Drug-induced Psychosis Research Articles

Non-Human Primates: Model Animals for Developmental Psychopathology

Non-human primates have been used to model psychiatric disease for several decades. The success of this paradigm has issued from comparable cognitive skills, brain morphology, and social complexity in adult monkeys and humans. Recently, interest in biological psychiatry has focused on similar brain, social, and emotional developmental processes in monkeys. In part, this is related to evidence that early postnatal experiences in human development may have profound implications for subsequent mental health. Non-human primate studies of postnatal phenomenon have generally fallen into three basic categories: experiential manipulation (largely manipulations of rearing), pharmacological manipulation (eg drug-induced psychosis), and anatomical localization (defined by strategic surgical damage). Although these efforts have been very informative each of them has certain limitations. In this review we highlight general findings from the non-human primate postnatal developmental literature and their implications for primate models in psychiatry. We argue that primates are uniquely capable of uncovering interactions between genes, environmental challenges, and development resulting in altered risk for psychopathology.

The Frizzled 3 gene is associated with methamphetamine psychosis in the Japanese population

BackgroundFrizzled 3 (Fzd3) is a receptor required for the Wnt-signaling pathway, which has been implicated in the development of the central nervous system, including synaptogenesis and structural plasticity. We previously found a significant association between the FZD3 gene and susceptibility to schizophrenia, but subsequent studies showed inconsistent findings. To understand the roles of the FZD3 gene in psychotic disorders further, it should be useful to examine FZD3 in patients with methamphetamine psychosis because the clinical features of methamphetamine psychosis are similar to those of schizophrenia.MethodsSix SNPs of FZD3, rs3757888 in the 3' flanking region, rs960914 in the intron 3, rs2241802, a synonymous SNP in the exon5, rs2323019 and rs352203 in the intron 5, and rs880481 in the intron 7, were selected based on the previous schizophrenic studies and analyzed in 188 patients with methamphetamine psychosis and 240 age- and gender-matched controls.ResultsA case-control association analyses revealed that two kinds of FZD3 haplotypes showed strong associations with methamphetamine psychosis (p < 0.00001). Having the G-A-T-G or A-G-C-A haplotype of rs2241802-rs2323019-rs352203-rs880481 was a potent negative risk factor (odds ratios were 0.13 and 0.086, respectively) for methamphetamine psychosis.ConclusionOur present and previous findings indicate that genetic variants of the FZD3 gene affect susceptibility to two analogous but distinct dopamine-related psychoses, endogenous and substance-induced psychosis.

Individual Differences in Psychotic Effects of Ketamine Are Predicted by Brain Function Measured under Placebo

The symptoms of major psychotic illness are diverse and vary widely across individuals. Furthermore, the prepsychotic phase is indistinct, providing little indication of the precise pattern of symptoms that may subsequently emerge. Likewise, although in some individuals who have affected family members the occurrence of disease may be predicted, the specific symptom profile may not. An important question, therefore, is whether predictive physiological markers of symptom expression can be identified. We conducted a placebo-controlled, within-subjects study in healthy individuals to investigate whether individual variability in baseline physiology, as assessed using functional magnetic resonance imaging, predicted psychosis elicited by the psychotomimetic drug ketamine and whether physiological change under drug reproduced those reported in patients. Here we show that brain responses to cognitive task demands under placebo predict the expression of psychotic phenomena after drug administration. Frontothalamic responses to a working memory task were associated with the tendency of subjects to experience negative symptoms under ketamine. Bilateral frontal responses to an attention task were also predictive of negative symptoms. Frontotemporal activations during language processing tasks were predictive of thought disorder and auditory illusory experiences. A subpsychotic dose of ketamine administered during a second scanning session resulted in increased basal ganglia and thalamic activation during the working memory task, paralleling previous reports in patients with schizophrenia. These results demonstrate precise and predictive brain markers for individual profiles of vulnerability to drug-induced psychosis.

Major physical and psychological harms of methamphetamine use

The major physical and psychological health effects of methamphetamine use, and the factors associated with such harms. Comprehensive review. Physical harms reviewed included toxicity and mortality, cardiovascular/cerebrovascular pathology, dependence and blood-borne virus transmission. Psychological harms include methamphetamine psychosis, depression, suicide, anxiety and violent behaviours. While high-profile health consequences, such as psychosis, are given prominence in the public debate, the negative sequelae extend far beyond this. This is a drug class that causes serious heart disease, has serious dependence liability and high rates of suicidal behaviours. The current public image of methamphetamine does not portray adequately the extensive, and in many cases insidious, harms caused.

