Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors.

BACKGROUND: We examined longitudinally the course and predictors of treatment resistance in a large cohort of first-episode psychosis (FEP) patients from initiation of antipsychotic treatment. We hypothesized that antipsychotic treatment resistance is: (a) present at illness onset; and (b) differentially associated with clinical and demographic factors. METHOD: The study sample comprised 323 FEP patients who were studied at first contact and at 10-year follow-up. We collated clinical information on severity of symptoms, antipsychotic medication and treatment adherence during the follow-up period to determine the presence, course and predictors of treatment resistance. RESULTS: From the 23% of the patients, who were treatment resistant, 84% were treatment resistant from illness onset. Multivariable regression analysis revealed that diagnosis of schizophrenia, negative symptoms, younger age at onset, and longer duration of untreated psychosis predicted treatment resistance from illness onset. CONCLUSIONS: The striking majority of treatment-resistant patients do not respond to first-line antipsychotic treatment even at time of FEP. Clinicians must be alert to this subgroup of patients and consider clozapine treatment as early as possible during the first presentation of psychosis.

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.

Antipsychotic-related fatal poisoning, England and Wales, 1993-2013: impact of the withdrawal of thioridazine.

CONTEXT: Use of second generation antipsychotics in England and Wales has increased in recent years whilst prescription of first generation antipsychotics has decreased. METHODS: To evaluate the impact of this change and of the withdrawal of thioridazine in 2000 on antipsychotic-related fatal poisoning, we reviewed all such deaths in England and Wales 1993-2013 recorded on the Office for National Statistics drug poisoning deaths database. We also reviewed antipsychotic prescribing in the community, England and Wales, 2001-2013. Use of routine mortality data: When an antipsychotic was recorded with other drug(s), the death certificate does not normally say if the antipsychotic caused the death rather than the other substance(s). A second consideration concerns intent. A record of "undetermined intent" is likely to have been intentional self-poisoning, the evidence being insufficient to be certain that the individual intended to kill. A record of drug abuse/dependence, on the other hand, is likely to have been associated with an unintentional death. Accuracy of the diagnosis of poisoning: When investigating a death in someone prescribed antipsychotics, toxicological analysis of biological samples collected post-mortem is usually performed. However, prolonged attempts at resuscitation, or diffusion from tissues into blood as autolysis proceeds, may serve to alter the composition of blood sampled after death from that circulating at death. With chlorpromazine and with olanzapine a further factor is that these compounds are notoriously unstable in post-mortem blood. Deaths from antipsychotics: There were 1544 antipsychotic-related poisoning deaths. Deaths in males (N = 948) were almost twice those in females. For most antipsychotics, the proportion of deaths in which a specific antipsychotic featured either alone, or only with alcohol was 30-40%, but for clozapine (193 deaths) such mentions totalled 66%. For clozapine, the proportion of deaths attributed to either intentional self-harm, or undetermined intent was 44%, but for all other drugs except haloperidol (20 deaths) the proportion was 56% or more. The annual number of antipsychotic-related deaths increased from some 55 per year (1.0 per million population) between 1993 and 1998 to 74 (1.5 per million population) in 2000, and then after falling slightly in 2002 increased steadily to reach 109 (1.9 per million population) in 2013. Intent: The annual number of intentional and unascertained intent poisoning deaths remained relatively constant throughout the study period (1993: 35 deaths, 2013: 38 deaths) hence the increase in antipsychotic-related deaths since 2002 was almost entirely in unintentional poisoning involving second generation antipsychotics. Clozapine, olanzapine, and quetiapine were the second generation antipsychotics mentioned most frequently in unintentional poisonings (99, 136, and 99 deaths, respectively). Mentions of diamorphine/morphine and methadone (67 and 99 deaths, respectively) together with an antipsychotic were mainly (84 and 90%, respectively) in either unintentional or drug abuse-related deaths. Deaths and community prescriptions: Deaths involving antipsychotics (10 or more deaths) were in the range 11.3-17.1 deaths per million community prescriptions in England and Wales, 2001-2013. Almost all (96%) such deaths now involve second generation antipsychotics. This is keeping with the increase in annual numbers of prescriptions of these drugs overall (<1 million in 2000, 7 million in 2013), largely driven by increases in prescriptions for olanzapine and quetiapine. In contrast, deaths involving thioridazine declined markedly (from 40 in 2000 to 10 in 2003-2013) in line with the fall in prescriptions for thioridazine from 2001. CONCLUSIONS: The removal of thioridazine has had no apparent effect on the incidence of antipsychotic-related fatal poisoning in England and Wales. That such deaths have increased steadily since 2001 is in large part attributable to an increase in unintentional deaths related to (i) clozapine, and (ii) co-exposure to opioids, principally diamorphine and methadone.

The quality of reporting of phase II and III trials for new antipsychotics: a systematic review.

