Betaine prevents and reverses the behavioral deficits and synaptic dysfunction induced by repeated ketamine exposure in mice.

As an N-methyl-D-aspartate (NMDA) receptor inhibitor, ketamine has become a popular recreational substance and currently is used to address treatment-resistant depression. Since heavy ketamine use is associated with persisting psychosis, cognitive impairments, and neuronal damage, the safety of ketamine treatment for depression should be concerned. The nutrient supplement betaine has been shown to counteract the acute ketamine-induced psychotomimetic effects and cognitive dysfunction through modulating NMDA receptors. This study aimed to determine whether the adjunctive or subsequent betaine treatment would improve the enduring behavioral disturbances and hippocampal synaptic abnormality induced by repeated ketamine exposure. Mice received ketamine twice daily for 14 days, either combined with betaine co-treatment or subsequent betaine post-treatment for 7 days. Thereafter, three-chamber social approach test, reciprocal social interaction, novel location/object recognition test, forced swimming test, and head-twitch response induced by serotonergic hallucinogen were monitored. Data showed that the enduring behavioral abnormalities after repeated ketamine exposure, including disrupted social behaviors, recognition memory impairments, and increased depression-like and hallucinogen-induced head-twitch responses, were remarkably improved by betaine co-treatment or post-treatment. Consistently, betaine protected and reversed the reduced hippocampal synaptic activity, such as decreases in field excitatory post-synaptic potentiation (fEPSP), long-term potentiation (LTP), and PSD-95 levels, after repeated ketamine treatment. These results demonstrated that both co-treatment and post-treatment with betaine could effectively prevent and reverse the adverse behavioral manifestations and hippocampal synaptic plasticity after repeated ketamine use, suggesting that betaine can be used as a novel adjunct therapy with ketamine for treatment-resistant depression and provide benefits for ketamine use disorders.

Do neurocognitive functions in cannabis induced psychosis groups differ from schizophrenia with cannabis use? A controlled cross-sectional study.

OBJECTIVE: Cannabis-induced psychosis (CIP) has received little research attention. We compared neurocognitive functions in CIP, Schizophrenia with cannabis use (SZC) and healthy control group (CG). METHODS: Twenty age, education, and handedness-matched participants were recruited in each of the three groups. CIP and SZC were diagnosed with Psychiatric research interviews for substance use and mental disorders. Level of cannabis exposure, global intelligence, executive function, attention, vigilance, working, and verbal memory, and motor speed were compared by analysis of variance with post-hoc Scheffe's test. We did a post-hoc power calculation. RESULTS: Age at initiation, frequency, duration, and preparation of cannabis use did not differ significantly between CIP and SZC. CIP performed significantly better (than SZC) in tests of general cognitive ability or intelligence and attention, perceptual tracking and sequencing. SZC showed significant dysfunctions (than CG) in all parameters of the tests for executive dysfunction, sustained attention, short-term verbal memory and psychomotor functioning. CIP and CG did not differ in any cognitive domains except for non-perseverative errors in the test for executive functioning. CONCLUSIONS: CIP and SZC had different degrees of impairment compared to controls, but on direct comparisons CIP had better general intelligence and attention.KEY POINTSCannabis-induced psychosis (CIP) may have different neurocognitive impairment than Schizophrenia with cannabis use (SZC)CIP performed better in tests for general intelligence and visual attention than SZCSZC had significant impairment in executive function, attention, verbal memory, and psychomotor speed than controlsCompared to controls, CIP performed significantly worse in some domains of executive functionCIP and SZC had different degrees of cognitive impairments as compared to the controls.

Glutamate transporter-1 link astrocytes with heightened aggressive behavior induced by steroid abuse in male CF1 mice.

