The development of Cannabidiol as a psychiatric therapeutic:a review of its antipsychotic efficacy and possible underlying pharmacodynamic mechanisms

Cannabidiol (CBD), a once-considered inert cannabis constituent, is one of two primary constituents of cannabis, alongside delta-9-tetrahydrocannabinol (?9-THC/THC). In the last 30 years, CBD has become implicated with a range of pharmaceutical mechanisms of great therapeutic interest and utility. This review details the literature speculating CBD’s attenuation of psychotic symptoms, particularly in light of a marked elevation in mean THC concentrations, and a concomitant decline in CBD concentrations in the prevalent U.K street market cannabis derivatives since c. 2000. CBD is purported to exhibit pharmacology akin to established atypical antipsychotics, whilst THC has been implicated with the precipitation of psychosis, and the induction of associated symptoms. The aim of the review was to clarify the conjecture surrounding CBD’s antipsychotic efficacy, before going on to detail prominent theories about its associated pharmacodynamics. Were CBD’s antipsychotic efficacy established, then there is potential for major latent anthropological repercussions to manifest, such as significant elevations in psychosis manifestations in the U.K. The review found a largely affirmative body of evidence asserting CBD’s antipsychotic efficacy. CBD exhibited capacity to attenuate natural and artificially induced psychoses in both animal and human cohorts, the latter of which included individuals considered resistant to conventional treatment. CBD also shows promising potential for use as an antipsychotic drug for Parkinson’s disease (PD) patients with psychosis, owing to its low rate of extra-pyramidal side-effect induction. A range of potential pharmacological mechanisms behind CBD’s neuroleptic pharmacology are outlined, with particular emphasis on its prevention of the hydrolysis and reuptake of the endogenous cannabinoid, anandamide. However, given the nebular aetiological basis for psychoses, explicit conclusions on how CBD attenuates psychotic symptoms remains to be determined.

Neuropsychiatric manifestations in inflammatory neuropathies:a systematic review

We conducted a systematic literature review on psychological and behavioral comorbidities in patients with inflammatory neuropathies. In Guillain-Barré syndrome (GBS), psychotic symptoms are reported during early stages in 30% of patients. Typical associations include mechanical ventilation, autonomic dysfunction, inability to communicate, and severe weakness. Anxiety and depression are frequent comorbidities. Anxiety may increase post-hospital admissions and be a predictor of mechanical ventilation. Post-traumatic stress disorder may affect up to 20% of ventilated patients. Sleep disturbances are common in early-stage GBS, affecting up to 50% of patients. In chronic inflammatory demyelinating polyradiculoneuropathy, memory and quality of sleep may be impaired. An independent link between depression and pre-treatment upper limb disability and ascites was reported in POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin) syndrome, with an association with early death. Hematological treatment of POEMS appears effective on depression. Published literature on psychological/behavioral manifestations in inflammatory neuropathies remains scarce, and further research is needed. This article is protected by copyright. All rights reserved.

Hyperprolinemia as a clue in the diagnosis of a patient with a psychiatric disorder

Background: Over the last few years, microdeletions of the 22q11.2 region responsible for DiGeorge syndrome, or velocardiofacial syndrome, have been increasingly related to neuropsychiatric disorders including schizophrenia and bipolar disorders. These signs seem to be related to certain genes located in the hemideleted region as the proline dehydrogenase (PRODH) and the catecholo-methyltransferase (COMT) genes. The PRODH or proline oxidase deficiency is responsible for hyperprolinemia type 1 (HPI) also causing psychiatric manifestations. Case Report: We describe a 17 year old boy with previous mild psychomotor and speech delay, mild cognitive impairment, and obsessive behaviours who started his adolescent psychiatric care presenting irritablemood and aggressive behaviour with schizophrenia symptoms that scored a “severely ill” level PANSS assessment. Symptoms got worse when he was treated with valproic acid and plasma aminoacids showing increase in alanine and proline, suggested a mitochondrial involvement of the proline metabolic pathway. Results: Mild dysmorphia suggested a possible 22q11.2 deletion genetically confirmed involving both the PRODH and COMT regions. HPI that can present with psychiatric features is however a recessive disorder and therefore the symptoms could not be solely explained by this genetic deletion. Additional investigations also showed disclosed a p.L289m (c.1865 T > A) mutation in the PRODH gene. Discussion: We believe that the association of this mutation together with the 22q11.2 deletion would lead to a decrease of functional protein. Although it may be difficult to diagnosis chromosomal abnormalities in patients with no clear malformations and mild dysmorphic features as in this patient we emphasize need to investigate the aetiology in patients with psychiatric symptoms, especially if they have other systemic manifestations such as developmental delay or psychotic symptoms, as it may be important in the management of the patients.

