LAIs as effective. Most attitudes and knowledge have remained stable although concerns about stigma with LAI use have decreased. Concerns about patient acceptance continue as do negative views about some aspects of LAI use; these may compromise medication choices offered to patients.

Efficacy, safety and tolerability of quetiapine augmentation in treatment resistant depression: an open-label, pilot study.

BACKGROUND: Atypical antipsychotics may have efficacy as augmentation therapy in treatment resistant depression (TRD) but evidence is limited. METHODS: An open label study of quetiapine augmentation in 24 patients (mean age: 46.3 years) with a DSM-IV major depressive episode resistant to at least 2 trials of antidepressant medication, and currently taking a monoamine reuptake inhibitor. An 8-week treatment phase was followed by an 18-week extension in patients who showed clinical benefit. RESULTS: Eighteen patients (75%) completed the 8-week treatment phase with seven patients (29%) being responders on the Montgomery Asberg Depression Rating Scale and 13 (54%) on the CGI-I. Fewer patients responded if they had previously received olanzapine in the current episode but this was not statistically significant (0% v 37%, p=0.27). Of the eleven patients entering the extension phase, 3 patients (27%) experienced a significant worsening of mood. The most common adverse events were sedation (54%), dry mouth (38%) and dizziness (29%). Significant weight gain was found in 40% of patients treated for 26 weeks. Average quetiapine doses were 245 mg at 8 weeks and 346 mg at 26 weeks. CONCLUSIONS: Quetiapine may be a helpful adjunctive agent for some patients with TRD but placebo-controlled trials are needed to establish its place in management. LIMITATIONS: The trial was open-label and the numbers were small.

A UK consensus on the administration of aripiprazole for the treatment of mania.

Aripiprazole has recently received approval for the treatment of moderate to severe manic episodes in bipolar I disorder and prevention of new manic episodes in aripiprazole-responsive patients. Aripiprazole differs from other antipsychotics in its pharmacology, and the need for prescribing guidance in the UK was recently identified. A UK multidisciplinary panel was convened in November 2007. This report describes the consensus agreed during the meeting on the optimal approach to prescribing aripiprazole: how best to approach initiation of, and switching to, treatment with aripiprazole and management strategies for side effects. A literature review of the randomised controlled clinical trials of aripiprazole in mania supports these recommendations. Aripiprazole should be initiated at 15 mg/day (range 5-20 mg/day). If necessary, adjunctive medication should be used in early treatment to manage side effects or assist in management of symptoms such as agitation. When switching to aripiprazole, the therapeutic dose of current treatment should be maintained while adding aripiprazole 15 (5-20) mg/day. Only once an effective dose of aripiprazole is reached should previous medication be reduced. Nausea, insomnia and agitation typically resolve within days. Some principles for dosing and switching are provided to assist with a successful treatment outcome with aripiprazole in mania.

Psychiatric nurses' attitudes to antipsychotic depots in Hong Kong and comparison with London.

Psychiatric nurses' attitudes to depots have only been explored in the UK. We conducted a cross-sectional attitudinal study for Hong Kong psychiatric nurses and also conducted international comparisons for nurses' views about depots. A pre-existing UK questionnaire on clinicians' attitudes and knowledge regarding depots was updated for the present study. Participants were 98 psychiatric nurses who attended an academic meeting. The majority of respondents had positive views regarding their role in depot administration; most reported that they had sufficient training (84%). However, many did not feel involved in treatment decision making (60%) and other negative views were expressed including: (1) most patients always prefer to have oral (vs. depot) (80%); and (2) force is sometimes required when administering a depot (40%). Interestingly, most reported that patients' friends and family were more accepting of depot (vs. oral) (69%). When compared with a former sample of London community psychiatric nurses, Hong Kong nurses had less favourable patient-focussed attitudes (mean 56% vs. 60%, P = 0.051) and depot-specific attitudes regarding depots (mean 63% vs. 69%, P < 0.001). In conclusion, therefore, international variation exists and encompasses clinical practice aspects for both the patient and the depot formulation per se. Our participants wanted more involvement in treatment decision making.

Thirty-five months experience of risperidone long-acting injection in a UK psychiatric service including a mirror-image analysis of in-patient care.

OBJECTIVE: To report the use of risperidone long-acting injection (RLAI) in a UK psychiatric service. METHOD: Retrospective case note review of all patients prescribed RLAI over a 35-month period. In the mirror-image analysis patients initiated on RLAI as in-patients had the index admission attributed to previous treatment. RESULTS: Patients prescribed RLAI had significantly higher baseline rates of drug misuse, alcohol misuse, unemployment and forensic markers than control patients prescribed oral antipsychotics. Most patients started RLAI because of poor compliance with oral antipsychotics. Inefficacy accounted for more discontinuations than intolerability. Fifty-eight percent (39/67) of patients were continuing RLAI 12 months after initiation. Mirror-image analysis (n = 74) showed that RLAI was associated with a reduction in the number of admissions (65 vs. 33, P < 0.005) and in total in-patient days (4550 vs. 2188 days, P < 0.005). The mean reduction in in-patient care was 29 days per patient-year of treatment, equivalent to a net financial saving over the acquisition and administration costs of RLAI of pound1172. CONCLUSION: Risperidone long-acting injection was associated with reduced in-patient care and was cost-effective.

