Neural and Behavioral Correlates of Aberrant Salience in Individuals at Risk for Psychosis

The “aberrant salience” model proposes that psychotic symptoms first emerge when chaotic brain dopamine transmission leads to the attribution of significance to stimuli that would normally be considered irrelevant. This is thought to occur during the prodromal phase of psychotic disorders, but this prediction has not been tested previously. In the present study, we tested this model in 18 healthy volunteers and 18 unmedicated individuals at ultra-high risk of psychosis. Subjects performed the Salience Attribution Test, which provides behavioral measures of adaptive and aberrant motivational salience, during functional magnetic resonance imaging to assess neural responses to relevant and irrelevant stimulus features. On a separate occasion, the same subjects were also studied with [¹⁸F]fluorodopa positron emission tomography to measure dopamine synthesis capacity. Individuals at ultra-high risk of psychosis were more likely to attribute motivational salience to irrelevant stimulus features (t(26.7) = 2.8, P = .008), and this bias was related to the severity of their delusion-like symptoms (r = .62, P = .008). Ventral striatal responses to irrelevant stimulus features were also correlated with delusion-like symptoms in the ultra-high risk group (r = .59, P = .017). Striatal dopamine synthesis capacity correlated negatively with hippocampal responses to irrelevant stimulus features in ultra-high risk individuals, but this relationship was positive in controls. These data are consistent with the hypothesis that aberrant salience processing underlies psychotic symptoms and involves functional alterations in the striatum, hippocampus, and the subcortical dopamine system.Key words: psychosis, aberrant salience, salience attribution test, functional magnetic resonance imaging, positron emission tomography, dopamine     

Transition to Psychosis Associated With Prefrontal and Subcortical Dysfunction in Ultra High-Risk Individuals

Background: People at ultra high risk (UHR) of psychosis have an elevated risk of developing a psychotic disorder, but it is difficult to predict which individuals will make a transition to frank illness. We investigated whether functional magnetic resonance imaging (fMRI) in conjunction with a phonological fluency task at presentation could distinguish subjects who subsequently developed psychosis from those who did not. Methods: Sixty-five subjects (41 with an UHR and 24 healthy controls) were assessed at clinical presentation using fMRI, in conjunction with a verbal fluency task. [18F]-DOPA positron emission tomography (PET) data were also available in a subgroup of 21 UHR and 14 healthy controls subjects. UHR subjects were followed clinically for at least 2 years. Results: Compared with UHR subjects who did not become psychotic, UHR subjects who subsequently developed psychosis showed increased activation in bilateral prefrontal cortex (PFC), brainstem (midbrain/basilar pons), the left hippocampus, and greater midbrain-PFC connectivity. Furthermore, exploratory analysis of [18F]-DOPA PET data showed that transition to psychosis was associated with elevated dopaminergic function in the brainstem region. Conclusions: In people at high risk of psychosis, increased activation in a network of cortical and subcortical regions may predict the subsequent onset of illness. Functional neuroimaging, in conjunction with clinical assessment and other investigations, may facilitate the prediction of outcome in subjects who are vulnerable to psychosis.     

Familial Liability to Psychosis Is Associated With Attenuated Dopamine Stress Signaling in Ventromedial Prefrontal Cortex

Objective: Patients diagnosed with a psychotic disorder and their first-degree relatives display increased reactivity to stress. Theory predicts that experience of psychosocial stress is associated both with ventromedial prefrontal and mesolimbic dopamine neurotransmission. However, while there is evidence of aberrant striatal dopamine processing in psychotic disorder, the role of the prefrontal cortex remains under-researched. This study aimed at investigating stress-induced in vivo dopamine release in ventromedial prefrontal cortex (vmPFC) of individuals at familial risk for psychosis. Method: Fourteen healthy first-degree relatives of patients with a diagnosis of psychotic disorder and 10 control subjects underwent a single dynamic positron emission tomography (PET) scanning session after intravenous administration of 183.2 (SD = 7.6) MBq [¹⁸F]fallypride. Psychosocial stress was initiated at 100min postinjection using a computerized mental arithmetic task with social evaluative threat components. PET data were analyzed using the linearized simplified reference region model. Regression analyses were performed to compare the spatial extent of task-related ligand displacement between control subjects and relatives and to find how it related to self-rated experiences of psychosocial stress and psychosis. Results: First-degree relatives displayed hyporeactive dopamine signaling in the vmPFC in response to stress. Increased levels of subjectively rated stress were associated with increased intensity of psychotic experiences. This effect was particularly pronounced in first-degree relatives. Conclusion: Although previous studies have hypothesized a role for prefrontal dopamine dysfunction in psychosis, this study, to our knowledge, is the first in vivo human imaging study showing attenuated (ie, hyporeactive) dopamine stress neuromodulation in vmPFC of individuals at familial risk for psychosis.Key words: schizophrenia, positron emission tomography, neuromodulation, relatives, mesolimbic, salience     