Involvement of Pallidotegmental Neurons in Methamphetamine- and MK-801-Induced Impairment of Prepulse Inhibition of the Acoustic Startle Reflex in Mice: Reversal by GABAB Receptor Agonist Baclofen

We have previously demonstrated that pallidotegmental GABAergic neurons play a crucial role in prepulse inhibition (PPI) of the startle reflex in mice through the activation of GABA(B) receptors in pedunculopontine tegmental neurons. In this study, we investigated whether PPI disruption induced by methamphetamine (METH) or MK-801 is associated with the dysfunction of pallidotegmental neurons. Furthermore, we examined the effects of baclofen, a GABA(B) receptor agonist, on METH- and MK-801-induced PPI impairment. Acute treatment with METH (3 mg/kg, subcutaneouly (s.c.)) and MK-801 (>0.3 mg/kg, s.c.) significantly disrupted PPI, accompanied by the suppression of c-Fos expression in lateral globus pallidus induced by PPI. Furthermore, acute treatment with METH and MK-801 stimulated c-Fos expression in the caudal pontine reticular nucleus (PnC) in mice subjected to the PPT test, although PPI alone had no effect on c-Fos expression. Repeated treatment with 1 mg/kg METH for 7 days, which did not affect PPI acutely, showed similar effects on PPI and c-Fos expression to acute treatment with METH (3 mg/kg). Baclofen dose-dependently ameliorated PPI impairment induced by acute treatment with METH (3 mg/kg) and MK-801 (1 mg/kg), and decreased METH- and MK-801-stimulated c-Fos expression in PnC to the basal level. These results suggest that dysfunction of pallidotegmental neurons is involved in PPI disruption caused by METH and MK-801 in mice. GABA(B) receptor may constitute a putative target in treating neuropsychiatric disorders with sensorimotor gating deficits, such as schizophrenia and METH psychosis.

Substance-Induced Psychosis

To critically examine the DSM-IV-TR criteria for substance-induced psychotic disorder (SIPD). Leading electronic databases (such as MEDLINE, PubMed) were searched for the years 1992 through 2007, using combinations of the following key search terms: substance abuse/dependence, alcohol, marijuana, cannabis, methamphetamine, crack, cocaine, amphetamine, ecstasy, ketamine, phencyclidine, LSD, mental health, drug-induced psychosis, substance-induced psychosis, psychosis, and schizophrenia. References identified from bibliographies of pertinent articles and books in the field were also collected and reviewed. Only research studies or case reports/series that presented data on populations diagnosed with SIPD by using clinical or structured diagnostic interviews and that were published in English were used to assess the validity of the current SIPD criteria. We identified 49 articles that presented clinical data on SIPD. Almost half of these publications were case reports, with 18 articles specifically focusing on delineating the clinical characteristics or outcomes of individuals diagnosed with SIPD. While several large studies have recently been conducted to assess the stability of SIPD, there is a dearth of research that rigorously examines the validity of DSM-IV diagnostic criteria across substances. There remains a striking paucity of information on the outcome, treatment, and best practice for substance-associated psychotic episodes. Further work is clearly required before the advent of DSM-V. We propose an alternative, broader classification that better reflects the current evidence base, inferring association rather than causation.

Protein expression profile in the amygdala of rats with methamphetamine-induced behavioral sensitization

Repeated exposure to methamphetamine (MAP) results in a progressively enhanced and enduring behavioral response to the drug. This phenomenon is known as behavioral sensitization. MAP-induced sensitization has been suggested to underlie certain aspects of MAP psychosis and schizophrenia. The mesolimbic dopamine system including the ventral tegmental area, nucleus accumbens (NAc) and associated brain regions such as the amygdala (AMG) are proposed to be involved in the behavioral sensitization. However, the molecular mechanisms underlying this protracted alteration of behavior are almost unknown. Here we examined protein expression profiles in the AMG of acute MAP-treated and MAP-sensitized rats using 2-DE-based proteomics. Analysis revealed that 64 and 43 protein spots were differentially regulated in the AMG of acute MAP-treated and MAP-sensitized rats, respectively, when compared to control rats. A total of 48 and 34 proteins were identified in these two models, respectively using MALDI-ToF-MS. When the results were compared between acute and chronic MAP-treated groups, only 9 proteins were identified in common. These proteins could be related to acute MAP effects and/or non-specific effects. It is therefore suggested that AMG react differently to the acute and repeated administration of MAP at least at the protein expression level. A number of proteins in the categories of synaptic, cytoskeletal, oxidative stress, apoptosis, and mitochondria related proteins were differentially expressed in the AMG of sensitized animals. Changes of these protein expressions in the AMG could be associated with the mechanism underlying behavioral sensitization.