The astrocytic glutamate transporter GLT-1 performs glutamate uptake thereby mediating NMDAr responses in neurons. Ceftriaxone (CEF) upregulates astrocytic GLT-1 expression/activity, which could counteract excessive glutamate levels and aggressive behavior induced by anabolic synthetic steroids such as nandrolone decanoate (ND). Here, adult male CF-1 mice were allocated to oil (VEH), ND, CEF, and ND/CEF groups. Mice were subcutaneously (s.c.) injected with ND (15 mg/kg) or VEH for 19 days, and received intraperitoneal (i.p.) injections of CEF (200 mg/kg) or saline for 5 days. The ND/CEF group received ND for 19 days plus coadministration of CEF in the last 5 days. On the 19th day, the aggressive phenotypes were evaluated through the resident-intruder test. After 24 h, cerebrospinal fluid was collected to measure glutamate levels, and the pre-frontal cortex was used to assess GLT-1, pGluN2BTyr1472, and pGluN2ATyr1246 by Western blot. Synaptosomes from the left brain hemisphere was used to evaluate mitochondrial function including complex II-succinate dehydrogenase (SDH), Ca2+ handling, membrane potential (ΔÑ°m), and H2O2 production. ND decreased the latency for the first attack and increased the number of attacks by the resident mice against the intruder, mechanistically associated with an increase in glutamate levels and pGluN2BTyr1472 but not pGluN2ATyr1244, and GLT-1 downregulation. The abnormalities in mitochondrial Ca2+ influx, SDH, ΔÑ°m, and H2O2 implies in deficient energy support to the synaptic machinery. The ND/CEF group displayed a decreased aggressive behavior, normalization of glutamate and pGluN2BTyr1472levels, and mitochondrial function at synaptic terminals. In conclusion, the pharmacological modulation of GLT-1 highlights its relevance as an astrocytic target against highly impulsive and aggressive phenotypes.

Psicosis inducida por cannabis: características clínicas y su diferenciación con la esquizofrenia con y sin consumo de cannabis asociado / Cannabis-induced psychosis: clinical characteristics and its differentiation from schizophrenia with and without cannabis use

El consumo de cannabis se considera un factor de riesgo establecido para el desarrollo de psicosis. Diferenciar los trastornos inducidos por cannabis de la esquizofrenia resulta útil desde el punto de vista pronóstico y terapéutico. Se diferenciaron tres grupos de pacientes hospitalizados: psicosis inducida por cannabis (PIC) (n = 69; Media de edad = 27,4, DE = 6,5; 82,6 % varones), esquizofrenia con abuso o dependencia de cannabis (EZ + CB) (n = 57; Media de edad = 31,9, DE = 10,1; 94,7% varones) y esquizofrenia sin abuso o dependencia de cannabis (EZ) (n = 181; Media de edad = 41,8, DE = 13,3; 54,1% varones). Se utilizó la escala Psychiatric Research Interview for Substance and Mental Disorders (PRISM-IV) para la diferenciación de cuadros inducidos. El grupo PIC presentó puntaciones inferiores en la subescala PANSS negativa (M = 12,9, DE = 5,9; F = 32,24; p < 0,001), menos alucinaciones auditivas (60,3%; ÷² = 6,60; p = 0,037) y mayor presencia de manía (26,1% vs. 12,3%; ÷² = 32,58; p < 0,001) en comparación con el grupo EZ + CB. Hubo pocas diferencias clínicas entre los pacientes con esquizofrenia, independientemente del consumo de cannabis. La edad del primer ingreso por psicosis fue menor en ambos grupos de psicóticos consumidores (M = 26,1, DE = 6,4 en PIC y M = 25,3, DE = 6,2 en EZ + CB; ÷² = 20,02; p < 0,001). No se observó un patrón clínico característico de las psicosis inducidas por cannabis, aunque sí se demostró el papel precipitante del cannabis en la aparición de psicosis, dada la menor edad de ingreso en los consumidores

Cannabis use is considered an established risk factor for psychosis development. Differentiating between cannabis-induced disorders and schizophrenia is useful for prognostic and therapeutic purposes. Three inpatients groups were differentiated: cannabis-induced psychosis (CIP) (n = 69; mean age = 27.4, SD = 6.5; 82.6% males), schizophrenia with cannabis abuse or dependence (SZ + CB) (n = 57; mean age = 31.9, SD = 10.1; 94.7% males) and schizophrenia without cannabis abuse or dependence (SZ) (n = 181; mean age = 41.8, SD = 13.3; 54.1% males). The Psychiatric Research Interview for Substance and Mental Disorders (PRISM-IV) scale was used to differentiate induced psychosis. The CIP group presented lower mean scores on the negative PANSS subscale (M = 12.9, SD = 5.9; F = 32.24, p < 0.001), fewer auditory hallucinations (60.3%; χ² = 6.60, p = 0.037) and greater presence of mania (26.1% vs. 12.3%; χ² = 32.58, p < 0.001) than the SZ + CB group. There were few clinical differences between patients with schizophrenia, regardless of previous cannabis use. The age of first admission due to psychosis was lower in both psychotic inpatients groups with cannabis use (M = 26.1, SD = 6.4 in CIP and M = 25.3, SD = 6.2 in SZ + CB; χ² = 20.02, p < 0,001). A clinical pattern characteristic of cannabis-induced psychosis was not observed, but the precipitating role of cannabis in the appearance of psychotic symptoms was demonstrated, given the lower age of first admission due to psychosis in cannabis user groups

