Phytocannabinoids and schizophrenia: Focus on adolescence as a critical window of enhanced vulnerability and opportunity for treatment.

The recent shift in socio-political debates and growing liberalization of Cannabis use across the globe has raised concern regarding its impact on vulnerable populations such as adolescents. Concurrent with declining perception of Cannabis harms, more adolescents are using it daily in several countries and consuming marijuana strains with high content of psychotropic delta (9)-tetrahydrocannabinol (THC). These dual, related trends seem to facilitate the development of compromised social and cognitive performance at adulthood, which are described in preclinical and human studies. Cannabis exerts its effects via altering signalling within the endocannabinoid system (ECS), which modulates the stress circuitry during the neurodevelopment. In this context early interventions appear to circumvent the emergence of adult neurodevelopmental deficits. Accordingly, Cannabis sativa second-most abundant compound, cannabidiol (CBD), emerges as a potential therapeutic agent to treat neuropsychiatric disorders. We first focus on human and preclinical studies on the long-term effects induced by adolescent THC exposure as a "critical window" of enhanced neurophysiological vulnerability, which could be involved in the pathophysiology of schizophrenia and related primary psychotic disorders. Then, we focus on adolescence as a "window of opportunity" for early pharmacological treatment, as novel risk reduction strategy for neurodevelopmental disorders. Thus, we review current preclinical and clinical evidence regarding the efficacy of CBD in terms of positive, negative and cognitive symptoms treatment, safety profile, and molecular targets.

Harmala Alkaloids Identify Ayahausca Intoxication in a Urine Drug Screen.

BACKGROUND: Ayahausca is an ethnobotanical drink of South America and the compound dimethyltryptamine (DMT) is primarily responsible for the hallucinogenic effects. DMT has a short half-life and its detection in urinary drug screens is challenging. We investigate a simple alternate approach to detect ayahuasca consumption by relying on other constituents of the drink, the ß-carboline harmala alkaloids. METHODS: Three commercially sourced harmala alkaloids were characterized and added to a non-targeted high-resolution mass spectrometry urine drug screening method. All analyses were performed on a Waters Xevo G2-XS LC-QTof, in positive electrospray ionization mode. The mass detector was operated in MSE mode and data processed with UNIFI™ software. A urine specimen from a patient suspected to have consumed ayahuasca was analyzed by a non-targeted drug screen. RESULTS: The harmala alkaloids: harmine, harmaline and tetrohydroharmaline (THH) were characterized and their detection data added to the toxicology screening library. Harmaline and THH were detected in the patient's urine specimen. CONCLUSION: The inclusion of the harmala alkaloids into the drug screen method library may enable the detection of ayahuasca use in patients that undergo non-targeted drug screen.

Functional foods: How functional are they? A case report of supplement-induced psychosis.

There is rising evidence of patients' use of alternative and complementary medicine. The percentage of the U.S. population who used at least one dietary supplement increased from 42% in 1988-1994 to 53% in 2003-2006. We present a case of an Asian female in her 40s, with no previous psychiatric illness, who presented to the emergency room following a brief psychotic episode, during which she self-amputated the tips of her fingers, after using multivitamins and herbal supplements including ginseng, gui yuan rou (Chinese herb), astaxanthin, goji (Chinese fruit), selenium, saw palmetto, grape seed extract, citrus bioflavanoid, lutein (zeaxantin), resvexatrol, sun chlorella, spirulina powder, phytoceramides, phytoestrogen, glucosatrin, bromelain plus, and American bee pollen. Comprehensive laboratory workup, drug screening, and diagnostic imaging were negative. Vital signs were stable. Other than the amputated finger tips, the remainder of her physical examination was unremarkable. Her mental status improved significantly after treatment with risperidone 1 mg twice daily, during a five-day psychiatric hospitalization. This case draws attention to the fact that supplements have the potential of producing frank psychosis and require close monitoring and study by physicians.

Caffeine-induced psychiatric manifestations: a review.

The association between caffeine consumption and various psychiatric manifestations has long been observed. We present two cases that show the ability of caffeine to induce psychotic and manic symptoms, and we also review the extant literature on caffeine-induced psychiatric manifestations. On the basis of our own and others' findings, we suggest that caffeine may be related to not only de-novo psychotic or mood symptoms but also to aggravation of pre-existing psychotic or mood disorders. We therefore suggest that caffeine consumption among patients with mood or psychotic symptoms should be assessed carefully in clinical practice as part of routine psychiatric evaluations.