When dual diagnosis means no diagnosis: co-occurring mental illness and problematic drug use in clients of alcohol and drug services in eastern metropolitan Melbourne

Background: Most previous studies examining the prevalence of co-occurring psychiatric illness and problematic substance use in Australia have been population studies or focused on clients of psychiatric services. There is little literature on the prevalence of psychiatric disorders in persons attending Alcohol and Drug Services (ADS). Aims: This study attempted to estimate the incidence of mental health disorders in people treated at two ADS in Melbourne and to describe the mental disorders with which they present. Method: 165 client records from two ADS were reviewed to determine the incidence and characteristics of psychiatric problems in people presenting for management of substance use. Results: Psychiatric diagnoses were recorded in 42% of client records but rarely substantiated by further documentation. The most common diagnoses were mood disorders (31.5%). Only 4.9% clients were diagnosed with drug-induced psychosis. Personality disorders were not recorded. While 52.7% of clients were documented a...

Reporting Patterns for “Lapses of Consciousness” by California Emergency Physicians

Physician reporting of lapses of consciousness (LOC) to the Department of Motor Vehicles is a controversial topic in medicine. The objective of this study was to describe current LOC reporting practices by emergency physicians (EPs) in a state with mandatory reporting requirements (California). A questionnaire describing 14 different clinical scenarios involving LOC was distributed to a diverse sample of California EPs. Clinical scenarios included new seizure, hypoglycemia, atrial fibrillation/rapid heart rate, cerebrovascular accident, micturation syncope, vasovagal syncope, hepatic encephalopathy, alcohol intoxication, closed head injury, hyperosmolar coma, methamphetamine psychosis, dementia, hyperventilation syndrome, and hypercalcemia. Emergency physicians were asked how often they would report these LOC-related conditions to the state. Simple summary statistics were calculated. The response rate was 207/340 (61%) of the forms distributed. The average number of years in Emergency Medicine practice among respondents was 12 (range 1–35), and 57% were Emergency Medicine trained. Of the 14 scenarios, only one (new-onset seizure) was reported frequently by EPs (89% reported “nearly always” or “most of the time”). The remaining 13 scenarios were rarely reported (mean of 86% for “occasionally” or “never”). Although reporting of LOC, from any cause, is mandatory in California, only new-onset seizures are frequently reported by California EPs.

Association study between polymorphisms in glutathione‐related genes and methamphetamine use disorder in a Japanese population

Accumulating evidence suggests that oxidative stress plays a role in the mechanisms of action of methamphetamine (METH) in the brain. In the present study, we investigated the association between the genetic polymorphisms among glutathione (GSH)-related enzymes; glutathione S-transferases (GSTs) such as GSTT1 (Non-deletion/Null), GSTT2 (Met139Ile), GSTA1 (-69C/T), and GSTO1 (Ala140Asp); glutathione peroxidase 1 (GPX1) (Pro198Leu); and glutamate-cysteine ligase modifier (GCLM) subunit and METH use disorder in a Japanese population. Two hundred eighteen METH abusers and 233 healthy controls were enrolled in the study. There was a significant difference in GSTT1 genotype frequency between patients with METH psychosis and controls (P = 0.039, odds ratio: 1.52, 95% CI 1.03-2.24). Furthermore, the frequency (66.0%) of the GSTT1 null genotype among prolonged-type METH psychotic patients with spontaneous relapse was significantly higher (P = 0.025, odds ratio: 2.43, 95% CI 1.13-5.23) than that (44.4%) of transient-type METH psychotic patients without spontaneous relapse. However, there were no associations between the polymorphisms of other genes and METH abuse. The present study suggests that the polymorphism of the GSTT1 gene might be a genetic risk factor of the development of METH psychosis in a Japanese population.

New-Onset Diabetes Mellitus among Parkinsonian Patients Treated with Long-term Quetiapine

Atypical antipsychotics (AA) are commonly used to manage drug-induced psychosis (DIP) in parkinsonian patients. In the treatment of schizophrenia, AA's have been associated with increasing reports of new-onset diabetes mellitus (DM). This study examined the risk of developing new-onset DM among parkinsonian patients on long-term, low dose quetiapine. Fifty-three parkinsonian subjects (mean age: 71.3 years) taking an average quetiapine dose of 70.5 mg/day (range: 12.5–350 mg/day) for a mean duration of 21.3 months (range 3–61 months) were reviewed. Eight out of 53 subjects carried a diagnosis of DM prior to quetiapine treatment. Four out of 45 patients (8.9%) met criteria for new diagnosis of DM, giving a total prevalence rate of 22.6% (12 out of 53). This prevalence rate of 22.6% was slightly higher than that reported in the aged-matched general population (year 2003 DM prevalence = 17.3% for 65–74 years) but methodological differences could explain the difference. Larger epidemiologic studies will be nee...

