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Partial agonists of dopamine receptors are used in combination with full antagonists in treating psychosis, either to mitigate side-effects or in the hope of increasing effectiveness. We examine how combinations may affect the occupancy of D2/D3 dopamine receptors and explore how these can explain the outcomes in the light of the dopamine hypothesis of psychosis. The combinations considered here are from published studies combining aripiprazole with amisulpride, with risperidone in people with hyperprolactinaemia and with olanzapine to mitigate weight gain. We discuss possible worsening of symptoms by the addition of a partial agonist or switching. We also examine the potentially adverse interaction with a full antagonist such as haloperidol given during a subsequent relapse to control severe agitation.
Partial agonists such as aripiprazole are often used in addition to a full antagonist such as amisulpride, risperidone or olanzapine in an attempt to mitigate side-effects such as sedation, hyperprolactinaemia and weight gain. However, there can be unintended consequences, including worsening of psychosis. Moreover, previous exposure to a partial agonist may impair the subsequent response to a potent antipsychotic such as haloperidol used to control symptoms of relapse. To understand the mechanisms involved, a method is needed to compare potency in the pharmacological effects of different drugs used in combinations. This article is intended to explore and explain the theoretical principles based on the dopamine hypothesis of schizophrenia. We apply the method to analyse a recently described trial in which two full antagonists (olanzapine and amisulpride) are compared individually and in combination.
Aripiprazole, brexpiprazole and cariprazine are partial dopamine (and serotonin) agonists developed as novel antipsychotics. This article discusses their pharmacology, evidence on their licensed and off-licence uses (including psychosis, mania, bipolar depression, Tourette syndrome and autism spectrum disorder) and side-effects. In schizophrenia, they have a low risk of Parkinsonism or hyperprolactinaemia, cause modest increases in body weight and are of moderate efficacy.
This article discusses dopamine partial agonism, which is the main mechanism of action of the psychiatric drugs aripiprazole, brexpiprazole and cariprazine. It outlines the principles of receptor theory and the structure of dopamine receptors; characterises agonists, antagonists and partial agonists; and summarises the dopamine hypothesis of psychosis and the role of dopamine and serotonin in depression.
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.
‘Rapid tranquillisation’ refers to the use of medication to calm highly agitated individuals experiencing mental disorder who have not responded to non-pharmacological approaches. Commonly it is the initial stage in the treatment of severe and enduring illness. Using medication in this way requires particularly robust evidence of efficacy and the management of side-effects. This article attempts to integrate current understanding of the neurochemical mechanisms of underlying illness and drug actions with therapeutic interventions. It distinguishes arousal from agitation, and effects on sedation from tranquillisation. It reviews critically the practice of rapid tranquillisation in the light of new evidence, changes in the NICE guidelines and British National Formulary recommendations and a national audit (POMH-UK). Broader aspects of management, known as ‘restrictive practices’ (such as control and restraint and seclusion), psychological support of team members, incident reporting, risk assessment, monitoring and medico-legal aspects are not covered.
• Recognise the role of brain transmitter pathways leading to arousal and to agitation
• Be aware of mechanisms of action of benzodiazepines, antipsychotics and antihistamines and distinguishing sedation from calming effects
• Know the recommendations of NICE guidelines for rapid tranquillisation and the findings of the national POMH-UK audit and be able to contribute to local policies
It is unclear whether there is a direct link between economic crises and changes in suicide rates.
The Lopez-Ibor Foundation launched an initiative to study the possible impact of the economic crisis on European suicide rates.
Data was gathered and analysed from 29 European countries and included the number of deaths by suicide in men and women, the unemployment rate, the gross domestic product (GDP) per capita, the annual economic growth rate and inflation.
There was a strong correlation between suicide rates and all economic indices except GPD per capita in men but only a correlation with unemployment in women. However, the increase in suicide rates occurred several months before the economic crisis emerged.
Overall, this study confirms a general relationship between the economic environment and suicide rates; however, it does not support there being a clear causal relationship between the current economic crisis and an increase in the suicide rate.
Clinical psychiatrists working today owe a great deal to the discoveries of the pharmaceutical industry since 1953, especially in relation to antipsychotic drugs. Yet patients need still better antipsychotics with greater efficacy and fewer side-effects. We should not let nostalgia cloud our judgement.
The evaluation of treatment effects is important to both the clinician and the patient. However, outcomes in randomised trials are often difficult to apply to the clinic. The number needed to treat (NNT) is one method that facilitates the interpretation of clinical trials in a meaningful way. When combined with the number needed to harm (NNH), the balance between the risks and benefits of a particular treatment can be appreciated. We illustrate the use of these concepts by focusing on recent large pragmatic studies of antipsychotics, including CATIE, EUFEST and CUtLASS.
The cover of this issue heralds a series of articles in which a visual image derived from cell biology or neuroscience is used to promote understanding of the biological mechanisms fundamental to psychiatry. ‘Images in neuroscience’ are intended to demonstrate the structures and mechanisms of the basic building blocks of brain function, including ionotropic and metabotropic receptors, second messenger systems, specialised ion channels, transmitter pathways, transporters, neuroglial function, and the complex mechanisms within cells that are being revealed, as new genetic associations for mental illness are discovered.
The development of atypical antipsychotics has stimulated research on the treatment of mania. Several well-established options now exist for monotherapy of mania. None of the atypicals has shown greater efficacy than haloperidol in improving manic symptoms, but they all produce fewer extrapyramidal side-effects and they may differ in their effects on depressive symptoms. Combinations of an antipsychotic with lithium or valproate offer further options, with somewhat greater efficacy in treating mania but also with more side-effects.