The Effects of Antipsychotic Treatment on Presynaptic Dopamine Synthesis Capacity in First-Episode Psychosis: A Positron Emission Tomography Study

Background

Elevated striatal dopamine synthesis capacity has been implicated in the etiology and antipsychotic response in psychotic illness. The effects of antipsychotic medication on dopamine synthesis capacity are poorly understood, and no prospective studies have examined this question in a solely first-episode psychosis sample. Furthermore, it is unknown whether antipsychotic efficacy is linked to reductions in dopamine synthesis capacity. We conducted a prospective [¹⁸F]-dihydroxyphenyl-L-alanine positron emission tomography study in antipsychotic naïve/free people with first-episode psychosis commencing antipsychotic treatment.

The psycholinguistics of auditory hallucinations

Abstract

The purpose of this study was to investigate psycholinguistic behaviour, as language processing, verbal reasoning and discourse production, in hallucinating and non-hallucinating subjects suffering from psychotic disorders. Nineteen hallucinating and 13 non-hallucinating subjects were assessed on a battery of tests of psycholinguistic functioning with complementary measures of abstraction and discourse cohesion. The experimental groups were matched with healthy controls by age, gender and education. Only a discourse score differentiated the patient groups. No tests of receptive or executive psycholinguistic functioning or abstraction distinguished the patient groups with hallucinating or non-hallucinating behaviour, thus disorders of linguistic processing in these domains are not specific to patients with auditory hallucinations. The patient groups did differ from their healthy controls on tests that required abstract processing and reasoning. There is also some evidence that both patient groups had difficulty with lexical retrieval or word generation, and with memory and comprehension. The conclusions support a concept of dysfunction of the executive system that facilitates linguistic processing in psychotic disorders. They also support further investigation of a comprehension deficit in psychosis and the use of discourse analysis as a diagnostic tool in this heterogeneous disease.     

Striatal Presynaptic Dopamine in Schizophrenia,Part II: Meta-Analysis of [18F/11C]-DOPA PET Studies

Background: Alterations in striatal dopamine neurotransmission are central to the emergence of psychotic symptoms and to the mechanism of action of antipsychotics. Although the functional integrity of the presynaptic system can be assessed by measuring striatal dopamine synthesis capacity (DSC), no quantitative meta-analysis is available. Methods: Eleven striatal (caudate and putamen) [¹¹C/¹⁸F]-DOPA positron emission tomography studies comparing 113 patients with schizophrenia and 131 healthy controls were included in a quantitative meta-analysis of DSC. Demographic, clinical, and methodological variables were extracted from each study or obtained from the authors and tested as covariates. Hedges’ g was used as a measure of effect size in Comprehensive Meta-Analysis. Publication bias was assessed with funnel plots and Egger’s intercept. Heterogeneity was addressed with the Q statistic and I ² index. Results: Patients and controls were well matched in sociodemographic variables (P > .05). Quantitative evaluation of publication bias was nonsignificant (P = .276). Heterogeneity across study was modest in magnitude and statistically nonsignificant (Q = 19.19; P = .078; I ² = 39.17). Patients with schizophrenia showed increased striatal DSC as compared with controls (Hedges’ g = 0.867, CI 95% from 0.594 to 1.140, Z = 6.222, P < .001). The DSC schizophrenia/control ratio showed a relatively homogenous elevation of around 14% in schizophrenic patients as compared with controls. DSC elevation was regionally confirmed in both caudate and putamen. Controlling for potential confounders such as age, illness duration, gender, psychotic symptoms, and exposure to antipsychotics had no impact on the results. Sensitivity analysis confirmed robustness of meta-analytic findings. Conclusions: The present meta-analysis showed consistently increased striatal DSC in schizophrenia, with a 14% elevation in patients as compared with healthy controls.     