Psychosis-Relevant Effects of Intravenous Delta-9-Tetrahydrocannabinol: A Mega Analysis of Individual Participant-Data from Human Laboratory Studies.

INTRODUCTION: There is increasing interest in the relationship between cannabinoids and psychosis. While individual human laboratory studies have been critical in demonstrating that cannabinoids (e.g., delta-9-tetrahydrocannabinol [THC]) can induce acute transient psychosis-like effects in healthy human volunteers, combining data from multiple studies offers a fine-grained view of these effects. METHODS: THC-induced psychosis-relevant effects were examined using a data repository of 10 double-blind, randomized, placebo-controlled, crossover studies with 400 i.v. THC infusions in healthy human volunteers. The Positive and Negative Syndrome scale was used to measure psychotomimetic effects. The profile of symptoms, frequency of a response, its relationship to THC dose and substance use, latent structure in Positive and Negative Syndrome scale response, and the relationships between psychotomimetic and perceptual alteration symptoms were evaluated. RESULTS: Clinically meaningful increases in positive symptoms were noted in 44.75% infusions; conceptual disorganization, hallucinations, blunted affect, somatic concern, motor retardation, and poor attention were the items most frequently altered by THC. The increase in Positive and Negative Syndrome scale positive symptoms was positively associated with THC dose (beta = 11.13, SE = 4.94, Wald χ 2 = 19.88, P < .001) and negatively associated with frequent cannabis use (beta = -0.575, SE = 0.14, Wald χ 2 = 18.13, P < .001). Furthermore, positive symptoms were strongly correlated with Clinician Administered Dissociative States Scale perceptual alterations score (rs = 0.514, P < .001). CONCLUSION: Intravenous administration of THC consistently induces psychotomimetic effects that include symptoms across Positive and Negative Syndrome scale domains. Moreover, healthy individuals who frequently use cannabis have a blunted psychotomimetic response.

[Alternative Psychoses and Forced Normalization after Seizure Control by Anticonvulsants with Special Consideration of the New Anticonvulsants]. / Alternativpsychose und forcierte Normalisierung durch Antiepileptika unter besonderer Berücksichtigung der neuen Antiepileptika.

In the case of alternative psychosis and forced normalization, the patient alternates between periods of clinically manifest seizures and normal behavior, and other periods of seizure freedom (or significant seizure reduction) accompanied by psychosis or behavioral disturbances. Unlike the clinically defined alternative psychosis, forced normalization is based on EEG findings. In clinical practice and in the literature, both terms are mostly used synonymously, and they also describe the same clinical pictures. This allowed a joint evaluation of the publications about alternative psychosis and forced normalization. Most often, these two disorders occur after seizure control by anticonvulsants. In the period of older anticonvulsants, the succinimides for the treatment of absence seizures were most often associated with the development of an alternative psychosis or forced normalization. In the era of newer anticonvulsants that started with the introduction of vigabatrin, mostly patients with intractable focal seizures were affected. In 1987 - 31 years ago - paranoid hallucinatory psychosis, triggered by vigabatrin in a patient with epilepsy was reported for the first time. In the following years, reports of alternative psychosis and forced normalization appeared to be related to most of the new anticonvulsants. A comprehensive literature search provided 66 cases with detailed information on such events. More than twice as many women were likely to be affected as compared to men; the reason for this phenomenon is unclear. In four retrospective studies, another 176 alternative events were reported but no details were given. The risk of alternative psychosis and forced normalization seems to be particularly low with the new anticonvulsants oxcarbazepine, eslicarbazepine, gabapentin and pregabalin.

Methamphetamine-associated psychosis: links to drug use characteristics and similarity to primary psychosis.