Treatment of refractory substance-induced psychosis in adolescent males with a genetic predisposition to mental illness.

This article presents two cases of adolescent males who were admitted to our inpatient psychiatric unit with a psychotic, disorganized presentation. Both males had a genetic vulnerability to mental illness and reported significant substance use. Their symptoms were refractory to treatment and required the use of clozapine. Both patients experienced significant side effects, which limited the maximum daily dose of clozapine. However, they responded to a dose that was much lower than that typically used in adults. There is significant evidence in the literature about cannabis use triggering psychotic breaks in vulnerable individuals. We speculate that substance use (including synthetic cannabinoids) triggers treatment-resistant psychosis that requires the use of clozapine. Further, lower doses of clozapine may be sufficient to treat the substance-induced psychotic symptoms than those typically used in adult schizophrenia.

Aripiprazole for treating cannabis-induced psychotic symptoms in ultrahigh-risk individuals.

Cannabis-induced psychotic symptoms (CIPSs) have both similarities and differences with positive symptoms of schizophrenia, and it remains unclear whether CIPSs result from dopaminergic mechanisms and can be treated with antipsychotics. We report the case of a 22-year-old male patient with ultrahigh risk criteria for psychosis, who reported cannabis addiction and recurrent CIPSs. Aripiprazole 10 mg/d could totally and durably suppress CIPSs in the patient, but had no effect on the smoking level. Treating CIPSs in ultrahigh risk individuals who cannot stop or refuse stopping cannabis might fit a harm-reduction strategy by preventing transition into psychosis.

¿Media la dopamina los efectos psicóticos del Cannabis? Revisión e integración de los hallazgos a través de disciplinas / Does dopamine mediate the psychosis-inducing effects of cannabis? A review and integration of findings across disciplines

Los estudios epidemiológicos efectuados en la población general han demostrado sistemáticamente que el consumo de Cannabis aumenta de modo dependiente de la dosis el riesgo de desarrollar trastornos psicóticos. Aunque los indicios epidemiológicos entre el consumo de Cannabis y las psicosis han obtenido una atención considerable, apenas se conoce el mecanismo biológico mediante el que esta droga aumenta el riesgo de psicosis. La investigación en estudios efectuados en animales sugiere que el delta- 9-tetrahidrocanabinol (THC, el componente psicoactivo principal del Cannabis) aumenta los niveles de dopamina en diversas regiones del cerebro, incluido el núcleo estriado y el área prefrontal. Dado que se ha formulado la hipótesis de que la dopamina representa una vía final común decisiva entre la biología del cerebro y la experiencia real de psicosis, inicialmente prestar atención a este neurotransmisor podría ser productivo en el examen de los efectos psicotomiméticos del Cannabis. Por consiguiente, en la presente revisión se examinan las pruebas concernientes a las interacciones entre el THC, los endocanabinoides y la dopamina en la región tanto cortical como subcortical implicadas en las psicosis, y se consideran los posibles mecanismos por los que una disregulación de la dopamina inducida por el consumo de Cannabis podría dar lugar a delirios y alucinaciones. Se concluye que podrían emprenderse productivamente estudios adicionales sobre los mecanismos subyacentes que relacionan el consumo de Cannabis y las psicosis desde una perspectiva de una sensibilización progresiva del desarrollo, como consecuencia de interacciones genes-ambiente (AU)

General population epidemiological studies have consistently found that cannabis use increases the risk of developing psychotic disorders in a dose-dependent manner. While the epidemiological signal between cannabis and psychosis has gained considerable attention, the biological mechanism whereby cannabis increases risk for psychosis remains poorly understood. Animal research suggests that delta-9- tetrahydrocannabinol (THC, the main psychoactive component of cannabis) increases dopamine levels in several regions of the brain, including striatal and prefrontal areas. Since dopamine is hypothesized to represent a crucial common final pathway between brain biology and actual experience of psychosis, a focus on dopamine may initially be productive in the examination of the psychotomimetic effects of cannabis. Therefore, this review examines the evidence concerning the interactions between THC, endocannabinoids and dopamine in the cortical as well as subcortical regions implicated in psychosis, and considers possible mechanisms whereby cannabis-induced dopamine dysregulation may give rise to delusions and hallucinations. It is concluded that further study of the mechanisms underlying the link between cannabis and psychosis may be conducted productively from the perspective of progressive developmental sensitization, resulting from gene-environment interactions (AU)

Antipsychotic property of aqueous and ethanolic extracts of Lonchocarpus cyanescens (Schumach and Thonn.) Benth. (Fabaceae) in rodents.