The Interplay Between Postsynaptic Striatal D2/3 Receptor Availability,Adversity Exposure and Odd Beliefs: A [11C]-Raclopride PET Study

BackgroundBetween unaffected mental health and diagnosable psychiatric disorders, there is a vast continuum of functioning. The hypothesized link between striatal dopamine signaling and psychosis has guided a prolific body of research. However, it has been understudied in the context of multiple interacting factors, subclinical phenotypes, and pre-postsynaptic dynamics.MethodThis work investigated psychotic-like experiences and D_2/3 dopamine postsynaptic receptor availability in the dorsal striatum, quantified by in vivo [¹¹C]-raclopride positron emission tomography, in a sample of 24 healthy male individuals. Additional mediation and moderation effects with childhood trauma and key dopamine-regulating genes were examined.ResultsAn inverse relationship between nondisplaceable binding potential and subclinical symptoms was identified. D_2/3 receptor availability in the left putamen fully mediated the association between traumatic childhood experiences and odd beliefs, that is, inclinations to see meaning in randomness and unfounded interpretations. Moreover, the effect of early adversity was moderated by a DRD2 functional variant (rs1076560). The results link environmental and neurobiological influences in the striatum to the origination of psychosis spectrum symptomology, consistent with the social defeat and diathesis–stress models.ConclusionsAdversity exposure may affect the dopamine system as in association with biases in probabilistic reasoning, attributional style, and salience processing. The inverse relationship between D_2/3 availability and symptomology may be explained by endogenous dopamine occupying the receptor, postsynaptic compensatory mechanisms, and/or altered receptor sensitivity. This may also reflect a cognitively stabilizing mechanism in non-help-seeking individuals. Future research should comprehensively characterize molecular parameters of dopamine neurotransmission along the psychosis spectrum and according to subtype profiling.     

Imaging Neuroinflammation in Gray and White Matter in Schizophrenia: An In-Vivo PET Study With [18F]-FEPPA

Neuroinflammation and abnormal immune responses have been implicated in schizophrenia (SCZ). Past studies using positron emission tomography (PET) that examined neuroinflammation in patients with SCZ in vivo using the translocator protein 18kDa (TSPO) target were limited by the insensitivity of the first-generation imaging agent [¹¹C]-PK11195, scanners used, and the small sample sizes studied. Present study uses a novel second-generation TSPO PET radioligand N-acetyl-N-(2-[¹⁸F]fluoroethoxybenzyl)-2-phenoxy-5-pyridinamine ([¹⁸F]-FEPPA) to evaluate whether there is increased neuroinflammation in patients with SCZ. A cross-sectional study was performed using [¹⁸F]-FEPPA and a high-resolution research tomograph (HRRT). Eighteen patients with SCZ with ongoing psychotic symptoms and 27 healthy volunteers (HV) were recruited from a tertiary psychiatric clinical setting and the community, respectively. All participants underwent [¹⁸F]-FEPPA PET and magnetic resonance imaging, and PET data were analyzed to obtain [¹⁸F]-FEPPA total volume of distribution (V _T) using a 2-tissue compartment model with an arterial plasma input function, as previously validated. All subjects were classified as high-, medium- or low-affinity [¹⁸F]-FEPPA binders on the basis of rs6971 polymorphism, and genotype information was incorporated into the analyses of imaging outcomes. No significant differences in neuroinflammation indexed as [¹⁸F]-FEPPA V _T were observed between groups in either gray (F _(1,39) = 0.179, P = .674) or white matter regions (F _(1,38) = 0.597, P = .445). The lack of significant difference in neuroinflammation in treated patients with SCZ in the midst of a psychotic episode and HV suggests that neuroinflammatory processes may take place early in disease progression or are affected by antipsychotic treatment.Key words: translocator protein 18kDa (TSPO), inflammation, positron emission tomography, psychosis, rs6971 polymorphism, microglia     

Functional dynamics of dopamine synthesis during monetary reward and punishment processing

The assessment of dopamine release with the PET competition model is thoroughly validated but entails disadvantages for the investigation of cognitive processes. We introduce a novel approach incorporating 6-[¹⁸F]FDOPA uptake as index of the dynamic regulation of dopamine synthesis enzymes by neuronal firing. The feasibility of this approach is demonstrated by assessing widely described sex differences in dopamine neurotransmission. Reward processing was behaviorally investigated in 36 healthy participants, of whom 16 completed fPET and fMRI during the monetary incentive delay task. A single 50 min fPET acquisition with 6-[¹⁸F]FDOPA served to quantify task-specific changes in dopamine synthesis. In men monetary gain induced stronger increases in ventral striatum dopamine synthesis than loss. Interestingly, the opposite effect was discovered in women. These changes were further associated with reward (men) and punishment sensitivity (women). As expected, fMRI showed robust task-specific neuronal activation but no sex difference. Our findings provide a neurobiological basis for known behavioral sex differences in reward and punishment processing, with important implications in psychiatric disorders showing sex-specific prevalence, altered reward processing and dopamine signaling. The high temporal resolution and magnitude of task-specific changes make fPET a promising tool to investigate functional neurotransmitter dynamics during cognitive processing and in brain disorders.     

