Exploring the overlap between ASD, Schizoid Personality and Schizophrenia

The following is an interesting read which I can relate to:

Peer-Professional First Person Account: Before Psychosis—Schizoid Personality From the Inside

The occurrence of schizophrenia as a worsening of schizoid traits previously present has been a topic of interest for some time. However, it is generally the case that information on a day-to-day basis about the premorbid personalities of psychotic patients when they come into care is fragmented and limited. In this article, I describe my own experience of schizoidism, into which I had insight, before I became psychotic. I also give some comments on how this worsened into psychosis.

As is the following:

Aspergers, or schizoid personality disorder?

austism-spectrum-schizoid-spectrum-edited_page_2

It is interesting to consider the different approach to treatments for SPD

Not self-diagnosing myself with SPD, just found the overlap interesting.

 

The role of inflammation in schizophrenia. (2015)

The role of inflammation in schizophrenia.

High levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients. Animal models of schizophrenia show that under certain conditions an immune disturbance during early life, such as an infection-triggered immune activation, might trigger lifelong increased immune reactivity. A large epidemiological study clearly demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia. Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, in a region related to the human leucocyte antigen (HLA) system and other immune functions. Another line of evidence demonstrates that chronic (dis)stress is associated with immune activation. The vulnerability-stress-inflammation model of schizophrenia includes the contribution of stress on the basis of increased genetic vulnerability for the pathogenesis of schizophrenia, because stress may increase pro-inflammatory cytokines and even contribute to a lasting pro-inflammatory state. Immune alterations influence the dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission. The activated immune system in turn activates the enzyme indoleamine 2,3-dioxygenase (IDO) of the tryptophan/kynurenine metabolism which influences the serotonergic and glutamatergic neurotransmission via neuroactive metabolites such as kynurenic acid. The described loss of central nervous system volume and the activation of microglia, both of which have been clearly demonstrated in neuroimaging studies of schizophrenia patients, match the assumption of a (low level) inflammatory neurotoxic process. Further support for the inflammatory hypothesis comes from the therapeutic benefit of anti-inflammatory medication. Metaanalyses have shown an advantageous effect of cyclo-oxygenase-2 inhibitors in early stages of schizophrenia. Moreover, intrinsic anti-inflammatory, and immunomodulatory effects of antipsychotic drugs are known since a long time. Anti-inflammatory effects of antipsychotics, therapeutic effects of anti-inflammtory compounds, genetic, biochemical, and immunological findings point to a major role of inflammation in schizophrenia.

Cyclooxygenase-2 (COX-2) inhibition as an anti-inflammatory therapeutic approach in schizophrenia

Modern anti-inflammatory agents have been explored in schizophrenia. The cyclooxygenase-2 (COX-2) inhibitor celecoxib was studied in a prospective, randomized, double-blind study of acute exacerbations of schizophrenia. The patients receiving celecoxib add-on to risperidone showed a statistically significantly better outcome than the patients receiving risperidone alone; the clinical effects of COX-2 inhibition in schizophrenia were especially pronounced in cognition (Müller et al., 2005). The efficacy of therapy with a COX-2 inhibitor seems most pronounced in the first years of the schizophrenic disease process (Müller, 2010; Müller et al., 2010). A recent study also demonstrated a beneficial effect of acetylsalicylic acid in schizophrenic spectrum disorders (Laan et al., 2010). A meta-analysis of the clinical effects of non-steroidal anti-inflammatory drugs in schizophrenia revealed significant effects on schizophrenic total, positive and negative symptoms (Sommer et al., 2012), while another meta-analysis found a significant benefit only in schizophrenia patients with a short duration of disease or in first manifestation schizophrenia (Nitta et al., 2013).

Further immune-related substances in the therapy of schizophrenia

Because of the role of microglia activation in inflammation, minocycline, an antibiotic and inhibitor of microglia activation, is an interesting substance for the treatment of schizophrenia. The improvement of cognition by minocycline has been described in animal models of schizophrenia (Mizoguchi et al., 2008) and in two double-blind, placebo-controlled add-on therapy trials in schizophrenia patients (Levkovitz et al., 2010; Chaudhry et al., 2012). In clinical studies, positive effects on schizophrenic negative symptoms were noted as well (Chaudhry et al., 2012). Case reports documented positive effects of minocycline on the whole symptom spectrum in schizophrenia (Ahuja and Carroll, 2007).

