Research - Mental Health - Schizophrenia / Psychosis / BiPolar
Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot Study
Sedlak T.W.a · Nucifora L.G.a · Koga M.a · Shaffer L.S.a · Higgs C.a · Tanaka T.a · Wang A.M.b ·Coughlin J.M.a · Barker P.B.b · Fahey J.W.c · Sawa A.a
Schizophrenia and other neuropsychiatric disorders await mechanism-associated interventions. Excess oxidative stress is increasingly appreciated to participate in the pathophysiology of brain disorders, and decreases in the major antioxidant, glutathione (GSH), have been reported in multiple studies. Technical cautions regarding the estimation of oxidative stress-related changes in the brain via imaging techniques have led investigators to explore peripheral GSH as a possible pathological signature of oxidative stress-associated brain changes. In a preclinical model of GSH deficiency, we found a correlation between whole brain and peripheral GSH levels. We found that the naturally occurring isothiocyanate sulforaphane increased blood GSH levels in healthy human subjects following 7 days of daily oral administration. In parallel, we explored the potential influence of sulforaphane on brain GSH levels in the anterior cingulate cortex, hippocampus, and thalamus via 7-T magnetic resonance spectroscopy. A significant positive correlation between blood and thalamic GSH post- and pre-sulforaphane treatment ratios was observed, in addition to a consistent increase in brain GSH levels in response to treatment. This clinical pilot study suggests the value of exploring relationships between peripheral GSH and clinical/neuropsychological measures, as well as the influences sulforaphane has on functional measures that are altered in neuropsychiatric disorders.
*Sulforaphane is a natural phytochemical compound abundant in the seeds and sprouts of cruciferous plants such as broccoli.
Source : Journal Molecular Neuropsychiatry
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Individualized Metacognitive Training (MCT+) Reduces Delusional Symptoms in Psychosis: A Randomized Clinical Trial
Ryan P. Balzan*,1 , Julie K. Mattiske1 , Paul Delfabbro2 , Dennis Liu3,4 , and Cherrie Galletly
Individualized metacognitive training (MCT+) is a novel psychotherapy that has been designed to specifically target delusional beliefs in people with psychosis. It works by developing an awareness of the implausible content of delusional beliefs, while also targeting the cognitive biases that contribute to their formation and maintenance. It was expected that MCT+ would lead to significantly greater reductions in delusional severity compared to a cognitive remediation (CR) active control condition. A total of 54 patients with a schizophrenia spectrum disorder and active delusions were randomized into four 2-hourly sessions of MCT+ (n = 27) or CR (n = 27). All participants completed posttreatment assessment, and only 2 participants did not complete 6-month follow-up assessment, resulting in MCT+ (n = 26) and CR (n = 26) for final analysis. The primary outcome measures of delusional and positive symptom severity were assessed rater-blind; secondary outcome assessment was non-blinded and included clinical and cognitive insight, the jumping to conclusions (JTC) bias, and cognitive functioning. Participants in the MCT+ condition showed significant reductions in delusional and overall positive symptom severity (large effect) and improved clinical insight (moderate effect) relative to CR controls. In contrast, CR controls showed moderate improvement in problem-solving ability relative to MCT+, but no other cognitive domain. Importantly, these findings were maintained at 6-month follow-up. The study adds further efficacy to the MCT program, and suggests that even brief psychotherapy can help to ameliorate the symptoms of psychosis.
Source : Journal of Psychosis and Related Disorders
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Clinical applications of herbal medicines for anxiety and insomnia; targeting patients with bipolar disorder
Objectives: Patients with bipolar disorder frequently continue to experience residual anxiety and insomnia between mood episodes. In real-world practice, patients increasingly self-prescribe alternative medicines.
Methods: We reviewed case reports, open-label, and placebo-controlled trials investigating the use of herbal medicines to treat anxiety and insomnia, and discussed their potential applications for bipolar disorder.
Results: Eleven herbal medicines that have been studied in human subjects are included in this review. Mechanisms of action, efficacy, side effects, and drug-drug interactions are discussed. Based on currently available evidence, valerian seems to be the most promising candidate for insomnia and anxiety in bipolar disorder.
Conclusions: Adjunctive herbal medicines may have the potential to alleviate these symptoms and improve the outcomes of standard treatment, despite limited evidence. Physicians need to have a more in-depth understanding of the evidence of benefits, risks, and drug interactions of alternative treatments.
Source : Australian & New Zealand Journal of Psychiatry
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Treating Depressive Symptoms in Psychosis: A Network Meta-Analysis on the Effects of Non-Verbal Therapies
The aim of this study was to examine whether non-verbal therapies are effective in treating depressive symptoms in psychotic disorders.
Material and Methods
A systematic literature search was performed in PubMed, Psychinfo, Picarta, Embase and ISI Web of Science, up to January 2015. Randomized controlled trials (RCTs) comparing a non-verbal intervention to a control condition in patients with psychotic disorders, whilst measuring depressive symptoms as a primary or secondary outcome, were included. The quality of studies was assessed using the ‘Clinical Trials Assessment Measure for psychological treatments’ (CTAM) scale. Cohen’s d was calculated as a measure of effect size. Using a Network Meta-analysis, both direct and indirect evidence was investigated.