Mood Instability and Psychosis: Analyses of British National Survey Data

Background: We used British national survey data to test specific hypotheses that mood instability (1) is associated with psychosis and individual psychotic phenomena, (2) predicts the later emergence of auditory hallucinations and paranoid ideation, and (3) mediates the link between child sexual abuse and psychosis. Methods: We analyzed data from the 2000 and 2007 UK national surveys of psychiatric morbidity (N = 8580 and 7403, respectively). The 2000 survey included an 18-month follow-up of a subsample (N = 2406). Mood instability was assessed from the Structured Clinical Interview for DSM-IV Axis II (SCID-II) questionnaire. Our dependent variables comprised auditory hallucinations, paranoid ideation, the presence of psychosis overall, and a 15-item paranoia scale. Results: Mood instability was strongly associated in cross-sectional analyses with psychosis (2000: OR: 7.5; 95% CI: I 4.1–13.8; 2007: OR: 21.4; CI: 9.7–41.2), paranoid ideation (2000: OR: 4.7; CI: 4.1–5.4; 2007: OR: 5.7; CI: 4.9–6.7), auditory hallucinations (2000: OR: 3.4; CI: 2.6–4.4; 2007: OR 3.5; CI: 2.7–4.7), and paranoia total score (2000: Coefficient: 3.6; CI: 3.3–3.9), remaining so after adjustment for current mood state. Baseline mood instability significantly predicted 18-month inceptions of paranoid ideation (OR: 2.3; CI: 1.6–3.3) and of auditory hallucinations (OR: 2.6; CI: 1.5–4.4). Finally, it mediated a third of the total association of child sexual abuse with psychosis and persecutory ideation and a quarter of that with auditory hallucinations. Conclusions: Mood instability is a prominent feature of psychotic experience and may have a role in its genesis. Targeting mood instability could lead to innovative treatments for psychosis.Key words: epidemiology, psychopathology, paranoia, auditory hallucination, child sexual abuse     

Evidence that onset of psychosis in the population reflects early hallucinatory experiences that through environmental risks and affective dysregulation become complicated by delusions

Objective:

To examine the hypothesis that the “natural” combination of delusions and hallucinations in psychotic disorders in fact represents a selection of early subclinical hallucinatory experiences associated with delusional ideation, resulting in need for care and mental health service use.

Methods:

In the Early Developmental Stages of Psychopathology study, a prospective, 10-year follow-up of a representative cohort of adolescents and young adults in Munich, Germany (n = 2524), clinical psychologists assessed hallucinations and delusions at 2 time points (T2 and T3). Analyses compared differences in psychopathology, familial liability for nonpsychotic disorder, nongenetic risk factors, persistence, and clinical outcome between groups characterized by: (1) absence of positive psychotic symptoms, (2) presence of isolated hallucinations, (3) isolated delusions, and (4) both hallucinations and delusions.

Results:

Delusions and hallucinations occurred together much more often (T2: 3.1%; T3: 2.0%) than predicted by chance (T2: 1.0%; T3: 0.4%; OR = 11.0; 95% CI: 8.1, 15.1). Content of delusions was contingent on presence of hallucinations but modality of hallucinations was not contingent on presence of delusions. The group with both hallucinations and delusions, compared to groups with either delusions or hallucinations in isolation, displayed the strongest associations with familial affective liability and nongenetic risk factors, as well as with persistence of psychotic symptoms, comorbidity with negative symptoms, affective psychopathology, and clinical need.

Conclusions:

The early stages of psychosis may involve hallucinatory experiences that, if complicated by delusional ideation under the influence of environmental risks and (liability for) affective dysregulation, give rise to a poor prognosis hallucinatory–delusional syndrome.     