Acute Psychosis as Major Clinical Presentation of Legionnaires’ Disease

We report a case of a 61-year-old woman who presented with acute psychosis as a major manifestation of Legionnaires’ disease in the absence of other neuropsychiatric symptoms. Clinical history revealed dry cough and nausea. Observation showed fever and auscultation crackles in the lower lobe of the right lung. Laboratory testing demonstrated elevated C-reactive protein and lung chest radiograph showed patchy peribronchial and right lower lobe consolidation. Soon after admission, she started producing purulent sputum. Epidemiological data suggested Legionella pneumophila as possible cause of the clinical picture that was confirmed by urinary antigen detection and polymerase chain reaction of the sputum. She was treated with levofloxacin 750 mg/day for 10 days with complete remission of pulmonary and psychiatric symptoms. She has not had further psychotic symptoms.

Feasibility of resting-state microstates neurofeedback

Despite major progress, currently available treatment options for patients suffering from schizophrenia remain suboptimal. Antipsychotic medication is one such option, and is helpful in acute phases of the disease. However, antipsychotics cause significant side-effects that often require additional medication, and can even trigger the discontinuation of treatment. Taken together, along with the fact that 20-30% of patients are medication-resistant, it is clear that new medical care options should be developed for patients with schizophrenia. Besides medication, an emerging option to treat psychiatric symptoms is through the use of neurofeedback. This technique has proven efficacy for other disorders and, more importantly, has also proven to be feasible in patients with schizophrenia. One of the major advantages of this approach is that it allows for the influence of brain states that otherwise would be inaccessible; i.e. the physiological markers underlying psychotic symptoms. EEG resting-state microstates are a very interesting electrophysiological marker of schizophrenia symptoms. Precisely, a specific class of resting-state microstates, namely microstate class D, has consistently been found to show a temporal shortening in patients with schizophrenia compared to controls, and this shortening is correlated with the presence positive psychotic symptoms. Under the scope of biological psychiatry, appropriate treatment of psychotic symptoms can be expected to modify the underlying physiological markers accompanying behavioral manifestations of a disease. We reason that if abnormal temporal parameters of resting-state microstates seem to be related to positive symptoms in schizophrenia, regulating this EEG feature might be helpful as a treatment for patients. The goal of this thesis was to prove the feasibility of microstate class D contribution self-regulation via neurofeedback. Given that no other study has attempted to regulate microstates via neurofeedback, we first tested its feasibility in a population of healthy subjects. In the first paper we describe the methodological characteristics of the neurofeedback protocol and its implementation. Neurofeedback performance was assessed by means of linear mixed effects modeling, which provided a complete profile of the neurofeedback’s training response within and between-subjects. The protocol included 20 training sessions, and each session contained three conditions: baseline (resting-state) and two active conditions: training (auditory feedback upon self-regulation performance) and transfer (self-regulation with no feedback). With linear modeling we obtained performance indices for each of them as follows: baseline carryover (baseline increments time-dependent) and learning and aptitude for each of the active conditions. Learning refers to the increase/decrease of the microstate class D contribution, time-dependent during each active condition, and aptitude refers to the constant difference of the microstate class D contribution between each active condition and baseline independent of time. The indices provided are discussed in terms of tailoring neurofeedback treatment to individual profiles so that it can be applied in future studies or clinical practice. In our sample of participants, neurofeedback proved feasible, as all participants at least showed positive results in one of the aforementioned learning indices. Furthermore, between-subjects we observed that the contribution of microstate class D across-sessions increased by 0.42% during baseline, 1.93% during training trials, and 1.83% during transfer. This range is expected to be effective in treating psychotic symptoms in patients. In the second paper presented in this thesis, we explored the possible predictors of neurofeedback success among psychological variables measured with questionnaires. An interesting finding was the negative correlation between “motivational incongruence” and some of the neurofeedback performance indices. Even though this finding requires replication, we discuss it in terms of the interfering effects of incompatible psychological processes with neurofeedback training requirements. In the third paper, we present a meta-analysis on all available studies that have related resting-state microstate abnormalities and schizophrenia. We obtained medium effect sizes for two microstate classes, namely C and D. Combining the meta-analysis results with the fact that microstate class D abnormalities are correlated with the presence of positive symptoms in patients with schizophrenia, these results add further support for the training of this precise microstate. Overall, the results obtained in this study encourage the implementation of this protocol in a population of patients with schizophrenia. However, future studies will have to show whether patients will be able to successfully self-regulate the contribution of microstate class D and, if so, whether this regulation will have an impact on symptomatology.