Objectives: Despite the prevalence of methamphetamine-associated psychosis, how characteristics of drug use affect the severity and clinical course, and its optimal treatments have not been established. We addressed these questions, assessing clinical features of methamphetamine-associated psychosis, and compared it with primary psychosis.Methods: Hospitalised patients with methamphetamine-associated (n = 70) or primary schizophrenic psychosis (n = 70) were matched on sex, age and duration of psychosis. Association of drug use variables (age at initiation, duration of methamphetamine use) with the Brief Psychiatric Rating Scale (BPRS) scores and psychosis duration were examined for patients with methamphetamine-associated psychosis, and the groups were compared on the BPRS scores.Results: Methamphetamine use initiation age correlated negatively with the BPRS total score and the Activation subscale score; methamphetamine use duration correlated positively with psychosis duration. Methamphetamine-associated psychosis group scored lower on the Hostility-Suspiciousness and Anergia subscales of the BPRS (adjusted p values < .05).Conclusions: Association of early initiation of methamphetamine with psychosis severity may suggest a lasting effect on brain development. Correlation of drug use and psychosis durations may suggest a cumulative effect of methamphetamine exposure. Less severe paranoia and negative symptoms in the methamphetamine-using group could implicate better social functioning of these patients. Further mechanistic studies are warranted.Key pointsEarly initiation of methamphetamine use is associated with psychosis severity.Methamphetamine use duration associates with psychosis duration.Methamphetamine-associated and primary schizophrenic psychoses were similar in symptoms.Methamphetamine psychosis patients were less severe in paranoia and negative symptoms.

Cannabis and Psychosis Through the Lens of DSM-5.

Evidence for an association between cannabis and psychosis has been documented in literature in many forms including experimental studies, epidemiological data, and case series. The association has implications for psychotic outcomes ranging from mild to severe and occurring over minutes to years. Due to the huge variety of exposures and outcome measures reported, creating a coherent account of all the available information is difficult. A useful way to conceptualize these wide-ranging results is to consider the association between cannabis and psychosis as it occurs within the context of widely used DSM-5 diagnoses. In the present review we examine cannabis/psychosis associations as they pertain to Cannabis Intoxication, Cannabis-Induced Psychotic Disorder, and Schizophrenia. This allows for an understanding of the cannabis and psychosis association along something approaching a continuum. Cannabis intoxication becomes Cannabis-Induced Psychotic Disorder once certain severity and duration criteria are met and Cannabis-Induced Psychotic Disorder is heavily associated with future schizophrenia diagnoses.

Psychostimulant use and the brain.

Psychostimulant users are typically young adults. We have conducted a narrative review of neuropsychiatric harms associated with the psychostimulants methamphetamine/amphetamine, cocaine and 3,4-methylenedioxymethamphetamine (MDMA), focusing on epidemiological factors, common clinical presentations, underlying causal mechanisms and treatment options. The major neuropsychiatric harms of psychostimulant use are stroke, neurocognitive impairment, Parkinson's disease, seizures and psychotic illness. These arise through a combination of acute monoamine release, longer-term neurotransmitter effects and indirect effects. These effects are moderated by factors in the individual and in the pattern of substance use. Neuropsychiatric harms associated with psychostimulant use can thus lead to severe long-term impairment.

The prevalence of psychotic symptoms in kratom (Mitragyna speciosa Korth.) Users in Malaysia.

BACKGROUND: Kratom is a traditional medicinal herb widely used in Malaysia and Thailand. Despite its widespread use and statements by regulatory agencies on the potential for kratom-associated psychosis, there is little data regarding the prevalence of psychotic symptoms among kratom users. This study investigated the prevalence of psychosis among kratom users, described psychotic symptomatology and severity, while examining associations between kratom use characteristics and the occurrence of psychotic symptoms. METHODS: This cross-sectional clinical survey recruited 150 regular kratom users. The Mini International Neuropsychiatric Interview (MINI) and Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-V) diagnostic criteria were used to evaluate psychotic symptomatology among kratom users, and the Brief Psychiatric Rating Scale (BPRS) was used to assess the severity of psychiatric symptoms. Chi-square tests with Yate's correction were performed to determine the association between kratom use characteristics and the occurrence of psychotic symptoms among kratom users in this study. RESULTS: Six out of 150 kratom users (4%) presented with any psychotic symptoms. The psychotic symptoms reported were positive symptoms and thought alienation, with a mean BPRS score of 33 (i.e., mild severity). Variables related to kratom use (such as intake of kratom with diphenhydramine, duration of kratom use, and quantity and frequency of daily kratom use) were not associated with the occurrence of psychotic symptoms among kratom users. CONCLUSION: Although psychotic symptoms could occur among regular kratom users, they were rare and not significantly associated with kratom use characteristics. We found no evidence of elevated psychosis among regular users.