No evidence for attenuated stress-induced extrastriatal dopamine signaling in psychotic disorder

Stress is an important risk factor in the etiology of psychotic disorder. Preclinical work has shown that stress primarily increases dopamine (DA) transmission in the frontal cortex. Given that DA-mediated hypofrontality is hypothesized to be a cardinal feature of psychotic disorder, stress-related extrastriatal DA release may be altered in psychotic disorder. Here we quantified for the first time stress-induced extrastriatal DA release and the spatial extent of extrastriatal DA release in individuals with non-affective psychotic disorder (NAPD). Twelve healthy volunteers (HV) and 12 matched drug-free NAPD patients underwent a single infusion [¹⁸F]fallypride positron emission tomography scan during which they completed the control and stress condition of the Montreal Imaging Stress Task. HV and NAPD did not differ in stress-induced [¹⁸F]fallypride displacement and the spatial extent of stress-induced [¹⁸F]fallypride displacement in medial prefrontal cortex (mPFC) and temporal cortex (TC). In the whole sample, the spatial extent of stress-induced radioligand displacement in right ventro-mPFC, but not dorso-mPFC or TC, was positively associated with task-induced subjective stress. Psychotic symptoms during the scan or negative, positive and general subscales of the Positive and Negative Syndrome Scale were not associated with stress-induced [¹⁸F]fallypride displacement nor the spatial extent of stress-induced [¹⁸F]fallypride displacement in NAPD. Our results do not offer evidence for altered stress-induced extrastriatal DA signaling in NAPD, nor altered functional relevance. The implications of these findings for the role of the DA system in NAPD and stress processing are discussed.     

COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of 'switching on' hallucinations in the flow of daily life

Objective: A functional polymorphism in the catechol‐o‐methyltransferase gene (COMT Val¹⁵⁸Met) may moderate the psychosis‐inducing effects of cannabis. In order to extend this finding to dynamic effects in the flow of daily life, a momentary assessment study of psychotic symptoms in response to cannabis use was conducted. Method: The experience sampling technique was used to collect data on cannabis use and occurrence of symptoms in daily life in patients with a psychotic disorder (n = 31) and healthy controls (n = 25). Results: Carriers of the COMT Val¹⁵⁸Met Val allele, but not subjects with the Met/Met genotype, showed an increase in hallucinations after cannabis exposure, conditional on prior evidence of psychometric psychosis liability. Conclusion: The findings confirm that in people with psychometric evidence of psychosis liability, COMT Val¹⁵⁸Met genotype moderates the association between cannabis and psychotic phenomena in the flow of daily life.     

Increased Striatal Dopamine Synthesis Capacity in Gambling Addiction

Background

The hypothesis that dopamine plays an important role in the pathophysiology of pathological gambling is pervasive. However, there is little to no direct evidence for a categorical difference between pathological gamblers and healthy control subjects in terms of dopamine transmission in a drug-free state. Here we provide evidence for this hypothesis by comparing dopamine synthesis capacity in the dorsal and ventral parts of the striatum in 13 pathological gamblers and 15 healthy control subjects.

Appraisals and Responses to Experimental Symptom Analogues in Clinical and Nonclinical Individuals With Psychotic Experiences

Objective: Cognitive models of psychosis suggest that anomalous experiences alone do not always lead to clinical psychosis, with appraisals and responses to experiences being central to understanding the transition to “need for care”. Methods: The appraisals and response styles of Clinical (C; n = 28) and Nonclinical (NC; n = 34) individuals with psychotic experiences were compared following experimental analogues of thought interference (Cards Task) and auditory hallucinations (Virtual Acoustic Space Paradigm). Results: The groups were matched in terms of their psychotic experiences. As predicted, the C group scored higher than the NC group on maladaptive appraisals following both tasks, rated the experience as more personally significant, and was more likely to incorporate the experimental setup into their ongoing experiences. The C group also appraised the Cards Task as more salient, distressing, and threatening; this group scored higher on maladaptive—and lower on adaptive—response styles, than the NC group on both tasks. Conclusions: The findings are consistent with cognitive models of psychosis, with maladaptive appraisals and response styles characterizing the C group only. Clinical applications of both tasks are suggested to facilitate the identification and modification of maladaptive appraisals.Key words: psychosis continuum, cognitive model of psychosis, appraisals, experimental analogues of psychotic symptoms     

Cognitive Behavioral Therapy for Subjects at Ultrahigh Risk for Developing Psychosis: A Randomized Controlled Clinical Trial

