Reversal of schizophrenia-like symptoms and immune alterations in mice by immunomodulatory drugs.

High dose melatonin for schizophrenia? Or 1-Methyl-D-tryptophan. I like the melatonin idea but is desensitising MT receptors likely to be detrimental?

Reversal of schizophrenia-like symptoms and immune alterations in mice by immunomodulatory drugs.

Immune dysregulation observed in schizophrenia alters tryptophan metabolism. Tryptophan metabolism is triggered by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Tryptophan is converted to quinolinic acid, a potent neurotoxin, and to kynurenic acid, an NMDA antagonist. 1-Methyl-D-tryptophan (MDT) inhibits IDO. Melatonin is metabolized by IDO while inhibiting TDO. We evaluated the reversal of ketamine-induced schizophrenia-like behavioral and neurochemical alterations in mice by the administration of MDT (20 or 40 mg/kg, i.p.) or melatonin (15 mg/kg, per os). Oxidative stress and inflammatory alterations, i.e. myeloperoxidase activity (MPO), reduced glutathione (GSH), lipid peroxidation (LPO) and interleukin (IL)-4 and IL-6 were measured in the prefrontal cortex (PFC), hippocampus and striatum. Risperidone was used as standard antipsychotic. Ketamine triggered positive- (PPI deficits and hyperlocomotion), cognitive- (working memory deficits) and negative (social interaction deficits) schizophrenia-like symptoms. These symptoms were accompanied by increased MPO activity, decreased GSH and increased LPO in all brain areas and increments in hippocampal IL-4 and IL-6. MDT and melatonin reversed all ketamine-induced behavioral alterations. Risperidone did not reverse working memory deficits. MDT and melatonin reversed alterations in MPO activity and GSH levels. LP was reversed only by melatonin and risperidone. Risperidone could not reverse MPO alterations in the PFC and striatum. All drugs reversed the alterations in IL-4 and IL-6. The hippocampus and striatum of ketamine+melatonin-treated animals had lower levels of IL-6. Our findings provide further preclinical evidence that immune-inflammatory and oxidative pathways are involved in schizophrenia and that targeting these pathways is a valid treatment option in schizophrenia.

Full text: http://sci-hub.bz/10.1016/j.jpsychires.2016.09.017

Suppressing Schizophrenia Symptoms Without Side Effects: Mouse Study

Suppressing Schizophrenia Symptoms Without Side Effects: Mouse Study

Rather than messing around with exotic M4 mAChR targeting compounds, one could try some β-caryophyllene from copaiba oil?

Full text: http://sci-hub.bz/10.1016/j.neuron.2016.08.017

Reversal of evoked gamma oscillation deficits is predictive of antipsychotic activity with a unique profile for clozapine. (2016)

Reversal of evoked gamma oscillation deficits is predictive of antipsychotic activity with a unique profile for clozapine.

Recent heuristic models of schizophrenia propose that abnormalities in the gamma frequency cerebral oscillations may be closely tied to the pathophysiology of the disorder, with hypofunction of N-methyl-d-aspartate receptors (NMDAr) implicated as having a crucial role. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating that is disrupted in schizophrenia. We tested the ability for antipsychotic drugs with diverse pharmacological actions to (1) ameliorate NMDAr antagonist-induced disruptions to gamma oscillations and (2) attenuate NMDAr antagonist-induced disruptions to PPI. We hypothesized that antipsychotic-mediated improvement of PPI deficits would be accompanied by a normalization of gamma oscillatory activity. Wistar rats were implanted with extradural electrodes to facilitate recording of electroencephalogram during PPI behavioural testing. In each session, the rats were administered haloperidol (0.25 mg kg(-1)), clozapine (5 mg kg(-1)), olanzapine (5 mg kg(-1)), LY379268 (3 mg kg(-1)), NFPS (sarcosine, 1 mg kg(-1)), d-serine (1800 mg kg(-1)) or vehicle, followed by the NMDAr antagonists MK-801(0.16 mg kg(-1)), ketamine (5 mg kg(-1)) or vehicle. Outcome measures were auditory-evoked, as well as ongoing, gamma oscillations and PPI. Although treatment with all the clinically validated antipsychotic drugs reduced ongoing gamma oscillations, clozapine was the only compound that prevented the sensory-evoked gamma deficit produced by ketamine and MK-801. In addition, clozapine was also the only antipsychotic that attenuated the disruption to PPI produced by the NMDAr antagonists. We conclude that disruptions to evoked, but not ongoing, gamma oscillations caused by NMDAr antagonists are functionally relevant, and suggest that compounds, which restore sensory-evoked gamma oscillations may improve sensory processing in patients with schizophrenia.

