To send content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about sending content to .
To send content items to your Kindle, first ensure email@example.com
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Despite its numerous side effects, clozapine is still the most effective antipsychotics making it an ideal reference substance to validate the efficacy of novel compounds for the treatment of schizophrenia. However, blood–brain barrier permeability for most new molecular entities is unknown, requiring central delivery. Thus, we performed a dose-finding study for chronic intracerebroventricular (icv) delivery of clozapine in mice.
Specifically, we implanted wild-type C57BL/6J mice with osmotic minipumps (Alzet) delivering clozapine at a rate of 0.15 µl/h at different concentrations (0, 3.5, 7 and 14 mg/ml, i.e. 0, 12.5, 25 and 50 µg/day). Mice were tested weekly in a modified SHIRPA paradigm, for locomotor activity in the open field and for prepulse inhibition (PPI) of the acoustic startle response (ASR) for a period of 3 weeks.
None of the clozapine concentrations caused neurological deficits or evident gross behavioural alterations in the SHIRPA paradigm. In male mice, clozapine had no significant effect on locomotor activity or PPI of the ASR. In female mice, the 7 and 14 mg/ml dose of clozapine significantly affected both open field activity and PPI, while 3.5 mg/ml of clozapine increased PPI but had no effects on locomotor activity.
Our findings indicate that 7 mg/ml may be the optimal dose for chronic icv delivery of clozapine in mice, allowing comparison to screen for novel antipsychotic compounds.
There is a paucity of available research to guide clinical practice in delusional disorder (DD), particularly in late life. This study aimed to evaluate antipsychotic use and treatment outcomes in patients with DD aged 65 years and older. Secondarily, we sought to examine associated clinical features and socio-demographic variables.
Design and setting:
This descriptive study reviewed all consecutive cases of DD referred to an Australian old age psychiatry service over a 12-year period. Fifty-five patients were assessed in the inpatient and/or community setting, with data verified from a review of all individual medical records.
Data were collected with respect to antipsychotic use, outcomes, and clinical features. Socio-demographic variables of DD cases were compared to a non-matched comparison group (n=278) and an age and gender matched comparison group with a 1:1 ratio (n=55).
The predominant type of DD was persecutory (87%). Non-prominent hallucinations were experienced by 18%, and depressive symptoms occurred in 22%. There was a statistically significant association between having DD and social isolation (χ2= 11.04 (DF=1) p<0.001; McNemar’s test p<0.001). Atypical antipsychotic medication was prescribed in 32 cases, with follow-up permitted in 51 of the 55 cases (mean duration 36.6 months). Sustained recovery occurred in 20%, and improvement in an additional 35% of the study sample. Four patients subsequently developed dementia, and two developed mild cognitive impairment.
Clinical improvement, including sustained recovery, occurred in more than half of those with late life DD. The majority of those who improved (96%) received atypical antipsychotics.
The author reflects on discoveries over the course of a century concerning histamine as a potent chemical signal and neurotransmitter, the development of antihistamines, including promethazine, and chlorpromazine from a common precursor, and the recognition of a major brain pathway involving histamine. Although chlorpromazine has been succeeded by numerous other antipsychotics, promethazine remains the antihistamine recommended for sedation in acutely disturbed patients, largely because it is potently anticholinergic at atropinic muscarinic receptors and therefore anti-Parkinsonian: this means it is also useful in combination with older antipsychotics such as haloperidol.
Because ethically and practically a randomized control trial of antipsychotics will never be done, we recently conducted and reported a 8- to 50-year, naturalistic follow-up from an academic clinic of patients with chronic schizophrenia on antipsychotic medication. We found that better medication adherence was a statistically significant predictor of better long-term global outcome and life satisfaction. Because there were important limitations on our findings, we now in this communication, using similar methodology, detail outcomes for a very different sample—inner city patients with chronic schizophrenia with a long past history of antipsychotic treatment, who were enrolled in clinical trials for new medications for schizophrenia.