Methamphetamine psychosis in which tardive dystonia was successfully treated with clonazepam

Reported herein is a case of methamphetamine psychosis in which tardive dystonia was treated successfully with clonazepam. The patient was a 69-year-old man who had taken methamphetamine habitually for approximately 40 years. Auditory hallucinations had developed 25 years previously, for which haloperidol had been prescribed. Tardive dystonia had developed in December 2005. Haloperidol was withdrawn and risperidone or olanzapine alone had been administered, but neither had improved the dystonic posture. However, when clonazepam was added, a gradual improvement in the dystonic posture became evident. Tardive dystonia is currently treated on a trial-and-error basis. Accumulation of further cases similar to the present one is very important for establishing an effective treatment.

Preliminary evidence of behavioral predictors of recurrent drug-induced psychosis in methamphetamine abuse

The goal of this study was to examine behavioral characteristics of currently drug-abstinent methamphetamine (MA)-dependent subjects ( n = 39) who experienced psychotic symptoms associated with MA abuse. All participants completed the Wender Utah Rating Scale (WURS), which retrospectively assesses Attention Deficit Hyperactivity Disorder-relevant childhood behaviors. The results suggest the existence of possible behavioral markers reflecting an early cognitive vulnerability to the development of frequent MA-induced psychotic symptoms as well as increased vulnerability associated with a family history of psychiatric illness.

Improvement by minocycline of methamphetamine-induced impairment of recognition memory in mice

Cognitive deficits are a core feature of patients with schizophrenia and methamphetamine (METH) psychosis. We have recently found that repeated METH treatment (1 mg/kg, s.c.) in mice, which induces behavioral sensitization, impairs long-term recognition memory in a novel object recognition test (NORT) and that the impairment is ameliorated by clozapine, but not haloperidol. Recent studies indicate that minocycline, a second-generation tetracycline, has potent neuroprotective effects in various animal models of neurological diseases. In the present study, we investigated the effect of minocycline on learning and memory in the NORT and behavioral sensitization in mice that had been administered METH for 7 days. When minocycline (20-40 mg/kg) was administered intraperitoneally once a day for seven consecutive days to mice that had previously been treated with METH for 7 days, it ameliorated the METH-induced impairment of recognition memory in a dose-dependent manner, although the same treatment with minocycline had no effect on behavioral sensitization to METH. The administration of minocycline, together with METH, inhibited the development of METH-induced behavioral sensitization. The improvement in memory caused by minocycline was associated with an amelioration of the novelty-induced activation of extracellular signal-regulated kinase 1/2 in the prefrontal cortex of METH-treated mice. These results suggest that minocycline is useful for the treatment of cognitive deficits in patients with METH psychosis or schizophrenia.

Two weeks' quetiapine treatment for schizophrenia, drug-induced psychosis and borderline personality disorder: a naturalistic study with drug plasma levels

Objective: To evaluate clinical outcomes and the tolerability of 2 weeks' quetiapine (QTP) treatment for hospitalised patients in a naturalistic setting. Methods: Patients with schizophrenia (n = 18), drug-induced psychosis (n = 10; 3 cocaine, 4 hashish and marijuana, and 3 all three substances) or borderline personality disorder (n = 13), were diagnosed by two expert clinicians on the basis of an unstructured clinical interview, and were treated with QTP (250 – 1000 mg/day). The subjects were then clinically assessed at baseline, and after 7 and 15 days, using the Brief Psychiatric Rating Scale, the Positive and Negative Symptoms Scale (PANSS) and the Hamilton Rating Scale for Depression. At the end of the study, plasma QTP levels were determined and examined in relation to clinical outcome and tolerability. Results: The mean scores of each rating scale were significantly lower at the end of the study in the population as a whole, and within each diagnostic group. The percentage improvement was significantly greater in the patients with drug-induced psychosis than in those with schizophrenia (42.4 ± 9.1% versus 23.6 ± 13.5%). QTP was well tolerated, and the incidence of extrapyramidal side effects was low. There was a linear correlation between plasma levels and dose/kg of QTP (r = 0.31; p < 0.05). The improvement in PANSS significantly correlated with plasma levels and dose/kg in each diagnostic category (Spearman's coefficient was 0.75 [p < 0.01] for schizophrenia and borderline personality disorder, and was 0.68 [p < 0.05] for drug-induced psychosis). Conclusion: The results suggest that 2 weeks' QTP treatment may improve the clinical outcome of psychotic re-exacerbation phases in different diagnostic categories and indicate that QTP improves clinical outcome in drug-induced psychosis, as QTP levels correlated with the clinical improvement measured by PANSS.