Lonchocarpus cyanescens (LC) is a medicinal plant commonly used in combination with other recipes in the treatment of psychotic disorders in traditional medicine. This study was designed to examine whether the aqueous and ethanolic extracts of LC possess antipsychotic property in rats. The antipsychotic effects of the extracts were assessed using the amphetamine animal model of psychosis in rats. The effect of the extracts on spontaneous motor activity was also studied in the open field test in mice. The extrapyramidal side effect of catalepsy was tested based on the ability of the extracts to alter the duration of akinesia in mice placed on a vertical wrapped string. Aqueous and ethanolic extracts of LC (25-400 mg/kg, i.p.) significantly (p < 0.05) suppressed stereotyped behaviour induced by amphetamine (10.0 mg/kg, i.p.) in rats, which suggest antipsychotic activity. The extracts (25-400 mg/kg, i.p.) further produced a significant (p < 0.05) reduction in spontaneous motor activity of the animals in the open field test. However, in contrast to chlorpromazine, a typical antipsychotic, the extracts did not induce cataleptic behaviour in the animals. Preliminary phytochemical screening showed the presence of alkaloids, anthraquinones, cardiac glycosides, cyanogenetic glycosides, flavonoids, saponins, steroids and tannins in the leaves of LC. The presence of these secondary metabolites was confirmed by thin-layer chromatography. Taken together, these findings suggest that the extracts possess phytochemically active constituents with antipsychotic property. Thus, this investigation provides evidence that may justify the ethnomedicinal applications of Lonchocarpus cyanescens as the major constituent of the recipe used for the management of psychosis in Nigeria.

['Steroid psychosis' during treatment for premature labour]. / 'Steroïdpsychose' bij behandeling van dreigende vroeggeboorte.

A 30-year-old woman, 33 weeks pregnant, without a significant psychiatric history, was admitted for treatment of premature labour. She was treated with betamethasone intramuscularly, with a total dose of 24 mg divided over 2 days, and nifedipine orally with beneficial effect on the contractions. However, within 24 h after completion of tocolytic treatment, she developed a psychosis with delusions and hallucinations necessitating readmission, first to an obstetric ward, later to a psychiatric ward. At least part of this episode may be characterized as delirium. Eventually, she was treated with haloperidol. It is argued that her psychosis was caused by the corticosteroid, since psychiatric disturbance is a well-known complication of corticosteroid therapy. To our knowledge, psychosis during pregnancy as a result of treatment with corticosteroids has not been reported previously.

[Acute psychotic access following the administration of isoniazid]. / L'accès psychotique aigu secondaire à la prise d'isoniazide.

INTRODUCTION: Acute psychotic access is defined as the occurrence of a single, acute, and intense psychotic episode in a subject without a neurological or psychiatric history. Isoniazid (INH), a major antibacillar, is the drug most often involved in the occurrence of this psychiatric disorder. However, this side effect is rare and only a few cases have been reported in the literature. CASE REPORT: A 57-year-old female patient with diabetes mellitus presented miliary tuberculosis for which an antibacillar treatment was prescribed. Three days later, she presented an acute psychotic access requiring the withdrawal of the INH and the prescription of neuroleptic drugs, without any pyridoxine supplementation. The lab tests were normal. The good clinical evolution after the INH withdrawal confirmed its imputabilty. CONCLUSION: Acute psychotic access is a severe and exceptional complication following the administration of INH. Emergency treatment is the only guarantee of a good outcome.

The GABA B receptor agonist CGP44532 and the positive modulator GS39783 reverse some behavioural changes related to positive syndromes of psychosis in mice.