That said, I really want to avoid using clozapine again! Would have been interesting to see if other SGAs augmented with NMDAR glycine site agonists etc  performed any better.

Microglia and stress

An excellent post by Ron Unger with a contribution from Brian Koehler:

“…the headlines were blaring: Schizophrenia breakthrough as genetic study reveals link to brain changes!  We heard that our best hope for treating “schizophrenia” is to understand it at a genetic level, and that this new breakthrough was now getting us really started on that mission, as it showed how a genetic variation could lead to the more intense pruning of brain connections which is often seen in those diagnosed with schizophrenia.  We were told that this study was very important.  “For the first time, the origin of schizophrenia is no longer a complete black box” was one quote.  And the acting director of the National Institute of Mental Health (NIMH) described the study as  “a crucial turning point in the fight against mental illness”.

But is all this hype justified?”

“Schizophrenia Breakthrough” – Or a Case of Ignoring the Most Important Evidence?

Modulating NMDA Receptor Function with D-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model. (2016)

Modulating NMDA Receptor Function with D-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model.

Deficits in N-methyl-D-aspartate receptor (NMDAR) function are increasingly linked to persistent negative symptoms and cognitive deficits in schizophrenia. Accordingly, clinical studies have been targeting the modulatory site of the NMDA receptor, based on the decreased function of NMDA receptor, to see whether increasing NMDA function can potentially help treat the negative and cognitive deficits seen in the disease. Glycine and D-serine are endogenous ligands to the NMDA modulatory site, but since high doses are needed to affect brain levels, related compounds are being developed, for example glycine transport (GlyT) inhibitors to potentially elevate brain glycine or targeting enzymes, such as D-amino acid oxidase (DAAO) to slow the breakdown and increase the brain level of D-serine. In the present study we further evaluated the effect of DAAO inhibitors 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and sodium benzoate (NaB) in a phencyclidine (PCP) rodent mouse model to see if the inhibitors affect PCP-induced locomotor activity, alter brain D-serine level, and thereby potentially enhance D-serine responses. D-Serine dose-dependently reduced the PCP-induced locomotor activity at doses above 1000 mg/kg. Acute CBIO (30 mg/kg) did not affect PCP-induced locomotor activity, but appeared to reduce locomotor activity when given with D-serine (600 mg/kg); a dose that by itself did not have an effect. However, the effect was also present when the vehicle (Trappsol^®) was tested with D-serine, suggesting that the reduction in locomotor activity was not related to DAAO inhibition, but possibly reflected enhanced bioavailability of D-serine across the blood brain barrier related to the vehicle. With this acute dose of CBIO, D-serine level in brain and plasma were not increased. Another weaker DAAO inhibitor NaB (400 mg/kg), and NaB plus D-serine also significantly reduced PCP-induced locomotor activity, but without affecting plasma or brain D-serine level, arguing against a DAAO-mediated effect. However, NaB reduced plasma L-serine and based on reports that NaB also elevates various plasma metabolites, for example aminoisobutyric acid (AIB), a potential effect via the System A amino acid carrier may be involved in the regulation of synaptic glycine level to modulate NMDAR function needs to be investigated. Acute ascorbic acid (300 mg/kg) also inhibited PCP-induced locomotor activity, which was further attenuated in the presence of D-serine (600 mg/kg). Ascorbic acid may have an action at the dopamine membrane carrier and/or altering redox mechanisms that modulate NMDARs, but this needs to be further investigated. The findings support an effect of D-serine on PCP-induced hyperactivity. They also offer suggestions on an interaction of NaB via an unknown mechanism, other than DAAO inhibition, perhaps through metabolomic changes, and find unexpected synergy between D-serine and ascorbic acid that supports combined NMDA glycine- and redox-site intervention. Although mechanisms of these specific agents need to be determined, overall it supports continued glutamatergic drug development.

Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised, double-blind, placebo-controlled trial (2015)

Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised, double-blind, placebo-controlled trial.