10 RCTs were included, of which three were of high quality according to the CTAM. The direct evidence demonstrated a significant effect on the reduction in depressive symptoms relative to treatment as usual (TAU), in favor of overall non-verbal therapy (ES: -0.66, 95% C.I. = -0.88, -0.44) and music therapy (ES: -0.59, 95% C.I. = -0.85, -0.33). Combining both direct and indirect evidence, yoga therapy (ES: -0.79, 95% C.I. = -1.24, -0.35) had a significant effect on depressive symptoms, and occupational therapy (ES: 1.81, 95% C.I. = 0.81, 2.81) was less effective, relative to TAU. Exercise therapy did not show a significant effect on depressive symptoms in comparison to TAU (ES: -0.02 95% C.I. = -0.67, 0.62). Due to inconsistency of study evidence, the indirect effects should be interpreted cautiously.
Non-verbal therapies appear to be effective in reducing depressive symptomatology in psychotic disorders, in particular music therapy and yoga therapy.
Source : PLOSone
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Original mechanisms of antipsychotic action by the indole alkaloid alstonine (Picralima nitida).
Alstonine is the major component of plant based remedies that traditional psychiatrists use in Nigeria. Alstonine is an indole alkaloid that has an antipsychotic experimental profile comparable with that of clozapine and is compatible with the alleged effects in mental patients. Representing a desirable innovation in the pharmacodynamics of antipsychotic medications, the evidence indicates that alstonine does not bind to D2 dopamine receptors (D2R) and differentially regulates dopamine in the cortical and limbic areas. The purpose of this study was to further investigate the effects of alstonine on D2R binding in specific brain regions using quantitative autoradiography (QAR) and its effects on dopamine (DA) uptake in mouse striatal synaptosomes. The effects of alstonine on D2R binding were determined in the nucleus accumbens and caudate-putamen using QAR in mice treated with alstonine doses that have antipsychotic effects. The effects of alstonine [3H]DA uptake were assessed in synaptosomes prepared from striatal tissue obtained from mice treated acutely or for 7 days with alstonine. Alstonine did not change the D2R binding densities in the studied regions. DA uptake was increased after acute (but not after 7 days) treatment with alstonine. Consistent with the alstonine behavioral profile, these results indicate that alstonine indirectly modulates DA receptors, specifically by modulating DA uptake. This unique mechanism for DA transmission modulation contributes to the antipsychotic-like effects of alstonine and is compatible with its behavioral profile in mice and alleged effects in patients. These results may represent an innovation in the antipsychotic development field.
Source : Intl Journal of Phytotherapy and Phytopharmacology
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Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar, schizophrenia, and impulsive behavior
Rhonda P. Patrick1 and Bruce N. Ames1
Nutrition and Metabolism Center, Children’s Hospital Oakland Research Institute, Oakland, California, USA
Serotonin regulates a wide variety of brain functions and behaviors. Here, we synthesize previous findings that serotonin regulates executive function, sensory gating, and social behavior and that attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and impulsive behavior all share in common defects in these functions. It has remained unclear why supplementation with omega-3 fatty acids and vitamin D improve cognitive function and behavior in these brain disorders. Here, we propose mechanisms by which serotonin synthesis, release, and function in the brain are modulated by vitamin D and the 2 marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Brain serotonin is synthesized from tryptophan by tryptophan hydroxylase 2, which is transcriptionally activated by vitamin D hormone. Inadequate levels of vitamin D (∼70% of the population) and omega-3 fatty acids are common, suggesting that brain serotonin synthesis is not optimal. We propose mechanisms by which EPA increases serotonin release from presynaptic neurons by reducing E2 series prostaglandins and DHA influences serotonin receptor action by increasing cell membrane fluidity in postsynaptic neurons. We propose a model whereby insufficient levels of vitamin D, EPA, or DHA, in combination with genetic factors and at key periods during development, would lead to dysfunctional serotonin activation and function and may be one underlying mechanism that contributes to neuropsychiatric disorders and depression. This model suggests that optimizing vitamin D and marine omega-3 fatty acid intake may help prevent and modulate the severity of brain dysfunction.--
Source : The FASEB Journal
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Antiepileptic and Antipsychotic Effects of Ipomoea Reniformis (convolvulaceae) in Experimental Animals
K. K. Chitra, S. Babitha, Sharanbasappa Durg, B. S. Thippeswamy, V. P. Veerapur, S. Badami
Ipomoea reniformis Chaos is claimed in Indian traditional medical practice to be useful in the treatment of epilepsy and neurological disorders. In the present study, pretreatment effect of methanolic extract of Ipomoea reniformis on epilepsy and psychosis was evaluated in rodents using standard procedures. Besides evaluating epileptic and behavioral parameters, neurotransmitters such as Gamma-Amino Butyric Acid (GABA) in epilepsy and in psychosis dopamine, noradrenaline and serotonin contents in the rodent brain were estimated. The extract pretreatment reduced maximal electro shock; Isoniazid (INH) and Pentylenetetrazole (PTZ) induced seizures and also significantly inhibited the attenuation of brain GABA levels by INH and PTZ in mice. These results suggested that the observed beneficial effect in epilepsy may be by enhancing the GABAergic system. The test drug also inhibited the apomorphine induced climbing and stereotyped behavior and showed significantly reduced levels of brain dopamine, noradrenaline and serotonin which may be due to blocking of central dopaminergic, noradrenergic and serotonergic pathways or by enhancing the GABAergic system. The results obtained in present study suggest that the title plant possesses antiepileptic and antipsychotic activities in rodents.