This is a retrospective, naturalistic, longitudinal 6- to 49-years antipsychotic treatment (mean average, 20) follow-up of a consecutive series of patients volunteering for screening for studies with schizophrenia. Lifetime data were collected on (1) their medication adherence, (2) long-term global outcome, and (3) life satisfaction. Outcomes were rated by 2 different clinicians, 1 with information on medication adherence (nonblind rater) and 1 without (blind rater). We used linear regression models adjusted for age, family support, substance use disorder, race, marital status, and number of years in treatment to estimate the association between adherence and each outcome.
A total of 34 patients were assessed. Medication adherence was positively associated with the blind clinician’s rating of global outcome (P value=0.03) and the global assessment of functioning (P value=0.05). In the nonblinded clinician rating, medication adherence was unrelated to global outcome (P value=0.26) and to patients’ report of life satisfaction (P value=0.54).
This replication study, like our previous study, is not inconsistent with the recommendation for continuous, long-term treatment for chronic schizophrenia unless medically contraindicated.
New studies of long-term outcomes claim to show that taking antipsychotics on a continuous and indefinite basis is the best approach for people diagnosed with a first episode of psychosis or schizophrenia. A 10-year follow-up of a trial of quetiapine maintenance, for example, found a higher proportion of people with a poor composite outcome in the group initially randomised to placebo. However, most people classified as showing poor outcome were rated as having a mild score on a single psychotic symptom; there were no differences in overall symptoms, positive or negative symptoms or level of functioning. Moreover, 16% of participants did not have a follow-up interview and data from the end of the original trial were used instead. A study using a Finnish database suggested that mortality and readmission were higher in people who did not start long-term antipsychotic treatment or who discontinued it as compared with long-term continuous users. However, the analysis did not control for important confounders and is likely to reflect the fact that people who do not comply with treatment are at higher risk of death due to underlying health risks and behaviours. The analysis showed a slightly higher risk of readmission among non-users of antipsychotics compared with long-term users and a more substantial increased risk among people who discontinued treatment. However, follow-up ceased at the first readmission and therefore eventual, long-term outcome was not assessed. Speed of reduction and whether it was done with or without clinical support were also not distinguished.
Recently the Norwegian Health Minister ordered the creation of medication-free treatment wards as a result of the lobbying by patients’ groups and activists. The idea behind this is that patients should have the right to choose their treatment, but for the first time, with this arrangement, the user/patient does not choose between treatment options; he literally determines by himself what efficacious treatment is. In our opinion this is another step towards a ‘reverse stigma’ which denies patients the right to be considered as such and eventually kicks them out of the health care system, deprives them of the right for proper treatment and care and instead puts them at the jurisdiction of the much cheaper and ineffective social services.
Research on the risk of stroke following the use of mood stabilisers specific to patients with bipolar disorder is limited.
In this study, we investigated the risk of stroke following the exposure to mood stabilisers in patients with bipolar disorder.
Data for this nationwide population-based study were derived from the Taiwan National Health Insurance Research Database. Among a retrospective cohort of patients with bipolar disorder (n = 19 433), 609 new-onset cases of stroke were identified from 1999 to 2012. A case–crossover study design utilising 14-day windows was applied to assess the acute exposure effect of individual mood stabilisers on the risk of ischaemic, haemorrhagic and other types of stroke in patients with bipolar disorder.
Mood stabilisers as a group were significantly associated with the increased risk of stroke in patients with bipolar disorder (adjusted risk ratio, 1.26; P = 0.041). Among individual mood stabilisers, acute exposure to carbamazepine had the highest risk of stroke (adjusted risk ratio, 1.68; P = 0.018), particularly the ischaemic type (adjusted risk ratio, 1.81; P = 0.037). In addition, acute exposure to valproic acid elevated the risk of haemorrhagic stroke (adjusted risk ratio, 1.76; P = 0.022). In contrast, acute exposure to lithium and lamotrigine did not significantly increase the risk of any type of stroke.
Use of carbamazepine and valproic acid, but not lithium and lamotrigine, is associated with increased risk of stroke in patients with bipolar disorder.