Differences in Frontal Activation in Adult Patients with Schizophrenia and in Psychotic Adolescents with Schizophrenic Symptoms in Two Fmri Tasks

Background: Language processing abnormalities and inhibition difficulties are hallmark features of schizophrenia. The objective of this study is to asses the blood oxygenation level-dependent (BOLD) response at two different stages of the illness and compare the frontal activity between adolescents and adults with schizophrenia. Methods: 10 adults with schizophrenia (mean age 31,5 years) and 6 psychotic adolescents with schizophrenic symptoms (mean age 16,2 years) underwent functional magnetic resonance imaging while performing two frontal tasks. Regional activation is compared in the bilateral frontal areas during a covert verbal fluency task (letter version) and a Stroop task (inhibition task). Results: Preliminary results show poorer task performance and less frontal cortex activation during both tasks in the adult group of patients with schizophrenia. In the adolescent patients group, fMRI analysis show significant and larger activity in the left frontal operculum (Broca's area) in the verbal fluency task and greater activity in the medium cingulate during the inhibition phase of the Stroop task. Conclusions: These preliminary findings suggest a decrease of frontal activity in the course of the illness. We assume that schizophrenia contributes to frontal brain activity reduction.

Basic symptoms in the general population and in psychotic and non-psychotic psychiatric adolescents

Cognitive-perceptive 'basic symptoms' are used complementary to ultra-high-risk criteria in order to predict onset of psychosis in the pre-psychotic phase. The aim was to investigate the prevalence of a broad selection of 'basic symptoms' in a representative general adolescent population sample (GPS; N=96) and to compare it with adolescents first admitted for early onset psychosis (EOP; N=87) or non-psychotic psychiatric disorders (NP; N=137).

The continuum of quasi-psychotic beliefs and experiences in the Australian general public

When surveyed, many individuals without psychosis report a range of beliefs and experiences that are shared by patients with psychosis. This study aimed to examine quasi-psychotic beliefs and experiences in a sample of well Australians. 303 individuals were recruited from a defined catchment area as part of the Brisbane Psychosis Study. All subjects were screened with a modified SCAN in order to exclude psychoses. The Peters Delusional Inventory (PDI 40 items), items from the Chapmans' Psychosis Proneness Scale (PPS), the Communication Awareness Scale (CAS: a measure of awareness of thought disorder), items related to perceptions and beliefs from various schizotypy questionnaires and the Social Desirability (SD) items from the EPQ were administered. There was a significant negative correlation between age and total score on the PDI. There were significant positive correlations between the PDI, the PPS, the CAS and the items related to perception. There were no significant gender differences on any of the scores apart from SD (females had higher scores). Those with a positive family history of mental illness other than schizophrenia (n = 118) scored significantly higher on the PDI and scores related to perception, however they were no different on SD or the Psychosis Proneness items. There were no group differences on any of these items when those with a positive family history of schizophrenia (n = 27) were compared to the rest of the group. Well individuals who endorse delusional beliefs also tend to endorse items related to abnormal perceptions and awareness of thought disorder. The results of the study support the concept of a 'continuum of beliefs and experiences' in the general community that should inform our neurocognitive models of the symptoms of psychosis. The Stanley Foundation supported this project.