Genetic Vulnerabilities to Methamphetamine Abuse and Psychosis

Methamphetamine abuse is intimately tied to the effects of methamphetamine on the dopamine transporter. A synaptic protein, called “protein interacting

Altered EphA5 mRNA expression in rat brain with a single methamphetamine treatment

Methamphetamine is a potent and indirect dopaminergic agonist which can cause chronic brain dysfunctions including drug abuse, drug dependence and drug-induced psychosis. Methamphetamine is known to trigger molecular mechanisms involved in associative learning and memory, and thereby alter patterns of synaptic connectivity. The persistent risk of relapse in methamphetamine abuse, dependence and psychosis may be caused by such alterations in synaptic connectivity. EphA5 receptors constitute large families of tyrosine kinase receptor and are expressed almost exclusively in the nervous system, especially in the limbic structures. Recent studies suggest EphA5 to be important in the topographic projection, development, and plasticity of limbic structures, and to be involved in dopaminergic neurotransmission. We used in situ hybridization to examine whether methamphetamine alters EphA5 mRNA expression in the brains of adult male Wister rats. EphA5 mRNA was widely distributed in the medial frontal cortex, cingulate cortex, piriform cortex, hippocampus, habenular nucleus and amygdala. Compared to baseline expression at 0h, EphA5 mRNA was significantly decreased (by 20%) in the medial frontal cortex at 24h, significantly increased (by 30%) in the amygdala at 9 and 24h, significantly but transiently decreased (by 30%) in the habenular nucleus at 1h after a single injection of methamphetamine. Methamphetamine did not change EphA5 mRNA expression in the cingulate cortex, piriform cortex or hippocampus. Our results that methamphetamine altered EphA5 mRNA expression in rat brain suggest methamphetamine could affect patterns of synaptic connectivity, which might be responsible for methamphetamine-induced chronic brain dysfunctions.

Behavioral alterations in the pilocarpine model of temporal lobe epilepsy in mice

Psychiatric disorders frequently occur in patients with epilepsy, but the relationship between epilepsy and psychopathology is poorly understood. Frequent comorbidities in epilepsy patients comprise major depression, anxiety disorders, psychosis and cognitive dysfunction. Animal models of epilepsy, such as the pilocarpine model of acquired epilepsy, are useful to study the relationship between epilepsy and behavioral dysfunctions. However, despite the advantages of mice in studying the genetic underpinning of behavioral alterations in epilepsy, mice have only rarely been used to characterize behavioral correlates of epilepsy. This prompted us to study the behavioral and cognitive alterations developing in NMRI mice in the pilocarpine model of epilepsy, using an anxiety test battery as well as tests for depression, drug-induced psychosis, spatial memory, and motor functions. In order to ensure the occurrence of status epilepticus (SE) and decrease mortality, individual dosing of pilocarpine was performed by ramping up the dose until onset of SE. This protocol was used for studying the consequences of SE, i.e. hippocampal damage, incidence of epilepsy with spontaneous recurrent seizures, and behavioral alterations. SE was terminated by diazepam after either 60, 90 or 120 min. All mice that survived SE developed epilepsy, but the severity of hippocampal damage varied depending on SE length. In all anxiety tests, except the elevated plus maze test, epileptic mice exhibited significant increases of anxiety-related behavior. Surprisingly, a decrease in depression-like behavior was observed in the forced swimming and tail suspension tests. Furthermore, epileptic mice were less sensitive than controls to most of the behavioral effects induced by MK-801 (dizocilpine). Learning and memory were impaired in epileptic mice irrespective of SE duration. Thus, the pilocarpine-treated mice seem to reflect several of the behavioral and cognitive disturbances that are associated with epilepsy in humans. This makes these animals an ideal model to study the neurobiological mechanisms underlying the association between epilepsy and psychopathology.

A Success at the End of an Era, and a Glimpse of Things to Come

A Success at the End of an Era, and a Glimpse of Things to Come

A Success at the End of an Era, and a Glimpse of Things to Come

A Success at the End of an Era, and a Glimpse of Things to Come