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This chapter provides a wide-ranging review of the clinical pharmacology of drugs for the treatment of schizophrenia and psychosis other than clozapine. These are dopamine receptor antagonists and dopamine partial agonists (as per the new Neuroscience-based Nomenclature (NbN) classification). This chapter covers their pharmacodynamics, pharmacokinetics, adverse effects, the latest evidence regarding their ‘antipsychotic’ mechanism of action, their use in the acute and maintenance treatment of schizophrenia, other therapeutic indications and some controversies that surround their use.
Dopamine receptor antagonists and dopamine partial agonists are commonly referred to as antipsychotics. As a clinical shorthand the term ‘antipsychotic’ is likely to remain in use.
Heart disease is the leading cause of death in schizophrenia. However, there has been little research directly examining cardiac function in schizophrenia.
To investigate cardiac structure and function in individuals with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity.
In total, 80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity and glycated haemoglobin levels. Individuals with schizophrenia (‘patients’) and controls were matched for age, gender, ethnicity and body surface area.
Patients had significantly smaller indexed left ventricular (LV) end-diastolic volume (effect size d = −0.82, P = 0.001), LV end-systolic volume (d = −0.58, P = 0.02), LV stroke volume (d = −0.85, P = 0.001), right ventricular (RV) end-diastolic volume (d = −0.79, P = 0.002), RV end-systolic volume (d = −0.58, P = 0.02), and RV stroke volume (d = −0.87, P = 0.001) but unaltered ejection fractions relative to controls. LV concentricity (d = 0.73, P = 0.003) and septal thickness (d = 1.13, P < 0.001) were significantly larger in the patients. Mean concentricity in patients was above the reference range. The findings were largely unchanged after adjusting for smoking and/or exercise levels and were independent of medication dose and duration.
Individuals with schizophrenia show evidence of concentric cardiac remodelling compared with healthy controls of a similar age, gender, ethnicity, body surface area and blood pressure, and independent of smoking and activity levels. This could be contributing to the excess cardiovascular mortality observed in schizophrenia. Future studies should investigate the contribution of antipsychotic medication to these changes.
Given that only a subgroup of patients with schizophrenia responds to first-line antipsychotic drugs, a key clinical question is what underlies treatment response. Observations that prefrontal activity correlates with striatal dopaminergic function, have led to the hypothesis that disrupted frontostriatal functional connectivity (FC) could be associated with altered dopaminergic function. Thus, the aim of this study was to investigate the relationship between frontostriatal FC and striatal dopamine synthesis capacity in patients with schizophrenia who had responded to first-line antipsychotic drug compared with those who had failed but responded to clozapine.
Twenty-four symptomatically stable patients with schizophrenia were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 under clozapine (clozapine group), along with 12 matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging and [18F]DOPA PET scans.
No significant difference was found in the total PANSS score between the patient groups. Voxel-based analysis showed a significant correlation between frontal FC to the associative striatum and the influx rate constant of [18F]DOPA in the corresponding region in the first-line AP group. Region-of-interest analysis confirmed the result (control group: R2 = 0.019, p = 0.665; first-line AP group: R2 = 0.675, p < 0.001; clozapine group: R2 = 0.324, p = 0.054) and the correlation coefficients were significantly different between the groups.
The relationship between striatal dopamine synthesis capacity and frontostriatal FC is different between responders to first-line treatment and clozapine treatment in schizophrenia, indicating that a different pathophysiology could underlie schizophrenia in patients who respond to first-line treatments relative to those who do not.
Converging lines of evidence implicate an important role for the immune system in schizophrenia. Microglia are the resident immune cells of the central nervous system and have many functions including neuroinflammation, axonal guidance and neurotrophic support. We aimed to provide a quantitative review of in vivo PET imaging studies of microglia activation in patients with schizophrenia compared with healthy controls.
