Effect of the glycine transporter 1 inhibitor ALX-5407 on dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset.

Dyskinesia and psychosis are complications encountered in advanced Parkinson's disease (PD) following long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA). Disturbances in the glutamatergic system have been associated with both dyskinesia and psychosis, making glutamatergic modulation a potential therapeutic approach for these. Treatments thus far have sought to dampen glutamatergic transmission, for example through blockade of N-methyl-D-aspartate (NMDA) receptors or modulation of metabotropic glutamate receptors 5. In contrast, activation of the glycine-binding site on NMDA receptors is required for their physiological response. Here, we investigated whether indirectly enhancing glutamatergic transmission through inhibition of glycine re-uptake would be efficacious in diminishing both dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. Six marmosets were rendered parkinsonian by MPTP injection. Following repeated administration of L-DOPA to induce dyskinesia and PLBs, they underwent acute challenges of the glycine transporter 1 (GlyT1) inhibitor ALX-5407 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA, after which the severity of dyskinesia, PLBs and parkinsonian disability was evaluated. In combination with L-DOPA, ALX-5407 0.1 and 1 mg/kg significantly reduced the severity of dyskinesia, by 51% and 41% (both P < 0.001), when compared to vehicle. ALX-5407 0.01, 0.1 and 1 mg/kg also decreased the severity of global PLBs, by 25%, 51% and 38% (all P < 0.001), when compared to vehicle. The benefits on dyskinesia and PLBs were achieved without compromising the therapeutic effect of L-DOPA on parkinsonism. Our results suggest that GlyT1 inhibition may be a novel strategy to attenuate dyskinesia and PLBs in PD, without interfering with L-DOPA anti-parkinsonian action.

Psychotic Disorders in Patients Who Use Synthetic Cannabinoids.

OBJECTIVE: The main objective of this study was to investigate the structure of psychotic disorders due to synthetic cannabinoid use and to determine differences in clinical characteristics and disease course between such substance-induced psychosis and psychosis associated with a primary diagnosis of schizophrenia. METHODS: This was a longitudinal, observational cohort study that included male patients who underwent inpatient treatment in the intensive care unit or in the emergency department due to substance-induced psychoses. The follow-up period was up to 2 years. RESULTS: We identified 4 clinical variants of substance-induced psychoses in patients who use synthetic cannabinoids. CONCLUSIONS: Our study revealed that psychotic symptoms are typical manifestations in association with intoxication with synthetic cannabinoids, and we identified several nonspecific characteristics of the psychoses that may occur in patients intoxicated with synthetic cannabinoids. We also identified a number of signs that may indicate the presence of substance-induced psychoses.

Prediction of Onset of Substance-Induced Psychotic Disorder and Its Progression to Schizophrenia in a Swedish National Sample.

OBJECTIVE: The objective of this study was to clarify the etiology of substance-induced psychotic disorder and its progression to schizophrenia in a Swedish national sample. METHODS: Individuals with a registration of substance-induced psychotic disorder between 1997 and 2015 in national medical registries (N=7,606) were followed up for a mean of 84 months. Data from medical, criminal, and pharmacy registries on first-degree through third-degree relatives were used to calculate familial risk scores for nonaffective psychosis, drug abuse, and alcohol use disorder. RESULTS: Individuals with substance-induced psychotic disorder had large elevations in standardized familial risk scores for drug abuse (+1.09, 95% CI=1.02, 1.15) and alcohol use disorder (+0.98, 95% CI=0.93, 1.03) and modest elevations for nonaffective psychosis (+0.35, 95% CI=0.30, 0.41). The cumulative risk for progression to schizophrenia was 11.3%; it was lowest for alcohol-induced and highest for cannabis-induced psychotic disorder, and it was predicted by early age at diagnosis of substance-induced psychotic disorder, male sex, and further registrations for episodes of drug abuse, alcohol use disorder, and substance-induced psychotic disorder. A risk prediction model found that 47% of individuals who converted to schizophrenia were in the upper 20% of risk. Familial risk scores for drug abuse and alcohol use disorder did not significantly discriminate those who converted to schizophrenia from those who did not, while familial risk score for nonaffective psychosis did (0.67, 95% CI=0.40, 0.95, versus 0.33, 95% CI=0.28, 0.39). Familial risk scores for nonaffective psychosis were indistinguishable between individuals with schizophrenia with and without prior substance-induced psychosis. Assignment of early retirement by the Swedish Social Insurance Agency strongly discriminated between individuals with substance-induced psychotic disorder with and without later schizophrenia. CONCLUSIONS: Substance-induced psychotic disorder appears to result from substantial drug exposure in individuals at high familial risk for substance abuse and moderately elevated familial risk for psychosis. Familial risk for psychosis, but not substance abuse, predicts progression from substance-induced psychosis to schizophrenia. Schizophrenia following substance-induced psychosis is likely a drug-precipitated disorder in highly vulnerable individuals, not a syndrome predominantly caused by drug exposure.