Microstructural Findings in White Matter Associated with Cannabis and Alcohol Use in Early-Phase Psychosis: A Diffusion Tensor Imaging and Relaxometry Study.

Accumulating evidence suggests that brain white matter (WM) abnormalities may be central to the pathophysiology of psychotic disorders. In addition, there is evidence that cannabis use and alcohol use each is associated with WM abnormalities. However, there are very limited data on the effects of these substances on WM microstructure in patients with psychosis, especially for those at the early phase of illness. This project aimed to examine the impact of cannabis use and alcohol use on WM tissue in early-phase psychosis (EPP). WM was investigated in 21 patients with EPP using diffusion tensor imaging (DTI) and transverse relaxation time of tissue water (T2), with the primary outcomes being mean fractional anisotropy (FA) and T2. DTI analyses were performed at the full-brain level using tract-based spatial statistics with both DTI and T2 analysis done within a WM volume of interest (VOI) implicated in psychosis (containing the left superior longitudinal fasciculus). Our findings revealed that younger age of onset of regular alcohol use (more than one drink per week) was associated with lower FA values in the left thalamic radiation and left parahippocampal and left amygdalar WM. More frequent lifetime cannabis use was correlated with increased mean full-brain FA. There was no significant relationship found between FA and alcohol or cannabis use within the VOI. Relaxometry analysis revealed trend-level evidence of shortened T2 with later onset of regular alcohol use and with more frequent cannabis use. This study provides novel data demonstrating cortical and subcortical WM findings related to alcohol use in EPP and is the first to combine DTI and relaxometry, relating to this patient population.

Changes in Gray Matter Density, Regional Homogeneity, and Functional Connectivity in Methamphetamine-Associated Psychosis: A Resting-State Functional Magnetic Resonance Imaging (fMRI) Study.

BACKGROUND Using regional homogeneity (ReHo) blood oxygen level-dependent functional MR (BOLD-fMRI), we investigated the structural and functional alterations of brain regions among patients with methamphetamine-associated psychosis (MAP). MATERIAL AND METHODS This retrospective study included 17 MAP patients, 16 schizophrenia (SCZ) patients, and 18 healthy controls. Informed consent was obtained from all patients before the clinical assessment, the severity of clinical symptoms was evaluated prior to the fMRI scanning, and then images were acquired and preprocessed after each participant received 6-min fRMI scanning. The participants all underwent BOLD-fMRI scanning. Voxel-based morphometry was used to measure gray matter density (GMD). Resting-state fMRI (rs-fMRI) was conducted to analyze functional MR, ReHo, and functional connectivity (FC). RESULTS GMD analysis results suggest that MAP patients, SCZ patients, and healthy volunteers show different GMDs within different brain regions. Similarly, the ReHo analysis results suggest that MAP patients, SCZ patients, and healthy volunteers have different GMDs within different brain regions. Negative correlations were found between ReHo- and the PANSS-positive scores within the left orbital interior frontal gyrus (L-orb-IFG) of MAP patients. ReHo- and PANSS-negative scores of R-SFG were negatively correlated among SCZ patients. The abnormal FC of R-MFG showed a negative correlation with the PANSS score among MAP patients. CONCLUSIONS The abnormalities in brain structure and FC were associated with the development of MAP.

Electroencephalographic delta/alpha frequency activity differentiates psychotic disorders: a study of schizophrenia, bipolar disorder and methamphetamine-induced psychotic disorder.