Demographic, clinical and imaging measures were extracted from each study and meta-analysis was conducted using a random-effects model (Hedge's g). The difference in 18-kDa translocator protein (TSPO) binding between patients with schizophrenia and healthy controls, as quantified by either binding potential (BP) or volume of distribution (VT), was used as the main outcome. Sub-analysis and sensitivity analysis were carried out to investigate the effects of genotype, ligand and illness stage.
In total, 12 studies comprising 190 patients with schizophrenia and 200 healthy controls met inclusion criteria. There was a significant elevation in tracer binding in schizophrenia patients relative to controls when BP was used as an outcome measure, (Hedge's g = 0.31; p = 0.03) but no significant differences when VT was used (Hedge's g = −0.22; p = 0.29).
In conclusion, there is evidence for moderate elevations in TSPO tracer binding in grey matter relative to other brain tissue in schizophrenia when using BP as an outcome measure, but no difference when VT is the outcome measure. We discuss the relevance of these findings as well as the methodological issues that may underlie the contrasting difference between these outcomes.
The extent of metabolic and lipid changes in first-episode psychosis (FEP) is unclear.
To investigate whether individuals with FEP and no or minimal antipsychotic exposure show lipid and adipocytokine abnormalities compared with healthy controls.
We conducted a meta-analysis of studies examining lipid and adipocytokine parameters in individuals with FEP and no or minimal antipsychotic exposure v. a healthy control group. Studies reported fasting total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and leptin levels.
Of 2070 citations retrieved, 20 case–control studies met inclusion criteria including 1167 patients and 1184 controls. Total cholesterol and LDL cholesterol levels were significantly decreased in patients v. controls, corresponding to an absolute reduction of 0.26mmol/L and 0.15mmol/L respectively. Triglyceride levels were significantly increased in the patient group, corresponding to an absolute increase of 0.08 mmol/L However, HDL cholesterol and leptin levels were not altered in patients v. controls.
Total and LDL cholesterol levels are reduced in FEP, indicating that hypercholesterolaemia in patients with chronic disorder is secondary and potentially modifiable. In contrast, triglycerides are elevated in FEP. Hypertriglyceridaemia is a feature of type 2 diabetes mellitus, therefore this finding adds to the evidence for glucose dysregulation in this cohort. These findings support early intervention targeting nutrition, physical activity and appropriate antipsychotic prescription.
N-methyl-d-aspartate receptor (NMDA-R) autoantibodies have
been reported in people with acute psychosis. We hypothesised that their
presence may be implicated in the aetiology of treatment-refractory
psychosis. We sought to ascertain the point prevalence of NMDA-R antibody
positivity in patients referred to services for treatment-refractory
psychosis. We found that 3 (7.0%) of 43 individuals had low positive NMDA-R
antibody titres. This suggests that NMDA-R autoantibodies are unlikely to
account for a large proportion of treatment-refractory psychosis.
Schizophrenia is usually classified based on clinical presentation. However, the conventional paranoid–disorganised–residual distinctions have had limited clinical utility. Here we draw on the evidence for differences in pathophysiology underlying treatment response to propose a subclassification based on neurobiology to guide diagnostic testing and treatment.
The hypothesis that cortical dopaminergic alterations underlie aspects of schizophrenia has been highly influential.
To bring together and evaluate the imaging evidence for dopaminergic alterations in cortical and other extrastriatal regions in schizophrenia.
Electronic databases were searched for in vivo molecular studies of extrastriatal dopaminergic function in schizophrenia. Twenty-three studies (278 patients and 265 controls) were identified. Clinicodemographic and imaging variables were extracted and effect sizes determined for the dopaminergic measures. There were sufficient data to permit meta-analyses for the temporal cortex, thalamus and substantia nigra but not for other regions.