Source : Journal of Natural Remedies
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Omega-3 fatty acid supplementation changes intracellular phospholipase A2 activity and membrane fatty acid profiles in individuals at ultra-high risk for psychosis
S Smesny1, , B Milleit1, , U-C Hipler2, , C Milleit1,2, MR Scha¨ fer3,4, CM Klier3, , M Holub5, , I Holzer5, , GE Berger6
M Otto1, , I Nenadic1, M Berk4,7,8, PD McGorry4, , H Sauer1 and GP Amminger3,4
The identification of an ultra-high risk (UHR) profile for psychosis and a greater understanding of its prodrome have led to increasing interest in early intervention to delay or prevent the onset of psychotic illness. In a randomized placebo-controlled trial, we have identified long-chain ω-3 (ω-3) polyunsaturated fatty acid (PUFA) supplementation as potentially useful, as it reduced the rate of transition to psychosis by 22.6% 1 year after baseline in a cohort of 81 young people at UHR of transition to psychosis. However, the mechanisms whereby the ω-3 PUFAs might be neuroprotective are incompletely understood. Here, we report on the effects of ω-3 PUFA supplementation on intracellular phospholipase A2 (inPLA2) activity, the main enzymes regulating phospholipid metabolism, as well as on peripheral membrane lipid profiles in the individuals who participated in this randomized placebo-controlled trial. Patients were studied cross-sectionally (n=80) and longitudinally (n=65) before and after a 12-week intervention with 1.2 g per dayω-3 PUFAs or placebo, followed by a 40-week observation period to establish the rates of transition to psychosis. We investigated inPLA2 and erythrocyte membrane FAs in the treatment groups (ω-3 PUFAs vs placebo) and the outcome groups (psychotic vs non-psychotic). The levels of membrane ω-3 and ω-6 PUFAs and inPLA2were significantly related. Some of the significant associations (that is, long-chain ω-6 PUFAs, arachidonic acid) with inPLA2activity were in opposite directions in individuals who did (a positive correlation) and who did not (a negative correlation) transition to psychosis. Supplementation with ω-3 PUFA resulted in a significant decrease in inPLA2 activity. We conclude that ω-3 PUFA supplementation may act by normalizing inPLA2 activity and δ-6-desaturase-mediated metabolism of ω-3 and ω-6 PUFAs, suggesting their role in neuroprogression of psychosis.
Source : Molecular Psychiatry
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Cannabis and Schizophrenia
by Lindsay Stafford Mader
The proposition that cannabis causes schizophrenia has existed since at least the early days of the anti-marijuana movement in America, as illustrated in the 1936 film Reefer Madness, in which a character descends into psychosis after smoking a joint.1 The cannabis-schizophrenia connection intensified during the “War on Drugs,” which produced propaganda linking the herb to schizophrenia, as well as cancer and brain damage.2 Fast-forward more than seven decades since the film, and the academic and mainstream media continue to refer to cannabis’s ability to cause and increase the risk of developing this serious mental illness.3,4
The link between cannabis (Cannabis sativa, Cannabaceae) and schizophrenia, however, is much more complex and much less certain. Cannabis and the brain have an interesting and unique relationship, part of which remains a mystery to researchers even today. After more than two decades of scientific analysis, researchers know that the human body contains receptors that bind with tetrahydrocannabinol (THC) and other cannabinoids from the cannabis plant, and also has neurotransmitters that activate these receptors in much the same way. The body's receptors include the CB1 and CB2 receptors, and the endogenous cannabinoids, referred to as endocannabinoids, including anandamide and 2-AG.5,6
Although this intricate endocannabinoid system of receptors and neurotransmitters — as well as the exact role played by the cannabis plant — is not yet fully understood, it clearly is involved in numerous physiological and pathological processes that are essential to human health. As Ester Fride and Ethan Russo, MD, wrote in the neuropsychiatry chapter of the 2005 book Endocannabinoids: The Brain and Body’s Marijuana and Beyond (CRC Press), “Endocannabinoids serve a modulatory function in many neurochemical and psychopharmacological processes, and deficiencies or excesses in any of these may produce manifestations of psychopathology.”5
Even more perplexing to scientists is the severe brain disorder called schizophrenia, which affects about 24 million people worldwide — approximately one percent of the population. According to the PsychCentral mental health web resource, “In spite of advances in the understanding of its causes, course, and treatment, schizophrenia continues to confound both health professionals and the public. It is easier for the average person to cope with the idea of cancer than it is to understand the odd behavior, hallucinations, or strange ideas of the person with schizophrenia.”7
Medical researchers believe that schizophrenia is tied to a genetic link as incidence among those with afflicted family members is increased by about nine percent.8 It is also thought that schizophrenia might be caused by the malfunction of a gene that creates important brain chemicals, as well as possible environmental triggers, and/or an imbalance of the neurotransmitters dopamine and glutamate. Scans of schizophrenia patients’ brains have revealed that they have larger center-brain ventricles and less gray matter, and post-mortem brain analyses have shown differences in schizophrenics’ brain cell characteristics — perhaps occurring during abnormal fetal brain development. Schizophrenia presents itself through a variety of symptoms, including hallucinations, delusions, thought and movement disorders, monotonous voice, and motionless face when speaking (referred to as “positive” symptoms), as well as social withdrawal, inability to make decisions, lack of emotion and motivation, etc. (referred to as “negative” symptoms and “cognitive deficits”).