Electroencephalography (EEG) has been proposed as a neurophysiological biomarker to delineate psychotic disorders. It is known that increased delta and decreased alpha, which are apparent in psychosis, are indicative of inappropriate arousal state, which leads to reduced ability to attend to relevant information. On this premise, we investigated delta/alpha frequency activity, as this ratio of frequency activity may serve as an effective neurophysiological biomarker. The current study investigated differences in delta/alpha frequency activity, in schizophrenia (SCZ), bipolar I disorder with psychotic features and methamphetamine-induced psychosis. One hundred and nine participants, including individuals with SCZ (n = 28), bipolar I disorder with psychotic features (n = 28), methamphetamine-induced psychotic disorder (MPD) (n = 24) and healthy controls (CON, n = 29). Diagnosis was ascertained with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition disorders and current medication was recorded. EEG was undertaken in three testing conditions: resting eyes open, resting eyes closed and during completion of a simple cognitive task (visual continuous performance task). EEG delta/alpha frequency activity was investigated across these conditions. First, delta/alpha frequency activity during resting eyes closed was higher in SCZ and MPD globally, when compared to CON, then lower for bipolar disorder (BPD) than MPD for right hemisphere. Second, delta/alpha frequency activity during resting eyes open was higher in SCZ, BPD and MPD for all electrodes, except left frontal, when compared to CON. Third, delta/alpha frequency activity during the cognitive task was higher in BPD and MPD for all electrodes, except left frontal, when compared to CON. Assessment of EEG delta/alpha frequency activity supports the delineation of underlying neurophysiological mechanisms present in psychotic disorders, which are likely related to dysfunctional thalamo-cortical connectivity. Delta/alpha frequency activity may provide a useful neurophysiological biomarker to delineate psychotic disorders.

Case series: Salvia divinorum as a potential addictive hallucinogen.

BACKGROUND AND OBJECTIVE: Recreational use of salvia divinorum (salvia), a potent, naturally occurring hallucinogen, is on the rise internationally. Despite the paucity of information about its long-term health effects, salvia is readily available and generally portrayed as a safe non-addictive substance. METHODS AND RESULTS: We report on two patients who presented with an enduring and pervasive pattern of salvia use. DISCUSSION AND CONCLUSIONS: Evaluating patients for salvia use during clinical assessment is strongly encouraged, especially among young polysubstance users. SCIENTIFIC SIGNIFICANCE: Clinicians should be mindful of the multifaceted psychiatric effects of salvia, including the potential for a use disorder. (Am J Addict 2018;27:163-165).

Methamphetamine psychosis: insights from the past.

BACKGROUND AND AIMS: To review early case reports and experimental inductions of amphetamine and methamphetamine psychosis, prior to the prohibition of these drugs, to gain a better understanding of the nature and aetiology of methamphetamine psychosis. METHODS: Papers considered were historical case reports and case series of psychosis relating to the use and misuse of prescription amphetamine, focusing upon papers by Young & Scoville (1938), Connell (1958), and three subsequent experimental studies published in the early 1970s (Griffith 1972, Angrist & Gershon 1970 and Bell 1973), where psychosis was induced in volunteers using high-dose amphetamine and methamphetamine. RESULTS: High-dose methamphetamine and amphetamine can result in a paranoid psychosis which remits rapidly (within days) of discontinuing use. The central feature is paranoia occurring in a clear state of consciousness. This may be accompanied by other psychotic symptoms (e.g. hallucinations). Pre-existing schizophrenia is not necessary, and the syndrome is not due to sleep deprivation. CONCLUSIONS: Research findings from the 1930s to the 1970s suggest that paranoid psychosis should be considered a probable consequence of high-dose methamphetamine use. Individuals who experience psychotic symptoms for any substantive period after intoxication has ended should be suspected of having a functional non-organic psychosis, or a latent vulnerability thereto.

Increased hippocampal engagement during learning as a marker of sensitivity to psychotomimetic effects of δ-9-THC.

BACKGROUND: Cannabis and its main psychoactive ingredient δ-9-tetrahydrocannibidiol (THC) can induce transient psychotic symptoms in healthy individuals and exacerbate them in those with established psychosis. However, not everyone experience these effects, suggesting that certain individuals are particularly susceptible. The neural basis of this sensitivity to the psychotomimetic effects of THC is unclear. METHODS: We investigated whether individuals who are sensitive to the psychotomimetic effects of THC (TP) under experimental conditions would show differential hippocampal activation compared with those who are not (NP). We studied 36 healthy males under identical conditions under the influence of placebo or THC (10 mg) given orally, on two separate occasions, in a pseudo-randomized, double-blind, repeated measures, within-subject, cross-over design, using psychopathological assessments and functional MRI while they performed a verbal learning task. They were classified into those who experienced transient psychotic symptoms (TP; n = 14) following THC administration and those who did not (NP; n = 22). RESULTS: Under placebo conditions, there was significantly greater engagement of the left hippocampus (p < 0.001) in the TP group compared with the NP group during verbal encoding, which survived leave-one-out analysis. The level of hippocampal activation was directly correlated (Spearman's ρ = 0.44, p = 0.008) with the severity of transient psychotic symptoms induced by THC. This difference was not present when we compared two subgroups from the same sample that were defined by sensitivity to anxiogenic effects of THC. CONCLUSIONS: These results suggest that altered hippocampal activation during verbal encoding may serve as a marker of sensitivity to the acute psychotomimetic effects of THC.