Acetylcysteine (ACC) and other substances, including omega-3 fatty acids, that have anti-inflammatory and other effects also provide some benefit to schizophrenia patients (overview: Sommer et al., 2014)

First pilot experiences with cytokine interferon gamma (IFN-γ), which stimulates the monocytic type 1 immune response, as a therapeutic approach in schizophrenia are encouraging (Grüber et al., 2014), although side effects, including unwanted immune effects, have to be carefully monitored and the results are only preliminary. On the other hand, such a hypothesis-driven therapeutic approach opens interesting perspectives for the development of therapeutic substances based on etiopathology.

‘Altered expression of neuro-immune genes and increased levels of cytokines are observed, especially in patients with comorbid depression’ and first episode psychosis (FEP) ‘patients with depression show a different gene expression profile reinforcing the theory that depression in FEP is a different phenotype’ [1]

Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons [2] and ‘lowering brain KYNA levels might be a novel approach in the treatment of psychotic disorders’

New pharmacotherapy targeting the improvement of GABA neuronal function for the cognitive dysfunction of schizophrenia. (2015)

New pharmacotherapy targeting the improvement of GABA neuronal function for the cognitive dysfunction of schizophrenia.

Schizophrenia is considered a neurodevelopmental and neurodegenerative disorder. Cognitive impairment is a core symptom in patients with the illness, and has been suggested a major predictor of functional outcomes. Reduction of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) interneurons has been associated with the pathophysiology of schizophrenia, in view of the link between the abnormality of GABA neurons and cognitive impairments of the disease. It is assumed that an imbalance of excitatory and inhibitory (E-I) activity induced by low activity of glutamatergic projections and PV-positive GABA interneurons in the prefrontal cortex resulted in sustained neural firing and gamma oscillation, leading to impaired cognitive function. Therefore, it is important to develop novel pharmacotherapy targeting GABA neurons and their activities. Clinical evidence suggests serotonin (5-HT) 1A receptor agonist improves cognitive disturbances of schizophrenia, consistent with results from preclinical studies, through mechanism that corrects E-I imbalance via the suppression of GABA neural function. On the other hand, T-817MA, a novel neurotrophic agent, ameliorated loss of PV-positive GABA neurons in the medial prefrontal cortex and reduction of gamma-band activity, as well as cognitive dysfunction in animal model of schizophrenia. In conclusion, a pharmacotherapy to alleviate abnormalities in GABA neurons through 5-HT1A agonists and T-817MA is expected to prevent the onset and/or progression of schizophrenia.

 Fig. 1.
Chemical structure of T-817MA

Positive Emotions Program for Schizophrenia (PEPS): a pilot intervention to reduce anhedonia and apathy. (2015)

I’ve recently had the pleasure to meet a friend who has re-introduced some positive emotion into my world. While the negative emotions still dominate, it’s a refreshing change. Here’s a recent article:

Positive Emotions Program for Schizophrenia (PEPS): a pilot intervention to reduce anhedonia and apathy.

BACKGROUND:

Recent literature has distinguished the negative symptoms associated with a diminished capacity to experience (apathy, anhedonia) from symptoms associated with a limited capacity for expression (emotional blunting, alogia). The apathy-anhedonia syndrome tends to be associated with a poorer prognosis than the symptoms related to diminished expression. The efficacy of drug-based treatments and psychological interventions for these symptoms in schizophrenia remains limited. There is a clear clinical need for new treatments.

METHODS:

This pilot study tested the feasibility of a program to reduce anhedonia and apathy in schizophrenia and assessed its impact on 37 participants meeting the ICD-10 criteria for schizophrenia or schizoaffective disorders. Participants were pre- and post-tested using the Scale for the Assessment of Negative Symptoms (SANS) and the Calgary Depression Scale for Schizophrenia (CDSS). They took part in eight sessions of the Positive Emotions Program for Schizophrenia (PEPS)-an intervention that teaches participants skills to help overcome defeatist thinking and to increase the anticipation and maintenance of positive emotions.

RESULTS:

Thirty-one participants completed the program; those who dropped out did not differ from completers. Participation in the program was accompanied by statistically significant reductions in the total scores for Avolition-Apathy and Anhedonia-Asociality on the SANS, with moderate effect sizes. Furthermore, there was a statistically significant reduction of depression on the CDSS, with a large effect size. Emotional blunting and alogia remain stable during the intervention.

DISCUSSION:

Findings indicate that PEPS is both a feasible intervention and is associated with an apparently specific reduction of anhedonia and apathy. However, these findings are limited by the absence of control group and the fact that the rater was not blind to the treatment objectives.

CONCLUSIONS:

PEPS is a promising intervention to improve anhedonia and apathy which need to be tested further in a controlled study.

See also:

Self-Compassion and Self-Criticism in Recovery in Psychosis: An Interpretative Phenomenological Analysis Study.