BACKGROUND AND PURPOSE: An important role of GABAergic neurotransmission in schizophrenia was proposed a long time ago, but there is limited data to support this hypothesis. In the present study we decided to investigate GABA(B) receptor ligands in animal models predictive for the antipsychotic activity of drugs. The GABA(B) receptor antagonists CGP51176 and CGP36742, agonist CGP44532 and positive allosteric modulator GS39783 were studied. EXPERIMENTAL APPROACH: The effects of all ligands were investigated in MK-801- and amphetamine-induced hyperactivity tests. The anti-hallucinogenic-like effect of the compounds was screened in the model of head twitches induced by (±)1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Furthermore, the effect of GS39783 and CGP44532 on DOI-induced frequency of spontaneous excitatory postsynaptic currents (EPSCs) in slices from mouse brain frontal cortices was investigated. The anti-cataleptic properties of the compounds were also assessed. KEY RESULTS: The GABA(B) receptor activators CGP44532 and GS39783 exhibited antipsychotic-like effects both in the MK-801- and amphetamine-induced hyperactivity tests, as well as in the head-twitch model in mice. Such effects were not observed for the GABA(B) receptor antagonists. DOI-induced increased frequency of spontaneous EPSCs was also decreased by the compounds. Moreover, CGP44532 and GS39783 inhibited haloperidol-induced catalepsy and EPSCs. CONCLUSION AND IMPLICATIONS: These data suggest that selective GABA(B) receptor activators may be useful in the treatment of psychosis.

To medicate or not to medicate, when diagnosis is in question: decision-making in first episode psychosis.

OBJECTIVE: This paper reports on a brief survey of clinicians' judgements when making treatment decisions in the context of diagnostic uncertainty. Specifically, attitudes and opinions were sought from practising consultant psychiatrists regarding two key areas of clinical decision-making in first episode psychosis (FEP), namely, when to initiate medication and, how long to continue treatment. METHOD: Interviews were conducted with consultant psychiatrists using a combination of structured and semi-structured questions that examined and explored pharmacological treatment decisions in FEP. RESULTS: Twenty-three consultant psychiatrists participated in the interviews. The threshold to initiate pharmacological treatment was lower when a risk to self or others is present, when symptoms are primarily positive, when the patient is in distress, or where there is a family history of mental illness. Atypical antipsychotics are routinely used as front-line medication in FEP and the choice of medication is determined largely by their likely side effect profile. However, the greater the perceived efficacy, the greater the anticipated tolerability burden. The ideal duration of treatment is considered to be 1-2 years in instances of full remission, and 5 years where only a partial response has been achieved or where recovery has not been sustained. CONCLUSIONS: The 'first episode' represents a unique period in the management of psychosis where by definition there is no history of pattern of illness, diagnostic certainty is rare, and the patient usually does not have any prior exposure to medications. Therefore, each management decision needs to be considered following a risk benefit analysis which takes into account the context of the individual.

Case of acute psychosis from herbal supplements.

A recent study estimates that 15.2 percent of American adults use nonprescription dietary supplements for weight loss. Sale of ephedrine- and ephedrine-alkaloid-containing products was prohibited by the Food and Drug Administration in February 2004 after research demonstrated an increased risk of arrhythmia, mortality and hypertension following use of products containing these sympathomimetics. Subsequently, nutritional supplement manufacturers have turned to other products to promote weight loss. The following paper reports a case study of a 28-year-old woman with no prior psychiatric history who was hospitalized secondary to an acute psychotic episode. The patient reported starting several weight-loss and nutritional sports supplements approximately one week prior to admission. The relationship between the onset of psychosis and the initiation of the dietary supplements strongly suggests a correlation exists. Heightened consumer education regarding the contents of dietary supplements, along with their potential for causing adverse effects when used alone or in combination with other medications, is warranted. Patients who choose to take dietary supplements should be encouraged to inform their health care providers about the supplements they are taking.

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.

Treatment of drug-induced psychosis in Parkinson's disease with ziprasidone can induce severe dose-dependent off-periods and pathological laughing.

"Atypical anti-psychotics" are substances of choice in treating drug-induced psychosis (DP) in Parkinson's disease (PD). We report on four patients with DP who received treatment with ziprasidone after previously applied clozapine and quetiapine had failed. Three patients showed a significant improvement of DP, without deterioration of motor function. In one case, ziprasidone considerably increased decline in off-periods. Two patients developed pathological laughing as a possible side-effect of ziprasidone. Ziprasidone may serve as an additional "atypical anti-psychotic" for the treatment of DP in PD but can also induce deterioration of motor function.