While a fair amount of scientific research has examined the relationship between cannabis and schizophrenia, most of this consists of laboratory, animal, epidemiological, or post-mortem human studies. Recognizing the “tremendous amount” of preclinical research on cannabis and schizophrenia, Martin Lee — author of the 2012 book Smoke Signals: A Social History of Marijuana – Medical, Recreational, and Scientific — noted the ethical implications of studying cannabis in humans.
“You’re not going to get experiments in the United States where the federal government will approve a researcher or a scientist giving marijuana to a schizophrenic, but you could do a survey of schizophrenics,” said Lee (oral communication, March 15, 2013).
Cannabis is well known to cause physiological and psychological side effects in almost all people who use it, particularly varieties that contain higher levels of THC. Thus, the concept that cannabis causes negative mental experiences is not ridiculous; anecdotal reports of momentary post-cannabis psychosis and hallucinations have been shared for quite some time.2
While the psychological side effects of cannabis can be similar to the symptoms experienced by diagnosed schizophrenics — such as visual illusions, paranoia, mood alterations, and memory deficits9 — cannabis-produced symptoms typically disappear after three to five hours.10
Still, the allegation persists that cannabis can cause schizophrenia, a disease in which psychotic symptoms typically last throughout a patient’s life. When experts discuss this cannabis-schizophrenia relationship, they make sure to differentiate between cannabis’s impact on healthy populations and cannabis’s impact on diagnosed schizophrenic patients and individuals with risk factors for developing schizophrenia.9 This important detail is often not provided in media reports on the topic.
“I don’t think we should say cannabis induces schizophrenia, and so we should discourage people from using cannabis because they’ll become psychotics,” said Andrea Giuffrida, PhD, an associate professor of pharmacology at the University of Texas Health Science Center in San Antonio, who researches this topic (oral communication, March 25, 2013). “Maybe some of them have a higher risk, but not the entire population.”
Researchers and proponents of the argument that cannabis does not cause schizophrenia in the general population often cite epidemiological data that shows a significant increase in cannabis usage during the last several decades while the rates of schizophrenia have remained largely static. As stated by the authors of a recent article titled, “Cannabis and Psychosis: What Causes What?,” “Most people who use cannabis do not develop schizophrenia, and many people diagnosed with schizophrenia have never used cannabis.”9
“As marijuana usage has increased in culture in the last 50 years, you haven’t seen that increase in schizophrenia,” said Lee. “If it was causing schizophrenia, you would probably see an increase, so the causal thing is just not there.”
But according to psychiatrists Patricia Gerbarg, MD, who has a clinical practice in New York City, and Richard Brown, MD, a professor at Columbia University, the lack of correlation could be explained in other ways. “For example,” they said, “improvements in prenatal nutrition and healthcare are more likely to lower the incidence of schizophrenia…. Also, there may appear to be a lack of increase in schizophrenia because of a lack of increase in the diagnosis of schizophrenia, which could be due to the many changes in diagnostic categories since the 1970s. Many cases that would previously have been diagnosed as schizophrenia, would now be diagnosed as Asperger’s or bipolar disorder” (email, March 16, 2013).
Some epidemiological surveys have shown that schizophrenic patients abuse cannabis more than any other illegal drug and also have cannabis usage rates higher than healthy population rates, which has been used as an argument that cannabis possibly causes or increases the chance of developing schizophrenia in otherwise healthy populations.11 But according to Dr. Giuffrida, this is just a correlation, which, he points out, cannot establish causality. He additionally noted the hypothesis that schizophrenic patients might use cannabis more because they are attempting to self-medicate.
“Whether they smoke more because they are schizophrenic or they are schizophrenic because they smoke more cannabis, we don’t know the direction of the connection,” he explained.
Further, a Swedish survey published in 1987 of almost 50,000 male participants conducted over the course of 15 years found that those who self-reported heavy cannabis use were 50 times more likely to be diagnosed with schizophrenia.12 But when these findings were reanalyzed and adjusted to account for other risk factors, the increased likelihood dropped to 6.7 times, and many of the participants who reported cannabis use also reported the use of other drugs that have the ability to precipitate psychosis.13
In examining the connection between cannabis and schizophrenia, researchers also study brain morphology. In a 2012 paper in the European Archives of Psychiatry and Clinical Neuroscience, a team of researchers from Germany and England analyzed 16 neuroimaging studies. The authors concluded that there is “no convincing evidence” that cannabis-related brain alterations happen before the onset of schizophrenia.11 In fact, essentially none of the changes seen in the brains of schizophrenic patients using cannabis were observed in healthy individuals who used cannabis.