BACKGROUND: The findings of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) called previous trials of antipsychotics into question, including pre-licensing trials. Concerns regarding methodological robustness and quality of reporting increased. This systematic review aimed to examine the quality of reporting of phase II and III trials for new antipsychotics in the aftermath of the CATIE and CUtLASS studies. METHOD: Electronic searches were conducted in EMBASE, Medline and Cochrane databases and also ClinicalTrials.gov for antipsychotic trials (published between January 2006 and February 2012). Phase II and III randomized controlled trials (RCTs) for iloperidone, asenapine, paliperidone, olanzapine, lurasidone and pomaglumetad methionil were selected for schizophrenia and schizoaffective disorder. The reporting of the methodology was evaluated in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines. RESULTS: Thirty-one articles regarding 32 studies were included. There was insufficient reporting of design in 47% of studies and only 13% explicitly stated a primary hypothesis. Exclusion criteria were poorly reported for diagnosis in 22% of studies. Detail regarding comparators, particularly placebos, was suboptimal for 56% of studies, and permitted concomitant medication was often not reported (19%). Randomization methods were poorly described in 56% of studies and reporting on blinding was insufficient in 84% of studies. Sample size calculations were insufficiently reported in 59% of studies. CONCLUSIONS: The quality of reporting of phase II and III trials for new antipsychotics does not reach the standards outlined in the CONSORT guidelines. Authors often fail to adequately report design and methodological processes, potentially impeding the progress of research on antipsychotic efficacy. Both policymakers and clinicians require high quality reporting before decisions are made regarding licensing and prescribing of new antipsychotics.

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.

Are depot antipsychotics more coercive than tablets? The patient's perspective.

Some clinicians consider depot antipsychotics to be stigmatising, coercive and unacceptable to patients. This cross-sectional study investigated patients' perspectives of coercion for depot and oral antipsychotics. In all, 72 participants with chronic mental illness on voluntary maintenance antipsychotic medication were interviewed for their views on oral and depot medication and experiences of coercion. The MacArthur Admission Experience (short form) was adapted to explore coercion regarding medication. Mean total coercion levels were higher for those on depot (depot: mean 4.39; oral: 2.80, P = 0.027), as were perceived coercion (2.52 vs 1.73, P = 0.041) and negative pressures subscales (1.17 vs 0.33, P = 0.009). No significant differences were found for the 'voice' subscale and affective reactions. Specifically, more participants on depot felt that people try to force them to take medication (30% vs 2%, P< 0.001). Depots were perceived as more coercive than oral antipsychotics. Greater perceived coercion may explain why some consider depots to be a more stigmatising form of treatment. Although forced medication is sometimes required, the experience of coercion should be minimised by giving patients a fair say in treatment decisions, regardless of formulation.

Amisulpride - dose, plasma concentration, occupancy and response: implications for therapeutic drug monitoring.

OBJECTIVE: To evaluate the relationships between dose, plasma concentration, pharmacological activity and clinical outcome to evaluate the appropriateness of therapeutic drug monitoring (TDM) in patients receiving amisulpride. METHOD: Literature search of Embase, Medline and PubMed databases. RESULTS: Amisulpride plasma concentration is closely correlated with dose (r(2) = 0.96, P < 0.0001), dopamine occupancy, response and with extra-pyramidal symptoms (EPS). Dose is correlated with response, dopamine occupancy and EPS. Optimal clinical response was found at doses of 400-800 mg/day, corresponding to plasma levels of approximately 200-500 ng/ml. EPS appears to be more reliably predicted by a plasma level above 320 ng/ml than by a particular dose. CONCLUSION: The effects and safety of amisulpride in the treatment of schizophrenia and schizoaffective disorder are predicted by daily dose. The plasma concentration threshold for response appears to be approximately 200 ng/ml. EPS are more reliably predicted by plasma level than by dose. TDM for patients prescribed amisulpride is thus of some clinical value.

Attitudes regarding mental health nurse prescribing among psychiatrists and nurses: a cross-sectional questionnaire study.

BACKGROUND: In the United Kingdom, mental health nurses (MHNs) can independently prescribe medication once they have completed a training course. This study investigated attitudes to mental health nurse prescribing held by psychiatrists and nurses. METHOD: 119 MHNs and 82 psychiatrists working in South-East England were randomly sampled. Participants completed a newly created questionnaire. This included individual item statements with 6-point likert scales to test levels of agreement which were summated into 7 subscales. RESULTS: Psychiatrists had significantly less favourable, albeit generally positive attitudes than MHNs regarding general beliefs (63% vs. 70%, p<0.001), impact (62% vs. 70%, p<0.001), uses (60% vs. 71%, p<0.001), clinical responsibility (69% vs. 62%, p<0.001) and legal responsibility (71% vs. 64%, p<0.001). More MHNs than psychiatrists believed that nurse prescribing would be useful in emergency situations for rapid tranquilisation (82% vs. 37%, p<0.001), and that the consultant psychiatrist should have ultimate clinical responsibility for prescribing by an MHN (42% vs. 28%, p<0.001). Approximately half of all participants agreed nurse prescribing would create conflict in clinical teams. CONCLUSIONS: The majority of both groups were in favour of mental health nurse prescribing, although significantly more psychiatrists expressed concerns. This may be explained by a perceived change in power balance.

Depot and oral antipsychotics: patient preferences and attitudes are not the same thing.