Lateral ventricle differences between first-episode schizophrenia and first-episode psychotic bipolar disorder: A population-based morphometric MRI study

Objectives. The extent to which psychotic disorders fall into distinct diagnostic categories or can be regarded as lying on a single continuum is controversial. We compared lateral ventricle volumes between a large sample of patients with first-episode schizophrenia or bipolar disorder and a healthy control group from the same neighbourhood. Methods. Population-based MRI study with 88 first-episode psychosis (FEP) patients, grouped into those with schizophrenia/schizophreniform disorder (N = 62), bipolar disorder (N = 26) and 94 controls. Results. Right and left lateral ventricular and right temporal horn volumes were larger in FEP subjects than controls. Within the FEP sample, post-hoc tests revealed larger left lateral ventricles and larger right and left temporal horns in schizophrenia subjects relative to controls, while there was no difference between patients with bipolar disorder and controls. None of the findings was attributable to effects of antipsychotics. Conclusions. This large-sample population-based MRI study showed that neuroanatomical abnormalities in subjects with schizophrenia relative to controls from the same neighbourhood are evident at the first episode of illness, but are not detectable in bipolar disorder patients. These data are consistent with a model of psychosis in which early brain insults of neurodevelopmental origin are more relevant to schizophrenia than to bipolar disorder.

Treatment motivation in adolescents with psychosis or at high risk: Determinants and impact on improvements in symptoms and cognitive functioning, preliminary results.

Abstract Low motivation is frequent in chronic disorders such as psychosis and may limit treatment efficacy. Although some evidence supports this view in adults, few studies so far have focused on adolescents. We assessed the impact of baseline symptoms, cognitive deficits and cognitive treatment characteristics on treatment motivation (TM), and examined whether TM affected treatment outcome. Twenty-eight adolescents with psychotic disorders participated in 16 sessions of computerized cognitive remediation or games. TM was assessed for each session. Lower TM was predicted by more severe symptoms at baseline, and was associated with smaller improvements in symptoms and both cognitive and psychosocial functioning at the end of the intervention. Experiencing success in the treatment exercises enhanced TM in all patients.

The impact of past direct-personal traumatic events on 12-month outcome in first episode psychotic mania: trauma and early psychotic mania.

OBJECTIVE: Past traumatic events have been associated with poorer clinical outcomes in people with bipolar disorder. However, the impact of these events in the early stages of the illness remains unclear. The aim of this study was to investigate whether prior traumatic events were related to poorer outcomes 12 months following a first episode of psychotic mania. METHODS: Traumatic events were retrospectively evaluated from patient files in a sample of 65 participants who had experienced first episode psychotic mania. Participants were aged between 15 and 28 years and were treated at a specialised early psychosis service. Clinical outcomes were measured by a variety of symptomatic and functioning scales at the 12-month time-point. RESULTS: Direct-personal traumatic experiences prior to the onset of psychotic mania were reported by 48% of the sample. Participants with past direct-personal trauma had significantly higher symptoms of mania (p=0.02), depression (p=0.03) and psychopathology (p=0.01) 12 months following their first episode compared to participants without past direct-personal trauma, with medium to large effects observed. After adjusting for baseline scores, differences in global functioning (as measured by the Global Assessment of Functioning scale) were non-significant (p=0.05); however, participants with past direct-personal trauma had significantly poorer social and occupational functioning (p=0.04) at the 12-month assessment with medium effect. CONCLUSIONS: Past direct-personal trauma may predict poorer symptomatic and functional outcomes after first episode psychotic mania. Limitations include that the findings represent individuals treated at a specialist early intervention centre for youth and the retrospective assessment of traumatic events may have been underestimated.

Characterisation of the prodrome to a first episode of psychotic mania: results of a retrospective study.