Involvement of posterior cingulate cortex in ketamine-induced psychosis relevant behaviors in rats.

The involvement of posterior cingulate cortex (PCC) on ketamine-induced psychosis relevant behaviors was investigated in rats. Bilateral infusion of muscimol, a GABAA receptor agonist, into the PCC significantly antagonized ketamine-induced deficit in prepulse inhibition of a startle reflex (PPI), deficit in gating of hippocampal auditory evoked potentials, and behavioral hyperlocomotion in a dose dependent manner. Local infusion of ketamine directly into the PCC also induced a PPI deficit. Systemic injection of ketamine (3mg/kg,s.c.) induced an increase in power of electrographic activity in the gamma band (30-100Hz) in both the PCC and the hippocampus; peak theta (4-10Hz) power was not significantly altered, but peak theta frequency was increased by ketamine. In order to exclude volume conduction from the hippocampus to PCC, inactivation of the hippocampus was made by local infusion of muscimol into the hippocampus prior to ketamine administration. Muscimol in the hippocampus effectively blocked ketamine-induced increase of gamma power in the hippocampus but not in the PCC, suggesting independent generation of gamma waves in PCC and hippocampus. It is suggested that the PCC is part of the brain network mediating ketamine-induced psychosis related behaviors.

Clinical characteristics of primary psychotic disorders with concurrent substance abuse and substance-induced psychotic disorders: A systematic review.

BACKGROUND: Distinguishing between a primary psychotic disorder with concurrent substance abuse (PPD+SA) and a substance-induced psychotic disorder (SIPD) can be diagnostically challenging. We aimed to determine if these two diagnoses are clinically distinct, particularly in relation to psychopathology. In addition, we aimed to examine the specific clinical features of cannabis-induced psychotic disorder (CIPD) as compared to primary psychotic disorder with concurrent cannabis abuse (PPD+CA) and also to SIPD associated with any substance. METHODS: A systematic review of SIPD literature using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Using strict inclusion criteria, a total of six studies examining SIPD were included in the review (two of which only considered psychosis induced by cannabis alone). The findings did not reveal many consistent differences in psychopathology. However, we did find that that compared to PPD+SA, individuals with SIPD have a weaker family history of psychotic disorder; a greater degree of insight; fewer positive symptoms and fewer negative symptoms; more depression (only in CIPD) and more anxiety. CONCLUSION: There remains a striking paucity of information on the psychopathology, clinical characteristics and outcome of SIPD. Our review highlights the need for further research in this area.

S-Ketamine-Induced NMDA Receptor Blockade during Natural Speech Production and Its Implications for Formal Thought Disorder in Schizophrenia: A Pharmaco-fMRI Study.

Structural and functional changes in the lateral temporal language areas have been related to formal thought disorder (FTD) in schizophrenia. Continuous, natural speech production activates the right lateral temporal lobe in schizophrenia, as opposed to the left in healthy subjects. Positive and negative FTD can be elicited in healthy subjects by glutamatergic NMDA blockade with ketamine. It is unclear whether the glutamate system is related to the reversed hemispheric lateralization during speaking in patients. In a double-blind, crossover, placebo-controlled study, 15 healthy, male, right-handed volunteers overtly described 7 pictures for 3 min each while BOLD signal changes were acquired with fMRI. As a measure of linguistic demand, the number of words within 20 s epochs was correlated with BOLD responses. Participants developed S-ketamine-induced psychotic symptoms, particularly positive FTD. Ketamine vs placebo was associated with enhanced neural responses in the right middle and inferior temporal gyri. Similar to a previous fMRI study in schizophrenia patients vs healthy controls applying the same design, S-ketamine reversed functional lateralization during speech production in healthy subjects. Results demonstrate an association between glutamatergic imbalance, dysactivations in lateral temporal brain areas, and FTD symptom formation.