The meta-analysis of dopamine D2/D3 receptor availability found summary effect sizes of d =–0.32 (95% CI −0.68 to 0.03) for the thalamus, d =–0.23 (95% CI −0.54 to 0.07) for the temporal cortex and d = 0.04 (95% CI −0.92 to 0.99) for the substantia nigra. Confidence intervals were wide and all included no difference between groups. Evidence for other measures/regions is limited because of the small number of studies and in some instances inconsistent findings, although significant differences were reported for D2/D3 receptors in the cingulate and uncus, for D1 receptors in the prefrontal cortex and for dopamine transporter availability in the thalamus.
There is a relative paucity of direct evidence for cortical dopaminergic alterations in schizophrenia, and findings are inconclusive. This is surprising given the wide influence of the hypothesis. Large, well-controlled studies in drug-naive patients are warranted to definitively test this hypothesis.
Clozapine is the only antipsychotic drug licensed for treatment-resistant schizophrenia but its use is often delayed. Since previous studies, national guidelines on the use of clozapine and other antipsychotics have been disseminated to clinicians.
To determine the theoretical delay to clozapine initiation and to quantify the prior use of antipsychotic polypharmacy and high-dose antipsychotic treatment.
Clinico-demographic data were extracted from the treatment records of all patients commencing clozapine in our centre between 2006 and 2010.
Complete records were available for 149 patients. The mean theoretical delay in initiating clozapine was 47.7 months (s.d. = 49.7). Before commencing clozapine, antipsychotic polypharmacy and high-dose treatment was evident in 36.2 and 34.2% of patients respectively. Theoretical delay was related to illness duration (β = 0.7, P<0.001) but did not differ by gender or ethnicity.
Substantial delays to clozapine initiation remain and antipsychotic polypharmacy and high doses are commonly used prior to clozapine, despite treatment guidelines.
Sexual dysfunction is common in psychotic disorder but it is not clear
whether it is intrinsic to the development of the illness or secondary to
To compare sexual function in people at ultra-high risk (UHR) of a
psychotic disorder, patients with first-episode psychosis predominantly
taking antipsychotic drugs and healthy volunteers.
Sexual function was assessed in a UHR group (n = 31), a
group with first-episode psychosis (n = 37) and a
matched control group of healthy volunteers (n = 56)
using the Sexual Function Questionnaire.
There was a significant effect of group on sexual function
(P<0.001). Sexual dysfunction was evident in 50%
of the UHR group, 65% of first-episode patients and 21% of controls.
Within the UHR group, sexual dysfunction was more marked in those who
subsequently developed psychosis than in those who did not. Across all
groups the severity of sexual dysfunction was correlated with the
severity of psychotic symptoms (P<0.001). Within the
first-episode group there was no significant difference in sexual
dysfunction between patients taking prolactin-raising v.
Sexual dysfunction is present prior to onset of psychosis, suggesting it
is intrinsic to the development of illness unlikely to be related to the
prolactin-raising properties of antipsychotic medication.
The dopamine hypothesis has been the major pathophysiological theory of
psychosis in recent decades. Molecular imaging studies have provided
in vivo evidence of increased dopamine synaptic
availability and increased presynaptic dopamine synthesis in the striata of
people with psychotic illnesses. These studies support the predictions of
the dopamine hypothesis, but it remains to be determined whether
dopaminergic abnormalities pre-date or are secondary to the development of
psychosis. We selectively review the molecular imaging studies of the
striatal dopaminergic system in psychosis and link this to models of
psychosis and the functional subdivisions of the striatum to make
predictions for the dopaminergic system in the prodromal phase of
Integrated planar circulator circuits operating at frequencies near 10 GHz have been fabricated using transferred film techniques. A 100 micrometer thick film of single-crystal yttrium iron garnet was transferred onto a metallized silicon die using a bond and lap-back process. The alloy bond layer was formed through a low-temperature solid-liquid interdiffusion process using films of indium and gold. This bond layer proved of sufficient strength to permit removal of the gadolinium gallium garnet substrate through grinding, but chemical analysis of the bond shows that interdiffusion occurs between the bond and metallization layers. These integrated gamet/silicon circulator circuits show good device performance.
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