Supplementation of antipsychotic treatment with sarcosine-G1yT1 inhibitor-causes changes of glutamatergic 1NMR spectroscopy parameters in the left hippocampus in patients with stable schizophrenia. (2015)

Supplementation of antipsychotic treatment with sarcosine-G1yT1 inhibitor-causes changes of glutamatergic 1NMR spectroscopy parameters in the left hippocampus in patients with stable schizophrenia.

Glutamatergic system, the main stimulating system of the brain, plays an important role in the pathogenesis of schizophrenia. Hippocampus, a structure crucial for memory and cognitive functions and rich in glutamatergic neurons, is a natural object of interest in studies on psychoses. Sarcosine, a glycine transporter (GlyT-1) inhibitor influences the function of NMDA receptor and glutamate-dependent transmission. The aim of the study was to assess the effects of sarcosine on metabolism parameters in the left hippocampus in patients with schizophrenia. Assessments were performed using proton nuclear magnetic resonance (1H NMR) spectroscopy (1.5T). Fifty patients diagnosed with schizophrenia (DSM-IV-TR), with dominant negative symptoms, in stable clinical condition and stable antipsychotics doses were treated either with sarcosine (n=25) or placebo (n=25). Spectroscopic parameters were evaluated within groups and between two groups before and after 6-month intervention. All patients were also assessed with the Positive and Negative Syndrome Scale (PANSS). In the sarcosine group, after 6-month treatment, we found significant decrease in hippocampal Glx/Cr (Glx-complex of glutamate, glutamine and GABA, Cr-creatine) and Glx/Cho (Cho-choline), while N-acetylaspartate (NAA), myo-inositol (mI), Cr and Cho parameters remained stable along the study and also did not differ significantly between both groups. This is the first study showing that a pharmacological intervention in schizophrenia, particularly augmentation of the antypsychotic treatment with sarcosine, may reverse the pathological increase in glutamatergic transmission in the hippocampus. The results confirm involvement of glutamatergic system in the pathogenesis of schizophrenia and demonstrate beneficial effects of GlyT-1 inhibitor on the metabolism in the hippocampus and symptoms of schizophrenia.

“Sarcosine – an exogenous amino acid – is serving in the brain as a glycine transporter type 1 (GlyT-1) inhibitor and as a source of glycine (natural coagonist of the NMDA receptor, metabolized from sarcosine by sarcosine dehydrogenase). It was reported to be effective in treating negative and cognitive symptoms .

Supplementation of sarcosine at a 2 grams daily dose is supposed to increase glycine concentration and normalize hypofunction of the NMDA receptors, which are present in high density in the the prefrontal cortex and hippocampus – areas associated with development of cognitive and negative symptomatology”

table 3
Study results

“We conclude that augmentation of the antypsychotic treatment with sarcosine may reverse the increase in glutamatergic transmission in the left hippocampus in schizophrenia along with improvement of mental state, assessed with the PANSS. The results confirm involvement of glutamatergic system in the pathogenesis of schizophrenia and demonstrate beneficial effects of GlyT-1 inhibitor on the metabolism in the hippocampus.”

See more:

Sarcosine Therapy – A New Complementary Direction for Schizophrenia Treatment?

Safety, tolerability and pharmacokinetics of open label sarcosine added on to anti-psychotic treatment in schizophrenia – preliminary study. (2015)

Glycinergic, NMDA and AMPA augmentation – a review

GlyT1 inhibitors

Adding Sarcosine to Antipsychotic Treatment in Patients with Stable Schizophrenia Changes the Concentrations of Neuronal and Glial Metabolites in the Left Dorsolateral Prefrontal Cortex.

Antipsychotic Maintenance Treatment: Time to Rethink? (2015)

Antipsychotic Maintenance Treatment: Time to Rethink?

Schizophrenia and psychotic disorders are estimated to affect 1% of the population and are one of the highest causes of global disability. They place a considerable burden on individuals, families, and society, with costs amounting to US$62.7 billion in the United States in 2002, for example. The highest costs are related to unemployment, and one long-term follow-up study found that more than 80% of people diagnosed with schizophrenia have some ongoing social disability.

Long-term antipsychotic treatment has been the norm for people diagnosed with schizophrenia and other recurrent psychotic disorders since the introduction of these drugs in the 1960s. Recent data from the United Kingdom indicate that 97.5% of mental health service patients diagnosed with schizophrenia are prescribed at least one antipsychotic. The practice is based on research believed to have established that continuous antipsychotic treatment reduces the risk of relapse. Interpreting the evidence is not straightforward, though, and other data are beginning to emerge that suggest that long-term treatment may have an adverse impact on levels of social functioning. Is it time, therefore, to review the practice of antipsychotic maintenance treatment and question whether it should continue to be the default treatment strategy in people diagnosed with schizophrenia or similar psychotic disorders?