Some journals and other sources report that young people are especially vulnerable for developing cannabis-induced schizophrenia. A large-scale survey conducted in 2005 by Henquet et al. suggested that ingesting cannabis at a young age (14 to 24 years) was associated with an increased chance of developing psychotic symptoms,14,15 but this data did not analyze the risk of developing full schizophrenia, and those with predisposed risks for psychosis were more likely to develop psychotic symptoms. According to an expert peer reviewer of this article, while extra caution is always advised in adolescents, there is still no evidence that permanent, schizophrenia-related de novo damage is done to young, healthy individuals.
“The work of Henquet is very interesting,” added Dr. Giuffrida, “but the assessment of cannabis use is based on an interview and consequently is not as precise as a study where cannabis is administered in a controlled fashion. I do believe we need more experiments before establishing a causal relation between cannabis exposure and schizophrenia development in the healthy population.”
At-Risk and Diagnosed Populations
Most researchers agree that because schizophrenia likely is brought on by a variety of “component causes,” one of which could include cannabis use, a healthy person with no risk factors is very unlikely to develop the disease from cannabis use alone.9,11,14 The situation is different, however, for individuals with predisposed risks.
Those at risk for developing schizophrenia include individuals with schizophrenic family members or those who exhibit symptoms of the prodromal stage (a precursor to a more full set of symptoms or disease), which typically consist of increased isolation and decreased motivation and appear a year before true schizophrenia symptoms.11 Interestingly, recent research suggests that a mutation in the AKT1 gene also might put an individual at increased risk for developing cannabis-associated schizophrenia.16 These at-risk groups are cautioned against using cannabis as epidemiological evidence and survey data show that they have worse psychotic-disorder outcomes when cannabis is a factor.15
The aforementioned 2012 brain morphology literature review by Malchow et al. found just three studies on high-risk individuals, in which an “additional effect of cannabis use on brain structure” was suggested.11 These studies found that cannabis use was associated with a bilateral volume loss of the thalamus, a region of the brain that integrates and processes sensory and cognitive functions; increased thinning of the cortex, the largest region of the brain; and an increased volume of the brain’s fluid-filled cavities known as ventricles. (The latter of these studies, however, analyzed cannabis and alcohol in high-risk subjects.)
The review authors conclude that there is “some weak evidence that cannabis abuse could affect brain structures in high-risk subjects, but replication of these findings is needed. The results of the identified neuroimaging studies are heterogeneous and inconclusive,” for various reasons, including differing definitions of regional volume boundaries and differing volume extraction methods (when measuring content of the brain), as well as differing MRI techniques.11
For patients who have been diagnosed with schizophrenia, the implications for using cannabis are somewhat better understood. Although few human clinical trials on cannabis and schizophrenics have been performed, epidemiological data and survey evidence indicate — and most experts agree — that ingesting cannabis can aggravate schizophrenia symptoms and/or increase their frequency.13 The few human studies found cannabis products (i.e., hashish, THC) to exacerbate symptoms, although these were temporary effects. According to Endocannabinoid’s neuropsychiatry chapter, “Taken together, most studies confirm the vulnerability hypothesis for cannabis use and schizophrenia. Thus, schizophrenia patients should probably not use cannabis because a psychotic episode can be induced in someone with a preexisting disorder and, indeed, increased hospitalization rates and symptom exacerbation have been demonstrated.”5
Malchow et al. noted that most brain imaging studies on cannabis and schizophrenia examined individuals with first-episode or recent-onset schizophrenia.11 Some of this research suggested that schizophrenic patients who used cannabis had subtle brain abnormalities, increased ventricle volumes, thinning of various cortical regions, decreased gray and white matter volume, and “altered brain structure in particular regions … with a high density of CB1 receptors.” The authors noted, however, that anti-psychotic medication has been strongly associated with reduced gray matter and that many of the studies included “comorbid patients consuming other substances than cannabis, for example, amphetamines, cocaine, and sometimes alcohol, making it difficult to focus on the effect of cannabis alone.”
“The results of these neuroimaging studies are again heterogeneous and remain inconclusive,” they wrote.
Researchers are beginning to understand that the connection between cannabis and schizophrenic individuals might lie in the human body’s mysterious and powerful endocannabinoid system. According to the authors of a 2008 article in Expert Review of Neurotherapeutics, “There are several lines of evidence suggesting that, at least in a subgroup of patients, alterations in the endocannabinoid system may contribute to the pathogenesis of schizophrenia.”15
Human studies have shown schizophrenics to have increased levels of anandamide and endocannabinoid-like molecules such as palmitylethanolamide, and these patients with higher levels of anandamide typically experience fewer psychotic symptoms.15 Additionally, frequent cannabis usage was found to decrease cerebral spinal fluid levels of anandamide, suggesting a possible explanation for why some schizophrenic patients sometimes have negative experiences after ingesting cannabis. Authors of additional studies have found a possible connection between lower levels of the endocannabinoid 2-AG and schizophrenia progression, as well as impaired endocannabinoid signaling associated with acute psychotic episodes.
“My preferred hypothesis is that frequent and intense cannabis smoking [reduces] an endogenous protective mechanism, mediated by anandamide, resulting in an increased risk for precipitation of psychosis,” said Daniele Piomelli, PhD, PharmD, a professor of anatomy and neurobiology at the University of California at Irvine (email, March 22, 2013). “Please note that anandamide is not the only endocannabinoid present in the brain and that this theory does not rule out the possibility that other endocannabinoids (e.g., 2-AG) might be pro-psychotic.”