A survey of antiepileptic prescribing to women of childbearing potential in psychiatry.

Antiepileptic drugs (AEDs) are teratogenic. The aim of this survey was to ascertain whether clinicians followed recently published guidelines for prescribing AEDs to women of childbearing potential in England and Wales. We reviewed the case notes of all women aged 16-47 years who were initiated on valproate or carbamazapine in the psychiatric departments of three teaching hospitals over a 12 month period. Standards of documentation regarding childbearing issues in this representative sample were poor. The results are of concern given the widespread use of antiepileptic drugs in psychiatry.

Neonatal symptoms following maternal paroxetine treatment: serotonin toxicity or paroxetine discontinuation syndrome?

We report a case of neonatal symptoms of irritability, increased tonus and convulsions after in-utero exposure to paroxetine 30 mg/day. The infant's symptoms commenced on the first day after birth and persisted for 10 days. Paroxetine levels were undetectable on day 6. Extensive investigations excluded infective and metabolic causes. Serotonin toxicity due to paroxetine seems the most likely mechanism, though an important differential diagnosis is a paroxetine discontinuation (withdrawal) syndrome. Differentiating between these two syndromes in the neonate presents a dilemma for clinicians. Irrespective of the mechanism, we recommend that all neonates exposed to antidepressants, particularly serotonin reuptake inhibitors (SSRIs), during the last trimester should be followed-up closely for adverse symptoms commencing in the first 10 days after birth. The possibility of such symptoms needs to be discussed with women who are considering starting or continuing antidepressant treatment in pregnancy. All neonatal adverse drug events should be reported to a pharmacovigilance centre. Further research is warranted.

Aripiprazole in schizophrenia: consensus guidelines.

Schizophrenia is a chronic disabling disease which in the majority of cases requires long-term treatment with antipsychotic medication. Before the development of atypical antipsychotics, treatment choice was restricted to conventional (or typical) antipsychotics, which are known to cause a range of side effects including extrapyramidal symptoms. Although atypical agents provide a favourable alternative (advocated by the National Institute of Clinical Excellence in the UK), they are associated with side effects. These differ between agents, but can include weight gain, sedation and hyperprolactinaemia. Aripiprazole is a newly available atypical antipsychotic for the treatment of schizophrenia. With the apparent imitations of currently available medications, aripiprazole provides clinicians with another treatment option. The purpose of these guidelines is to outline the consensus reached by the Schizophrenia Innovation Working Group on best practice in prescribing and appropriate use of aripiprazole in the UK.

Antipsychotic-induced hyperprolactinaemia in women: pathophysiology, severity and consequences. Selective literature review.

BACKGROUND: Hyperprolactinaemia has for decades been an inevitable and neglected side-effect of antipsychotic medication. The recent introduction of prolactin-sparing antipsychotic agents makes a re-examination of this problem timely. AIMS: To review the literature on antipsychotic-induced hyperprolactinaemia and its consequences. METHOD: A search was made of the Medline database (1966-2002) for key articles, supplemented by cross-referencing. RESULTS: During antipsychotic treatment prolactin concentrations can rise to ten times normal levels or above, and existing data indicate that 17-78% of female patients have amenorrhoea with or without galactorrhoea. Survey data, however, suggest that clinicians underestimate the prevalence of these conditions. Long-term consequences of antipsychotic-related hypo-oestrogenism require further research but are likely to include premature bone loss. CONCLUSIONS: Antipsychotic-induced hyperprolactinaemia should become a focus of interest in the drug treatment of psychiatric patients.

Antidepressant discontinuation (withdrawal) symptoms presenting as 'stroke'.

We report two patients who developed a severe discontinuation (withdrawal) reaction following stoppage of paroxetine and venlafaxine, respectively. Neurological symptoms were prominent and neither patient could walk unaided. Both patients feared they had suffered a 'stroke' and arranged an emergency medical consultation. One patient was correctly diagnosed, the antidepressant was recommenced and symptoms resolved within 24 h. Failure to recognize the reaction resulted in the other patient being referred to a neurologist, undergoing a computed tomography brain scan and an electroencephalogram and remaining symptomatic for over 8 weeks. Relevant pharmacological issues are discussed. The cases illustrate the importance of patients and clinicians being familiar with antidepressant discontinuation symptoms.