Some clinicians believe that antipsychotic depot injections are unacceptable to patients. This cross-sectional study investigated patients' attitudes regarding antipsychotics, and included within-participant comparisons. Two hundred and twenty-two out-patients with schizophrenia/schizoaffective disorder completed the Drug Attitude Inventory (DAI-10), scales on insight, side effects and treatment preferences. Formulation preference was associated with current medication formulation: depots were preferred by 43% (33/76) on depot vs 6% (8/146) on orals (P < 0.001). Attitudes (DAI scores) regarding current formulation were influenced by illness duration, extrapyramidal symptoms and insight but not by formulation (depot vs oral). For those with experience of both formulations, participants currently on tablets scored depots less favourably than oral (4.27 vs 6.89, P < 0.001); those on depot did not differentiate. When voluntary patients on maintenance antipsychotics are asked about their attitudes to their current medication, those on depot respond similarly to those on oral. However, when asked to state a preference for formulation (depot vs oral), patients tend to favour their current formulation. Whatever leads some to switch from depot to oral, leaves a lasting negative impression of the depot and this may limit uptake of newer depots.

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.

Antipsychotic depot medication and attitudes of community psychiatric nurses.

Utilization of long-acting antipsychotic injections (depots) shows wide regional variation. In many countries, community psychiatric nurses (CPNs) administer depots but their concerns and attitudes regarding these drugs are seldom considered. We aimed to investigate attitudes and knowledge towards depots in a cross-sectional survey of CPNs in London, and compare them with those of psychiatrists obtained in a previous study. Three subscales of a depot attitude/knowledge questionnaire were used with additional items which referred to aspects of the CPN role. Participants were 70 CPNs who attended an academic meeting. Most CPNs reported that they were involved in treatment decisions (78%) although some CPNs seldom asked their patients about side effects (19%) and felt that they did not have sufficient time for consultations (23%) or training (23%). Several CPNs believed that depots are old fashioned (34%) and stigmatizing (44%). Compared to psychiatrists, CPNs believed more that depots compromised patient autonomy (28%, P = 0.003) and were coercive (42%, P < 0.001). Familiarity with depots and their knowledge of side effects were positively associated with favourable attitudes. CPNs have several strongly endorsed attitudes towards depot medication. Interprofessional group differences also exist which may undermine the treatment process. Training/refresher courses about depots should highlight systematic treatment decision-making and side effect monitoring which, in turn, may improve professionals' attitudes, knowledge and clinical monitoring of depots.

Chronic fatigue syndrome in children: a cross sectional survey.

BACKGROUND: Chronic fatigue syndrome (CFS) in children is a controversial diagnosis with unclear aetiology, ill defined but likely increasing incidence, and debatable clinical management options. However these children experience real and considerable suffering. Appropriate research in this clinical population is sparse and usually occurs in tertiary referral units. METHODS: Cross sectional survey of 36 children attending a GP specialist interest clinic in southeast England. RESULTS: Patient sociodemographics and clinical morbidity were largely comparable to the literature from tertiary referral research centres. Some prognostic indicators for adults did not readily transfer to this younger age group, although several children had a positive family psychiatric history. Receiving treatment was associated with increased school attendance, but one third of subjects obtained no qualifications. Return to normal health or significant overall improvement was reported by 29/36 subjects. CONCLUSIONS: The outcomes in this setting are favourable and comparable to those seen in a controlled setting; this study supports the concept that the prognosis for CFS in children and adolescents is generally good. However, the impact of the illness is significant and this is perhaps most evident in terms of education. Current methods of reporting educational outcomes in the literature are varied and merit development of standardised tools.

Psychiatrists' attitudes to maintenance medication for patients with schizophrenia.

BACKGROUND: Maintenance antipsychotic medication is the mainstay of relapse prevention in patients with schizophrenia. Long acting depot antipsychotics were developed to promote treatment adherence and yet their utilization is variable, perhaps due to negative attitudes of both patients and psychiatrists. Recently, a shift away from depots has occurred, in favour of the newer atypical oral antipsychotics. METHOD: This study investigated the current attitudes and knowledge concerning depots, with a newly designed questionnaire, in a cross-sectional postal survey of qualified psychiatrists working in south-east England. RESULTS: A substantial minority of psychiatrists believe that depots are old fashioned (40%), stigmatizing (48%) and are associated with more side-effects than typical oral antipsychotics (38%). Many believe that depots are as efficacious as oral medication (91%) but are less acceptable to patients (69%) and relatives (66%). A large majority consider depots enhance patient compliance (81%) and prevent relapse (94%). Psychiatrists would be persuaded to prescribe depots if they were associated with fewer side-effects, in patients where compliance is an issue, and if atypical depot antipsychotics were available, presumably because they would have a lower incidence of side-effects. Additionally, psychiatrists' knowledge about depots was positively associated with attitudes. More favourable patient-centred attitudes were reported by psychiatrists with higher depot use. CONCLUSION: Practising psychiatrists have several strongly endorsed attitudes towards depot medication that are associated with knowledge and prescribing habits. By updating psychiatrists' knowledge about depots, in turn their attitudes may become more positive and prescribing practices may subsequently change.