In explaining why cannabis and endocannabinoids might not act in the same way, Dr. Giuffrida pointed to the different pharmacologic profiles of THC and anandamide. “For example, when you smoke cannabis and take in THC, you activate all the cannabinoid receptors in the brain. But when you elevate anandamide, the elevation does not happen all over the brain but happens in specific brain areas.”
Interestingly, the CB1 receptor is expressed in high levels in the prefrontal cortex — the region of the brain responsible for cognitive and emotional functions and thought to be the “primary dysfunctional area” in schizophrenia — as well as in other brain areas relevant to schizophrenia, such as the basal ganglia, hippocampus, and the anterior cingulate cortex.8,15 Some post-mortem studies have found schizophrenic patients’ brains to have even-further increased binding levels of the CB1 receptor.
“But again,” said Dr. Giuffrida, “whether this is a contributing factor to develop schizophrenia is unknown at this time.”
Dr. Giuffrida reiterated that cannabis can sometimes help certain schizophrenia symptoms, which might explain why some patients might self-medicate with the herb.
“We know that, in schizophrenic patients, cannabis intake can make positive symptoms worse. But, on the other side, there is some work showing that the cannabinoids have a beneficial effect on the negative symptoms of schizophrenia, so they make people interact more with each other. But what happens with marijuana, especially if you are a psychotic individual, the more you use cannabis, the worse your symptoms become over time. So it can be helpful in the beginning, but definitely not in the long run.”
Therapeutic Role of CBD
While THC, the compound in cannabis responsible for the euphoric “high,” is known to increase the severity of psychotic symptoms in schizophrenia patients, another cannabinoid in cannabis — the non-psychoactive cannabidiol (CBD) — has been shown to be therapeutic for schizophrenia symptoms.
Based on CBD’s known anti-anxiety activity, researchers conducted a small pilot study on CBD in 42 patients with paranoid schizophrenia in 2012. This Phase II, double-blind, four-week trial compared CBD treatment with the antipsychotic drug amisulpride and found that CBD improved symptoms as well as the pharmaceutical — and that it produced fewer negative side effects.17
“It’s a small study so we have to see if the data is replicated in larger groups of people,” said Dr. Giuffrida, noting that CBD “is definitely one of the most exciting areas in the cannabinoid field.” He explained that although CBD’s activity within the brain is not yet completely understood, this compound is pharmacologically different from THC in that it does not bind to the CB1 receptor in the brain, whereas THC does. Additionally, he said some animal and human studies show that CBD boosts levels of the endocannabinoid anandamide, and elevated anandamide seems to have a beneficial effect on schizophrenia.
“These results suggest that the inhibition of anandamide activation may contribute to the anti-psychotic effect of cannabidiol,” said Dr. Giuffrida, “which possibly represents a completely new mechanism of treatment for schizophrenia.”
While CBD presents an exciting possibility as a novel schizophrenia treatment, additional research must be conducted to validate early studies. Likewise, more human research on cannabis’s impact on schizophrenia would greatly broaden scientists’ and medical professionals’ understanding of this interesting and complex relationship. Based on the available evidence — which includes epidemiological studies, surveys, brain morphology analyses, and a few human studies — most experts accept that cannabis intake could have negative impact on individuals who have schizophrenia and that those vulnerable to developing schizophrenia can have psychotic episodes if they ingest high doses of cannabis.
“So there definitely is something there,” said Dr. Guiffrida. “However, this is probably one of the components that may contribute to schizophrenia. It is not the cause of schizophrenia. And so I don’t think we have yet enough evidence to say that cannabis causes schizophrenia, and this is particularly true for the healthy population.”
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17. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012 Mar 20;2:e94.
Source : American Botanical Council
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Evidence of Ginkgo Extract Efficacy in Patients with Dementia and as an Adjunct for Treating Patients with Chronic Schizophrenia
By Healther S. Oliff PhD
Reviewed: Brondino N, De Silvestri A, Re S, et al. A systematic review and meta-analysis of Ginkgo biloba in neuropsychiatric disorders: from ancient tradition to modern-day medicine. Evid Based Complement Alternat Med. 2013;2013:1-11. doi: 10.1155/2013/915691.
Ginkgo (Ginkgo biloba, Ginkgoaceae) extract is one of the most popular phytomedicines; however, according to the authors, there has been no systematic review on its effect on neuropsychiatric disorders other than dementia. Hence, the purpose of this report was to conduct a systematic review of ginkgo clinical trials for such disorders.
The authors searched MEDLINE®, Embase™, PsycINFO®, and the Cochrane Database of Systematic Reviews from inception through April 2012. The search terms were gingko biloba, ginkgo, ginko, gingko, bilobalid* [asterisk commands search to locate all terms that start with the preceding word], egb 761, dementia, cognitive impairment, Alzheimer, autism, autistic spectrum disorder, schizophrenia, psychosis, psychotic disorder, delusion, depression, major depression, depressive symptom, anxiety, generalized anxiety disorder, anxious, attention deficit disorder, ADHD, attention deficit, hyperactivity, and addiction. According to the article, “All search terms were searched individually in each database and combined together. The search strategy had no time restriction but was limited to articles in English, Italian, French, Spanish, and German. Additionally, all recovered papers were reviewed for further relevant references.” Study inclusion criteria were randomized, controlled clinical trials; a minimum of 10 patients per group; and treatment for less than six weeks. When possible, the data were pooled for a meta-analysis.