A Systematic Review of the Symptom Profile and Course of Methamphetamine-Associated PsychosisSubstance Use and Misuse.

OBJECTIVES: The psychiatric symptom profile of methamphetamine-associated psychosis (MAP) has varied considerably across studies of different research designs. We performed a systematic review to examine the available evidence for specific psychotic symptoms associated with MAP, including the clinical course and longitudinal changes in this symptom profile. METHODS: Five key electronic databases were searched to identify studies that examined the symptom profile or clinical course of MAP in individuals identified as having MAP. The reporting of specific psychiatric symptoms, and duration of symptoms where available, was recorded for each study. RESULTS: Ninety-four articles were identified (n = 7387), including case-control (k = 29), cross-sectional (k = 20), experimental (k = 6), case report (k = 29), and longitudinal (k = 20) studies. Persecutory delusions, auditory and visual auditory hallucinations were by far the most commonly reported symptoms (reported in 65-84% of studies). Hostility, conceptual disorganization, and depression were reported in a large proportion of studies (31-53%). Negative symptoms were mostly absent (<20%). The median percentage of participants with persistent psychotic symptoms (>1 month duration) across studies was 25% (excluding case reports). CONCLUSION: Persecutory delusions, auditory and visual hallucinations, hostility, depression and conceptual disorganization are central to MAP, whereas negative psychotic symptoms are typically absent. An overrepresentation of institutionalized or male participants may have overemphasized negative symptoms and underreported affective symptoms in past research. Symptoms of MAP may persist beyond one month after drug cessation in some individuals. Clinicians are encouraged to manage affective symptoms in MAP individuals, and monitor for the development of chronic psychotic symptoms.

Dopamine supersensitivity psychosis in schizophrenia: Concepts and implications in clinical practice.

Dopamine supersensitivity psychosis (DSP) is observed in patients with schizophrenia under antipsychotic treatment, and it is characterized by rebound psychosis, an uncontrollable psychotic episode following a stable state and tardive dyskinesia. DSP, first described in patients taking typical antipsychotics in the late 1970s, sometimes appears even in patients who are treated with current atypical antipsychotics. It was recently demonstrated that DSP can have a negative impact on the long-term prognosis of schizophrenia patients and that DSP could be involved in the etiology of some cases of treatment-resistant schizophrenia. Accumulating evidence suggests that an up-regulation of dopamine D2 receptors (DRD2) in the brain caused by long-term exposure to antipsychotics is related to the DSP phenomenon. The present review describes the clinical characteristics and the etiology of DSP in the era of second-generation antipsychotics for patients with schizophrenia. Based on the mechanism of DSP, several potential treatments for patients presenting with a DSP episode or the dopamine supersensitivity state are also discussed.

Cocaine Abuse, Traumatic Brain Injury, and Preexisting Brain Lesions as Risk Factors for Bupropion-Associated Psychosis.

BACKGROUND AND OBJECTIVE: Bupropion is generally considered safe and is widely used both as a monotherapy and as an augmentation agent for the treatment of major depression. Concerns have been raised about bupropion's propensity to precipitate new psychosis and worsen existing psychotic symptoms, although the mechanism is poorly understood. Three cases are reported in which bupropion use was associated with psychosis. The aim of the study was to explore the risk factors and possible mechanisms of psychosis in each case. CASE REPORTS: Case 1 describes the interaction of cocaine abuse sensitization in a patient who developed psychosis with a lower dosage of bupropion. Cases 2 and 3 discuss the role of traumatic brain injury and structural brain lesions in increasing the risk of psychosis when using bupropion. CONCLUSIONS: Cocaine abuse, traumatic brain injury, and preexisting brain lesions appear to be risk factors for developing psychosis in persons taking bupropion. In such cases, clinicians should carefully assess the risks and benefits and closely monitor patients for symptoms of psychosis.