Objectives Hypofunction of NMDA receptor is implicated in the pathophysiology, particularly cognitive impairment, of schizophrenia. Sarcosine, a glycine transporter I (GlyT-1) inhibitor, and sodium benzoate, a d-amino acid oxidase (DAAO) inhibitor, can both enhance NMDA receptor-mediated neurotransmission. We proposed simultaneously inhibiting DAAO and GlyT-1 may be more effective than inhibition of either in improving the cognitive and global functioning of schizophrenia patients. Methods This study compared add-on sarcosine (2 g/day) plus benzoate (1 g/day) vs. sarcosine (2 g/day) for the clinical symptoms, as well as the cognitive and global functioning, of chronic schizophrenia patients in a 12-week, double-blind, randomised, placebo-controlled trial. Participants were measured with the Positive and Negative Syndrome Scale and the Global Assessment of Functioning Scale every 3 weeks. Seven cognitive domains, recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia Committee, were measured at weeks 0 and 12. Results Adjunctive sarcosine plus benzoate, but not sarcosine alone, improved the cognitive and global functioning of patients with schizophrenia, even when their clinical symptoms had not improved. Conclusions This finding suggests N-methyl-d-aspartate receptor-enhancement therapy can improve the cognitive function of patients with schizophrenia, further indicating this pro-cognitive effect can be primary without improvement in clinical symptoms

Ketogenic Diets

.High fat/low carb diet could combat schizophrenia

Research by James Cook University scientists has found a diet favoured by body-builders may be effective in treating schizophrenia.

Associate Professor Zoltan Sarnyai and his research group from JCU’s Australian Institute of Tropical Health and Medicine (AITHM) have discovered that feeding mice a ketogenic diet, which is high on fat but very low on carbohydrates (sugars), leads to fewer animal behaviours that resemble schizophrenia.

The ketogenic diet has been used since the 1920s to manage epilepsy in children and more recently as a weight loss diet preferred by some body builders.

Dr Sarnyai believes the diet may work by providing alternative energy sources in the form of so-called ketone bodies (products of fat breakdown) and by helping to circumvent abnormally functioning cellular energy pathways in the brains of schizophrenics.

“Most of a person’s energy would come from fat. So the diet would consist of butter, cheese, salmon, etc. Initially it would be used in addition to medication in an in-patient setting where the patient’s diet could be controlled,” he said.

Schizophrenia is a devastating, chronic mental illness that affects nearly one per cent of people worldwide. There is no cure and medications used to alleviate it can produce side effects such as movement disorder, weight gain and cardiovascular disease.

But if the research findings can be translated into the effective management of schizophrenia they may offer a secondary benefit too.

The group’s paper, published online in the leading journal Schizophrenia Research, also shows mice on a ketogenic diet weigh less and have lower blood glucose levels than mice fed a normal diet.

“It’s another advantage that it works against the weight gain, cardiovascular issues and type-two diabetes we see as common side-effects of drugs given to control schizophrenia,” said Dr Sarnyai.

The JCU researchers will now test their findings in other animal schizophrenia models as they explore a possible clinical trial.

See more;

Ketogenic diet reverses behavioral abnormalities in an acute NMDA receptor hypofunction model of schizophrenia.

Effects of a ketogenic diet on auditory gating in DBA/2 mice: A proof-of-concept study.

Madness and the Family (Part One): The History and Research of Family Dynamics and Psychosis

I was very lucky to have great family dynamics but there were non-family related stressors such as bullying and other traumas in my teenage years. Here’s part one of an interesting topic:

Madness and the Family (Part One): The History and Research of Family Dynamics and Psychosis

There are very few things considered more taboo in the world of mental health than the suggestion that problematic family dynamics can lead to a child developing a psychotic disorder. And yet, when we look honestly at the history and research of psychosis and the broader concept of “mental illness,” it becomes apparent that there are few subjects in the mental health field that are more important. I’d like to invite you, then, to join me on a journey into this taboo territory, dividing our trip into three legs. In the first leg (Part One), we’ll go back in time to explore how such a crucial topic has become so vilified, and then embark upon a flight for an aerial view of some of the most essential findings of the last 60 plus years of research that look at the links between problematic family dynamics and psychosis. In the second leg of the journey (Part Two), we’ll explore a framework that offers us the potential to unify the research on the various problematic family dynamics, trauma, and other factors associated with psychosis, locating the roots of psychosis within two core existential and relational dilemmas that I believe we all struggle with to greater or lesser degrees. Finally, in the third and last leg of our journey (Part Three), we will reap the fruits of our exploration, and consider how what we have learned may guide us as parents, as family members, and as society as a whole in offering genuine support to those who continue to grapple with these extreme states of mind.

Recovering From Psychiatry- The Power of Psychiatric Diagnosis

Focus on the symptoms instead of on the illness and solve the ‘schizophrenia’ problem