A total of 1,109 studies were identified. Of these, 113 were obtained for additional evaluation, and 18 met the inclusion criteria and were incorporated in this review. There was one randomized, double-blind study of patients with attention deficit hyperactivity disorder, which included 50 children treated with 80 mg/day (for participants weighing < 30 kg) or 120 mg/day ginkgo compared with methylphenidate for six weeks. Methylphenidate — a psychostimulant marketed under several trade names, including Ritalin® — was much more effective than ginkgo, though the latter had significantly fewer adverse side effects.
There was one randomized, placebo-controlled study of patients with autism, which included 47 children who were treated with the antipsychotic drug risperidone (on the market as Risperdal® and generic) in addition to either 80 mg/day (if < 30 kg) or 120 mg/day ginkgo extract or placebo for 10 weeks. There was no significant difference between groups, which means that no added effect for risperidone could be shown for ginkgo extract.
There was one randomized, double-blind, placebo-controlled study in patients with cocaine addiction, which included 44 patients who received either 240 mg/day ginkgo extract, the nootropic piracetam, or placebo for 10 weeks. There was no significant difference among the three groups.
There was one randomized, placebo-controlled study in patients with generalized anxiety disorder (GAD) or adjustment disorder with anxious mood in which participants were treated with 240 mg/day ginkgo, 480 mg/day ginkgo, or placebo for four weeks. There was a significant dose-response improvement in the ginkgo-treated patients compared with placebo-treated patients.
There was one randomized, placebo-controlled study of medicated patients with chronic schizophrenia and tardive dyskinesia who were treated with 240 mg/day ginkgo extract or placebo for 12 weeks. The ginkgo group had a significant improvement in the Abnormal Involuntary Movement Scale but not on secondary outcomes — namely the psychopathological scales — as the placebo group also showed improvements over time.
There were three other randomized, controlled studies in patients with chronic schizophrenia treated with ginkgo extract and either clozapine, haloperidol, or olanzapine (antipsychotic drugs), and these data were pooled for meta-analysis. The studies with clozapine and haloperidol were double-blind and placebo-controlled (n=42 and n=109, respectively), and the third study was olanzapine-controlled (n=29). The pooled analysis favored ginkgo; however, the results had substantial heterogeneity (i.e., when looking at the individual outcome measures, not all outcomes favored ginkgo treatment).
There were 10 studies of dementia; eight placebo-controlled and two donepezil-controlled. (Donepezil [sold as Aricept® and DONEP] is an acetylcholinesterase inhibitor.) Only the eight placebo-controlled studies (which utilized 120 or 240 mg/day ginkgo for 12-52 weeks) could be included in a meta-analysis. All trials used the standardized extract EGb 761® (Dr. Willmar Schwabe GmbH & Co. KG; Karlsruhe, Germany). The methodological quality of the eight studies was judged to be “adequate.” The pooled data showed that the Alzheimer’s Disease Assessment Scale-cognitive subscale and Syndrom-Kurz test outcome measures favored ginkgo treatment. There was also a significant difference in activities of daily living (ADL) standardized change scores between treatment groups when combining different scales: the Alzheimer’s Disease Activities-of-Daily-Living International Scale, Geriatric Evaluation by Relatives Rating Instrument, Gottfries-Bråne-Steen-Activities of Daily Living scale, Nürnberger Alters-Alltagsaktivitäten-Skala, and Nürnberger Alters-Beobachtungsskala. The two studies comparing donepezil and ginkgo showed no significant differences between treatments.
The authors conclude that the general lack of evidence prevents them from drawing conclusions for most neuropsychiatric conditions. However, the meta-analysis of dementia studies shows that ginkgo provides benefits for cognition and ADL. The authors state that the benefits for dementia and schizophrenia were modest and that some studies showed statistical improvements that were not necessarily clinically meaningful. Nonetheless, the authors conclude that despite heterogeneous results, the evidence supports the use of the proprietary standardized ginkgo extract in patients with dementia and as an adjunct therapy for patients with schizophrenia.
Source : HerbalGram. 2013; American Botanical Council
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Chinese herbal medicine for schizophrenia Cochrane systematic review of randomised trials
- John Rathbone, MPhil
- Lan Zhang, MD
- Mingming Zhang, MSc
- Jun Xia, BSc
- Clive E. Adams, MD
- Cochrane Schizophrenia Group, Academic Department of Psychiatry and Behavioural Sciences, University of Leeds UK
- Institute of Mental Health, Chengdu, China
- Chinese Cochrane Centre, West China Hospital of Sichuan University, Chengdu, China
- Cochrane Schizophrenia Group, Academic Department of Psychiatry and Behavioural Sciences, University of Leeds, UK
- Institute of Mental Health, West China Hospital of Sichuan University, Chengdu, China
- Cochrane Schizophrenia Group, Academic Department of Psychiatry and Behavioural Sciences, University of Leeds, UK
Background Chinese herbal medicine has been used to treat millions of people with schizophrenia for thousands of years.