Psychotropic medications are frequently co-prescribed with antiretroviral therapy (ART), owing to a high prevalence of psychiatric illness within the population living with HIV, as well as a 7-fold increased risk of HIV infection among patients with psychiatric illness. While ART has been notoriously associated with a multitude of pharmacokinetic drug interactions involving the cytochrome P450 enzyme system, the magnitude and clinical impact of these interactions with psychotropics may range from negligible effects on plasma concentrations to life-threatening torsades de pointes or respiratory depression. This comprehensive review summarizes the currently available information regarding drug–drug interactions between antiretrovirals and pharmacologic agents utilized in the treatment of psychiatric disorders—antidepressants, stimulants, antipsychotics, anxiolytics, mood stabilizers, and treatments for opioid use disorder and alcohol use disorder—and provides recommendations for their management. Additionally, overlapping toxicities between antiretrovirals and the psychotropic classes are highlighted. Knowledge of the interaction and adverse effect potential of specific antiretrovirals and psychotropics will allow clinicians to make informed prescribing decisions to better promote the health and wellness of this high-risk population.
Movement disorders associated with exposure to antipsychotic drugs are common and stigmatising but underdiagnosed.
To develop and evaluate a new clinical procedure, the ScanMove instrument, for the screening of antipsychotic-associated movement disorders for use by mental health nurses.
Item selection and content validity assessment for the ScanMove instrument were conducted by a panel of neurologists, psychiatrists and a mental health nurse, who operationalised a 31-item screening procedure. Interrater reliability was measured on ratings for 30 patients with psychosis from ten mental health nurses evaluating video recordings of the procedure. Criterion and concurrent validity were tested comparing the ScanMove instrument-based rating of 13 mental health nurses for 635 community patients from mental health services with diagnostic judgement of a movement disorder neurologist based on the ScanMove instrument and a reference procedure comprising a selection of commonly used rating scales.
Interreliability analysis showed no systematic difference between raters in their prediction of any antipsychotic-associated movement disorders category. On criterion validity testing, the ScanMove instrument showed good sensitivity for parkinsonism (90%) and hyperkinesia (89%), but not for akathisia (38%), whereas specificity was low for parkinsonism and hyperkinesia, and moderate for akathisia.
The ScanMove instrument demonstrated good feasibility and interrater reliability, and acceptable sensitivity as a mental health nurse-administered screening tool for parkinsonism and hyperkinesia.
The influence of pharmaceuticals on the environment is an increasing concern among environmental toxicologists. It is known that their growing use is leading to detectable levels in wastewater, conceivably causing harm to aquatic ecosystems. Psychotropic medication is one such group of substances, particularly affecting high-income countries. While these drugs have a clear place in therapy, there is debate around the risk/benefit ratio in patients with mild mental health problems. Therefore, it is necessary to evaluate the wider implications as risks could extend beyond the individual to non-target organisms, particularly those in rivers and estuaries.
An ‘assertive approach’ to clozapine, where nasogastric administration is approved, is assessed through a case-load analysis to provide the first systematic description of its use and outcomes worldwide.
Five of the most extremely ill patients with treatment-resistant schizophrenia were established and/or maintained on clozapine, resulting in improvements to their mental state; incidents were reduced, segregation was terminated and progression to less restrictive environments was achieved.
Despite being underutilised and rarely enforced, in extreme circumstances, an assertive approach to clozapine can be justified. Nasogastric clozapine can be safely delivered and the approach itself, rather than actual nasogastric administration, may be enough to help establish and maintain patients with treatment-resistant schizophrenia on the most effective treatment.
Declaration of interest
E.S. has received speaker fees from Jansen Pharmaceuticals and Novartis.
Tardive dyskinesia is a common iatrogenic neurological and neurobehavioural syndrome associated with the use of antidopaminergic medication, especially antipsychotics. Prior to the introduction of the newer antipsychotics in the 1990s, it was one of the major areas of psychiatric research but interest waned as the new drugs were reputed to have a reduced liability to extrapyramidal adverse effects in general, a claim now discredited by numerous pragmatic research studies. Early small-scale short-term prevalence studies were presented as evidence to support the assumption that patients on the newer drugs did indeed have a lower prevalence of tardive dyskinesia but recent large-scale review of studies with patients exposed for longer suggest that things have not changed. This article presents a clinical overview of a complex and varied syndrome in terms of its phenomenology, epidemiology and risk factors; a companion article will consider treatment. This overview aims to highlight tardive dyskinesia once again, especially to practitioners who have trained in an environment where this was considered mainly in historical terms.