Psychological symptomatology and impaired prepulse inhibition of the startle reflex are associated with cannabis-induced psychosis.

BACKGROUND: Cannabis-induced psychotic disorder (CIPD) is a psychiatric disorder induced by cannabis consumption. The psychological and psychophysiological features of this disorder are still unknown. We aimed to examine the psychological, personality and psychophysiological features of patients with CIPD. This study is an analytical extension of our previously published data, which previously found prepulse inhibition (PPI) deficits in the CIPD group used in this current paper. METHODS: We used a sample of 45 patients with CIPD. After 9 months of follow up, these patients were assessed with a Symptom Checklist-90-R (SCL-90-R) questionnaire of psychopathology, with the Eysenck Personality Questionnaire, and with a psychophysiological paradigm of inhibition of the startle reflex (PPI). These results were compared with a group of patients with schizophrenia and cannabis abuse (SCHZ) ( n = 54); patients with cannabis dependence (CD) ( n = 21); and healthy controls ( n = 50). RESULTS: CIPD patients obtained significant higher scores in the SCL-90-R subscale of neuroticism. These patients showed PPI percentages similar to SCHZ patients within early attentional levels (30 ms). The variables with greater correlation, and that appeared in the CIPD group were interpersonal sensitivity, depression and phobia. CONCLUSIONS: Neurotic symptomatology and difficulties in inhibition of the startle reflex might be risk factors for developing CIPD.

Characterization of white matter integrity deficits in cocaine-dependent individuals with substance-induced psychosis compared with non-psychotic cocaine users.

With sufficient drug exposure, some individuals develop transient psychotic symptoms referred to as 'substance-induced psychosis' (SIP), which closely resemble the symptoms observed in schizophrenia spectrum disorders. The comparability in psychotic presentation between SIP and the schizophrenias suggests that similar underlying neural deficits may contribute to the emergence of psychosis across these disorders. Only a small number of studies have investigated structural alterations in SIP, and all have been limited to volumetric imaging methods, with none controlling for the effects of chronic drug exposure. To investigate white matter abnormalities associated with SIP, diffusion tensor imaging was employed in a group of individuals with cocaine-associated psychosis (CAP; n = 24) and a cocaine-dependent non-psychotic (CDN) group (n = 43). Tract-based spatial statistics was used to investigate group differences in white matter diffusion parameters. The CAP group showed significantly lower fractional anisotropy values than the CDN group (p < 0.05) in voxels within white matter tracts of fronto-temporal, fronto-thalamic and interhemispheric pathways. The greatest differences in white matter integrity were present in the corpus callosum, corona radiata, bilateral superior longitudinal fasciculi and bilateral inferior longitudinal fasciculi. Additionally, the CAP group had voxels of significantly higher radial diffusivity in a subset of the previously mentioned pathways. These results are the first description of white matter integrity abnormalities in a SIP sample and indicate that differences in these pathways may be a shared factor in the expression of different forms of psychosis.

Increased prevalence of self-reported psychotic illness predicted by crystal methamphetamine use: Evidence from a high-risk population.

BACKGROUND: The potential of methamphetamine, and high-potency crystal methamphetamine in particular, to precipitate psychotic symptoms and psychotic illness is the subject of much speculation internationally. Established psychotic illness is disabling for individuals and costly to society. The aim of this study was to investigate whether use of crystal methamphetamine was associated with greater prevalence of self-reported psychotic illness, compared to use of other forms of methamphetamine. METHODS: The sample comprised participants interviewed as part of an annual cross-sectional survey of Australian people who inject drugs. Comparisons were made between groups according to the nature of their methamphetamine use: crystal methamphetamine or other forms of methamphetamine. Self-reported diagnoses of psychotic illness and other mental health problems were compared between groups. Predictors of self-reported psychotic illness were examined using multivariable logistic regression analyses. RESULTS: Self-reported psychotic illness was highly prevalent among users of crystal methamphetamine (12.0%), and significantly more so than among users of other forms of methamphetamine (3.9%) (OR=3.36; CI: 1.03-10.97). Significant predictors of self-reported psychosis in the cohort were: use of crystal methamphetamine; dependent use; lack of education beyond high school; and younger age. CONCLUSION: Highly increased prevalence of self-reported psychotic illness is associated with use of high-potency crystal methamphetamine in people who inject drugs, particularly where there is dependent use. There is an urgent need to develop effective interventions for dependent crystal methamphetamine use; and a need to monitor for symptoms of psychotic illness in drug-using populations.