BACKGROUND: Little is known about the early phases of bipolar disorders (BPAD) and most of current knowledge derives from putative "high-risk" studies conducted in populations of bipolar off-spring; such information may therefore be relevant only to a sub-group of at-risk subjects. METHODS: Retrospective assessment of the phase preceding the emergence of mania and of premorbid characteristics of patients treated for a first episode of psychotic mania. The collected data was used mainly to generate hypotheses. RESULTS: Before onset of a first episode of psychotic mania, patients go through a phase of change from previous mental state where they present mood symptoms, sleep disruption and general functional decline. These clinical manifestations are however likely to have low specificity. However, their occurrence in patients presenting certain risk factors or markers of vulnerability that were identified at a relatively high prevalence in our sample, may be an indicator of impending first episode mania. LIMITATIONS: This is a retrospective study, in a small sample of patients presenting with psychotic mania. Criteria identified need therefore to be validated in larger prospective studies. CONCLUSIONS: Early identification of patients at risk to develop a first episode of psychotic mania is unlikely to be possible on the basis of symptoms alone. However, the occurrence of certain clinical characteristics in patients who have risk factors or markers of vulnerability to BPAD could be a sign of impending first episode mania.

Randomized controlled trial of olanzapine or chlorpromazine as addition to lithium in the treatment of a first manic episode with psychotic features: an 8-week, flexible dose, single-blind trial

Background: Association of mood stabiliser and antipsychotic medication is indicated in psychotic mania, but specific guidelines for the treatment of a first episode of psychotic mania are needed. Aims: To compare safety and efficacy profiles of chlorpromazine and olanzapine augmentation of lithium treatment in a first episode of psychotic mania. Methods: A total of 83 patients were randomised to either lithium + chlorpromazine or lithium + olanzapine in an 8-week trial. Data was collected on side effects, vital signs and weight modifications, as well as on clinical variables. Results: There were no differences in the safety profiles of both medications, but patients in the olanzapine group were significantly more likely to have reached mania remission criteria after 8 weeks. Mixed effects models repeated measures analysis of variance showed that patients in the olanzapine group reached mania remission significantly earlier than those in the chlorpromazine group. Conclusions: These results suggest that while olanzapine and chlorpromazine have a similar safety profile in a cohort of patients with first episode of psychotic mania, the former has a greater efficacy on manic symptoms. On this basis, it may be a better choice for such conditions.

Prediction of functional outcome 18 months after a first psychotic episode: a proton magnetic resonance spectroscopy study.

CONTEXT: Recent magnetic resonance imaging studies have attempted to relate volumetric brain measurements in early schizophrenia to clinical and functional outcome some years later. These studies have generally been negative, perhaps because gray and white matter volumes inaccurately assess the underlying dysfunction that might be predictive of outcome. OBJECTIVE: To investigate the predictive value of frontal and temporal spectroscopy measures for outcome in patients with first-episode psychoses. DESIGN: Left prefrontal cortex and left mediotemporal lobe voxels were assessed using proton magnetic resonance spectroscopy to provide the ratio of N-acetylaspartate (NAA) and choline-containing compounds to creatine and phosphocreatine (Cr) (NAA/Cr ratio). These data were used to predict outcome at 18 months after admission, as assessed by a systematic medical record audit. SETTING: Early psychosis clinic. PARTICIPANTS: Forty-six patients with first-episode psychosis. MAIN OUTCOME MEASURES: We used regression models that included age at imaging and duration of untreated psychosis to predict outcome scores on the Global Assessment of Functioning Scale, Clinical Global Impression scales, and Social and Occupational Functional Assessment Scale, as well as the number of admissions during the treatment period. We then further considered the contributions of premorbid function and baseline level of negative symptoms. RESULTS: The only spectroscopic predictor of outcome was the NAA/Cr ratio in the prefrontal cortex. Low scores on this variable were related to poorer outcome on all measures. In addition, the frontal NAA/Cr ratio explained 17% to 30% of the variance in outcome. CONCLUSIONS: Prefrontal neuronal dysfunction is an inconsistent feature of early psychosis; rather, it is an early marker of poor prognosis across the first years of illness. The extent to which this can be used to guide treatment and whether it predicts outcome some years after first presentation are questions for further research.