•Understand the complex phenomenology comprising the syndrome of tardive dyskinesia
•Appreciate recent data on prevalence and incidence with the newer antipsychotics
•Be aware of risk factors when recommending antipsychotic (and other antidopaminergic) drugs
In addition to suicide prediction, neuroscience can be expected to contribute in a unique and substantial way to the treatment of suicide risk. For psychotropic drugs such as lithium and clozapine a specific antisuicidal effect has been demonstrated, independent of effects on associated psychiatric disorders. The results from studies with ketamine are promising as they indicate a rapid and sustained relief of suicidal thoughts. Neurostimulation and neuromodulation provide new approaches to treatment, with a substantial impact on suicide risk. Novel pharmacological compounds targeting the vulnerability to suicidal behavior include drugs that affect the stress-response system and neuroprotective factors.
‘Deprescribing’ here comprises arguments against treating patients who have been psychotic beyond first episode. Nevertheless, four out of five patients relapse, compared with only two of five still taking medication. However, much first-episode psychosis is not schizophrenia, but persistent substance-induced psychotic disorder. Virtually nothing is known about factors which facilitate this in the minority who develop it, nor how to decide if the patient will relapse off medication. Patients who are well, stable and tolerating minimal doses of medication should be the first to suggest that they try to do without it, not us.
DECLARATION OF INTEREST
A.M. has worked with pharmaceutical companies regarding the introduction of atypical antipsychotic treatments for schizophrenia, received research funding and spoken at conferences.
Antipsychotic drugs are associated with movement disorders, especially with long-term use. Tardive dyskinesia, a condition characterised by repetitive involuntary muscle activity, is considered to be the most chronic, distressing and disabling of antipsychotic-associated movement disorders. There is theoretical justification for the use of cholinergic drugs in tardive dyskinesia, and they are used in clinical practice. A Cochrane systematic review synthesised randomised controlled trial data evaluating the effectiveness of cholinergic drugs for tardive dyskinesia, and for a range of secondary outcomes, including quality of life. In line with the authors of the review, this Commentary concludes that much higher-quality evidence on the use of cholinergic drugs in tardive dyskinesia is necessary, and that a patient with tardive dyskinesia should be offered the opportunity to try a newer cholinergic drug, ideally in the context of a well-conducted and reported clinical trial. At the same time, given uncertainty regarding clinical effectiveness, and in view of their accepted adverse effects, it would be understandable if a person with tardive dyskinesia decided to avoid cholinergic drugs.
The effect of antipsychotics medication on cognitive functioning in patients diagnosed with schizophrenia is poorly understood. Some studies of second generation antipsychotics indicated that they improved cognitive functioning while other studies have found that they decrease the level of cognitive functioning.
We included patients with schizophrenia who were in treatment with antipsychotics 1.5 years (baseline) after initiation of treatment and followed them up 3.5 years later (n = 189). At follow-up 60 (32%) had discontinued their antipsychotic treatment and 129 (68%) were still taking antipsychotics. Using the Brief Assessment of Cognition in Schizophrenia (BACS) we assessed cognition at baseline and follow-up.
The patients who discontinued their medication had a higher level of cognitive functioning in all domains at baseline, as well as Global cognitive function [mean z-score −1.50 (s.d. 1.24) v. −2.27 (s.d. 1.30), p = 0.00015]. After controlling for relevant confounders those who discontinued antipsychotic medication improved significantly more than those who remained on antipsychotic medication during the course of the follow-up on the Token Motor task [estimated mean change difference −0.46 (95% CI −0.89 to −0.04)], the Speed of Processing Domain [estimated mean change difference −0.38 (95% CI −0.68 to −0.08)] and global cognition [estimated mean change difference −0.36 (95% CI −0.66 to −0.07)].
Due to the naturalistic design, we cannot conclude on the direction of the relationship between antipsychotics and cognition. There is no evidence that discontinuation of medication had a negative effect on cognitive functioning. Rather, we found that that discontinuation of medication was associated with better cognitive functioning.