Antiepileptic-induced Psychosis as a Possible Predictor of Post-temporal Lobectomy Alternative Psychosis.

We present a patient with topiramate-induced psychosis who developed alternative psychosis following temporal lobectomy. The number of surgical candidates for temporal lobectomy is increasing as is the frequency of psychiatric co-morbidities. Preoperative planning should take account of these psychiatric co-morbidities. In particular, precautions should be taken when antiepileptic drug-induced psychosis occurs, as this could predict the occurrence of alternative psychosis following lobectomy.

Use of benzylglycinamide by a HIV-seropositive polysubstance user: The changing pattern of novel psychoactive substance use among youths.

A 24-year old woman with multisubstance use since the age of 13, including opioids and cocaine, and long-standing HIV/HCV seropositivity status, presented with psychosis, agitation, and insomnia at the emergency department of a university hospital. She had been abusive and physically aggressive frequently without specific reasons and was involved in criminal legal cases. She was hospitalized twice. During her first hospital stay she experienced a brief episode of detachment from her environment, similar to episodes reportedly suffered at home. Psychosis had developed following heavy polysubstance abuse. Her mother provided sachets containing benzylglycinamide, a substance with no known psychotropic effects, which were also present in the patient's urine. She was occasionally positive for cannabinoids. She used to buy various novel psychoactive substances (NPSs) from the internet and used experimentally various substances freely made available to her by drug suppliers/dealers. She was unable to explain clearly why she was taking any of the identified NPS. She stated she was taking benzylglycinamide to calm her when smoking synthetic cannabinoids. While it appears that benzylglycinamide is not likely to constitute a novel drug of abuse, her polysubstance use exemplifies trends in NPS use patterns among the youths in the Western world and should alert mental health workers as to the possible dangers of such behavior and its reflection on social behavior and psychopathology.

The profile of psychiatric symptoms exacerbated by methamphetamine use.

BACKGROUND: Methamphetamine use can produce symptoms almost indistinguishable from schizophrenia. Distinguishing between the two conditions has been hampered by the lack of a validated symptom profile for methamphetamine-induced psychiatric symptoms. We use data from a longitudinal cohort study to examine the profile of psychiatric symptoms that are acutely exacerbated by methamphetamine use. METHODS: 164 methamphetamine users, who did not meet DSM-IV criteria for a lifetime primary psychotic disorder, were followed monthly for one year to assess the relationship between days of methamphetamine use and symptom severity on the 24-item Brief Psychiatric Rating Scale. Exacerbation of psychiatric symptoms with methamphetamine use was quantified using random coefficient models. The dimensions of symptom exacerbation were examined using principal axis factoring and a latent profile analysis. RESULTS: Symptoms exacerbated by methamphetamine loaded on three factors: positive psychotic symptoms (suspiciousness, unusual thought content, hallucinations, bizarre behavior); affective symptoms (depression, suicidality, guilt, hostility, somatic concern, self-neglect); and psychomotor symptoms (tension, excitement, distractibility, motor hyperactivity). Methamphetamine use did not significantly increase negative symptoms. Vulnerability to positive psychotic and affective symptom exacerbation was shared by 28% of participants, and this vulnerability aligned with a past year DSM-IV diagnosis of substance-induced psychosis (38% vs. 22%, χ(2)(df1)=3.66, p=0.056). CONCLUSION: Methamphetamine use produced a symptom profile comprised of positive psychotic and affective symptoms, which aligned with a diagnosis of substance-induced psychosis, with no evidence of a negative syndrome.

Neuroleptic malignant syndrome in cycloserine-induced psychosis.

A 33-year-old multidrug-resistant tuberculosis female patient diagnosed as cycloserine-induced psychosis developed several neuroleptic side effects such as extrapyramidal reaction, neuroleptic malignant syndrome, and drug-induced parkinsonism while she was being treated with initially haloperidol and then olanzapine over a period of 2 months. Patient's antipsychotic medications were withdrawn, and treatment with bromocriptine showed prompt recovery. The multiple neurological adverse effects which the patient developed had implications on the management of the complications as well as her illness.