Background

: Evidence for the effectiveness of treatments for subjects at ultrahigh risk (UHR) for developing psychosis remains inconclusive. Objective : A new cognitive behavioral intervention specifically targeted at cognitive biases (ie, Cognitive Behavioral Therapy [CBT] for UHR patients plus treatment as usual [TAU] called CBTuhr) is compared with TAU in a group of young help-seeking UHR subjects. Methods : A total of 201 patients were recruited at 4 sites and randomized. In most cases, CBTuhr was an add-on therapy because most people were seeking help for a comorbid disorder. The CBT was provided for 6 months, and the follow-up period was 18 months. Results : In the CBTuhr condition, 10 patients transitioned to psychosis compared with 22 in the TAU condition (χ ² (1) = 5.575, P = .03). The number needed to treat (NNT) was 9 (95% confidence interval [CI]: 4.7–89.9). At 18-month follow-up the CBTuhr group was significantly more often remitted from an at-risk mental state, with a NNT of 7 (95% CI: 3.7–71.2). Intention-to-treat analysis, including 5 violations against exclusion criteria, showed a statistical tendency (χ ² (1) = 3.338, P = .06). Conclusions : Compared with TAU, this new CBT (focusing on normalization and awareness of cognitive biases) showed a favorable effect on the transition to psychosis and reduction of subclinical psychotic symptoms in subjects at UHR to develop psychosis. Key words: cognitive behavioral therapy, ultrahigh risk, cognitive biases, prevention, psychosis, schizophrenia     

Spontaneous eye blink rate and dopamine synthesis capacity: preliminary evidence for an absence of positive correlation

Dopamine is central to a number of cognitive functions and brain disorders. Given the cost of neurochemical imaging in humans, behavioural proxy measures of dopamine have gained in popularity in the past decade, such as spontaneous eye blink rate (sEBR). Increased sEBR is commonly associated with increased dopamine function based on pharmacological evidence and patient studies. Yet, this hypothesis has not been validated using in vivo measures of dopamine function in humans. To fill this gap, we measured sEBR and striatal dopamine synthesis capacity using [¹⁸F]DOPA PET in 20 participants (nine healthy individuals and 11 pathological gamblers). Our results, based on frequentist and Bayesian statistics, as well as region‐of‐interest and voxel‐wise analyses, argue against a positive relationship between sEBR and striatal dopamine synthesis capacity. They show that, if anything, the evidence is in favour of a negative relationship. These results, which complement findings from a recent study that failed to observe a relationship between sEBR and dopamine D2 receptor availability, suggest that caution and nuance are warranted when interpreting sEBR in terms of a proxy measure of striatal dopamine.     

Brave New Worlds—Review and Update on Virtual Reality Assessment and Treatment in Psychosis

In recent years, virtual reality (VR) research on psychotic disorders has been initiated. Several studies showed that VR can elicit paranoid thoughts about virtual characters (avatars), both in patients with psychotic disorders and healthy individuals. Real life symptoms and VR experiences were correlated, lending further support to its validity. Neurocognitive deficits and difficulties in social behavior were found in schizophrenia patients, not only in abstract tasks but also using naturalistic virtual environments that are more relevant to daily life, such as a city or encounters with avatars. VR treatments are conceivable for most dimensions of psychotic disorders. There is a small but expanding literature on interventions for delusions, hallucinations, neurocognition, social cognition, and social skills; preliminary results are promising. VR applications for assessment and treatment of psychotic disorders are in their infancy, but appear to have a great potential for increasing our understanding of psychosis and expanding the therapeutic toolbox.Key words: psychosis, schizophrenia, virtual reality     

Mianserin treatment of patients with psychosis induced by antiparkinsonian drugs

We evaluated the effects of mianserin, a relatively selective 5-HT₂ receptor antagonist, on symptoms related to drug-induced psychosis in patients with Parkinson's disease (PD). A total of 12 patients with PD who had developed drug-induced psychosis showed delirium (DSM-III-R criteria;n=10) and pure visual hallucinations (n=2). The antiparkinsonian drugs involved in the drug-induced psychosis werel-DOPA/carbidopa, bromocriptine, trihexyphenidyl, and amantadine. They received mainserin (mean 36.7 mg, range 20–60 mg) given orally for 8 weeks. Complete relief or marked improvement in psychotic symptoms was noted in 8 patients, moderate improvement in 2 patients, and no effect in 2 patients. The parkinsonian disability also decreased slightly in 8 patients. These results suggest that serotonin antagonism at 5-HT₂ receptors may not only play an important role in the treatment of drug-induced psychosis in PD, but may also ameliorate the symptoms of parkinsonism.