Aims To evaluate Chinese herbal medicine as a treatmentfor schizophrenia.
Method A systematic review of randomised controlled trials (RCTs).
Results Seven trials were included. Most studies evaluated Chinese herbal medicine in combination with Western antipsychotic drugs; in these trials results tended to favour combination treatment compared with antipsychotic alone (Clinical Global Impression `not improved/worse' n=123, RR=0.19, 95% CI 0.1-0.6, NNT=6,95% CI 5-11; n=109, Brief Psychiatric Rating Scale `not improved/worse' RR=0.78,95% CI 0.5-1.2; n=109, Scale for the Assessment of Negative Symptoms `not improved/worse' RR=0.87,95% CI 0.7-1.2; n=109, Scale for the Assessment of Positive Symptoms `not improved/worse' RR=0.69,95% CI 0.5-1.0, NNT=6 95% CI 4-162). Medium-term study attrition was significantlyless for people allocated the herbal/antipsychotic mix (n=897, four RCTs, RR=0.34,95% CI 0.2-0.7, NNT=23,95% CI18-43).
Conclusions Results suggest that combining Chinese herbal medicine with antipsychotics is beneficial.
Source : British Journal of Psychiatry
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Sleep ameliorating effects of acupuncture in a psychiatric population.
Bosch P, van Luijtelaar G, van den Noort M, Lim S, Egger J, Coenen A.
Donders Centre for Cognition, Radboud University Nijmegen, Postbus 9104, Montessorilaan 3, 6500 HR Nijmegen, The Netherlands ; LVR-Klinik Bedburg-Hau, Bahnstrasse 6, 47551 Bedburg-Hau, Germany ; Division of Acupuncture & Meridian, WHO Collaborating Center for Traditional Medicine, East-West Medical Research Institute and School of Korean Medicine, Kyung Hee University, Number 1 Hoegi-Dong, Dongdaemoon-ku, Seoul 130-701, Republic of Korea.
AbstractThe interest of psychiatric patients for complementary medicine, such as acupuncture, is stable, but effect studies in psychiatry remain scarce. In this pilot study, the effects of 3 months of acupuncture treatment on sleep were evaluated and compared between a group of patients with schizophrenia (n = 16) and a group with depression (n = 16). Healthy controls were included in order to establish reference values (n = 8). Patients with schizophrenia and depression were randomly assigned to either a waiting list or a treatment condition. The Pittsburgh Sleep Quality Inventory was completed before and after the acupuncture treatment (individualized and according to traditional Chinese medicine principles) or the waiting list condition. Both acupuncture groups showed significant lower scores on the sleep inventory, which was not the case for the waiting list condition. Moreover, it was found that the effectiveness of the acupuncture treatment was higher in the patients with schizophrenia than in the patients with depression. Acupuncture seems able to improve sleep in this convenient sample of patients with long-lasting psychiatric problems and may be a suitable and cost-effective add-on treatment for this group, particularly if conducted group-wise.
Source : Evidence Based Complementary and Alternative Medicine
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Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia
Vidhi Singh1, Surendra P. Singh2 and Kelvin Chan3
1MediWare Computer Software Engineering, Wolverhampton, West Midlands, UK
2Mental Health Directorate, Wolverhampton City Primary Care Trust and University of Wolverhampton, Wolverhampton,West Midlands, UK
3University of Wolverhampton, Wolverhampton, West Midlands, UK
This study aimed to review the roles of antioxidants in the pathophysiology of schizophrenia, whether the properties of ginkgo can ameliorate symptoms of this illness, and evaluate available literature to test this assumption. This review is based upon published works on antioxidants and ginkgo. A primary electronic search for meta-analysis on the usage of ginkgo or its derived products in schizophrenia was conducted using Pubmed, Cochrane Library, EMBASE, CINAHL, PsycINFO and AMED. Inclusion criteria were:criteria-based diagnosis of schizophrenia, randomized case assignment, use of ginkgo as an add-on therapy, and assessment using standardized rating scales to measure the state of psychopathology for negative and total symptoms of schizophrenia. Additionally, a detailed review was undertaken to investigate if antioxidants are involved in development of psychotic symptoms in schizophrenia. The six studies that fulfilled the selection criteria were constituted of 466 cases on ginkgo and 362 cases on placebo.They all used the Scale for the Assessment of Negative Symptoms (SANS) to measure negative symptoms,and the Scale for the Assessment of Positive Symptoms (SAPS) or the Brief Psychiatric Rating Scale (BPRS) to measure total symptoms. Difference between ginkgo and control groups from their pre- and post-trials cores and its pooled standard deviation were used to compute standardized mean difference (SMD).Ginkgo as an add-on therapy to antipsychotic medication produced statistically significant moderate improvement (SMD=x0.50) in total and negative symptoms of chronic schizophrenia. Ginkgo as add-on therapy ameliorates the symptoms of chronic schizophrenia. The role of antioxidants in pathogenesis of schizophrenia has also been explored
Source : International Journal of Neuropsychopharmacology (2010),13, 257–271
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