  • Existing studies of long-term antipsychotic treatment for people with schizophrenia and related conditions are too short and have ignored the impact of discontinuation-related adverse effects: “antipsychotic discontinuation studies may partially, or even wholly, reflect the adverse effects of antipsychotic withdrawal, rather than the benefits of initiating maintenance treatment”
  • Recent evidence confirms that antipsychotics have a range of serious adverse effects, including reduction of brain volume.
  • The first really long-term follow-up of a randomised trial found that patients with first-episode psychosis who had been allocated to a gradual antipsychotic reduction and discontinuation programme had better functioning at seven-year follow-up than those allocated to maintenance treatment, with no increase in relapse.
  • Further studies with long-term follow-up and a range of outcomes should be conducted on alternatives to antipsychotic maintenance treatment for people with recurrent psychotic conditions.

“The majority of people who experience more than one episode of psychosis are currently recommended to remain on long-term antipsychotic treatment, with little guidance about whether the treatment should ever be stopped, and if so, how this should be done. Many patients find this approach unacceptable, and stop of their own accord without support, which likely leads to the complications of sudden medication withdrawal, including relapse.

The studies used to justify current clinical practice do not provide reliable data about the costs and benefits of long-term antipsychotic therapy. In particular, questions remain about how maintenance treatment affects people’s overall functioning over the long term, with some indications it may be detrimental for some people. There is abundant evidence that long-term antipsychotic treatment is associated with other serious and disabling adverse effects.

We need to do more research to establish the pros and cons of long-term antipsychotic treatment for people with one or more episodes of psychosis or schizophrenia. Further studies that evaluate a gradual and individualised approach to antipsychotic discontinuation are particularly important, both in people with first episode psychosis, and more challengingly, in people with recurrent conditions. Such studies need to include assessment of outcomes other than relapse and could assess what additional support might facilitate patients to successfully reduce their antipsychotic burden. Longer-term follow-up of five to ten years is required to reflect the duration of treatment in clinical practice. Research on treatments for other medical conditions demonstrates this can be achieved when it is prioritised.

Response to long-term antipsychotic treatment is likely to be heterogeneous, although so far there has been little success in identifying factors that might predict successful discontinuation. Existing research rarely distinguishes people who recover and are symptom-free between episodes from those who have ongoing positive psychotic symptoms. In the former situation, long-term antipsychotic treatment is aimed solely at preventing relapse, whereas in the latter, long-term treatment may be a form of symptom control, instead of, or in addition to, its desired prophylactic effect. The considerations involved in these situations may be different, and research needs to identify the varying pros and cons of long-term treatment for the two groups. For example, in people who recover completely, the adverse consequences of having reduced social or neuropsychological function may be more significant than for those people who are already somewhat disabled by ongoing symptoms.

While we await the results of further long-term discontinuation studies, I suggest we need to reconsider antipsychotic maintenance treatment as the default strategy for people with recurrent psychotic disorders. In 1976, two leading psychiatrists felt that the cost-benefit ratio of long-term antipsychotic medication was often not favourable for patients and recommended that “every chronic schizophrenic outpatient maintained on antipsychotic medication should have the benefit of an adequate trial without drugs”. Recent evidence suggests that, when risks allow, modern-day clinicians and patients could also consider this option.”

Recognition of cognitive impairment in schizophrenia

It’s good to see some progress being made towards the recognition of cognitive impairment in schizophrenia and looking at possible treatment options:

http://www.needrecognition.com

Cognitive symptoms, which may include deficits in memory, attention, working memory, processing speed, and problem solving

  • Can be present prior to the onset of illness
  • Persist during periods of psychotic symptom remission
  • Are highly predictive of outcome and functioning

Despite the availability of effective antipsychotic therapy, cognitive impairment remains an important unmet treatment need


Patients With Schizophrenia Demonstrate Impairment in a Broad Range of Cognitive Domains vs Healthy Individuals

Cognitive domains impaired by schizophrenia

Proposed Mechanisms of Cognitive Impairment in Schizophrenia

Conversations on Cognition

Interventions:

  • Cognitive remediation
  • The MATRICS team identified drug mechanisms of interest, including cholinergic, dopaminergic, and glutamatergic approaches
  • Of the cholinergic approaches, the α7 was identified as a top target of investigation

Potential Mechanistic Targets for Treatment of Cognitive Impairment in Schizophrenia

CHOLINERGIC
  • α7 receptor
  • muscarinic M1 MAChR
DOPAMINERGIC
  • dopamine D1 receptor
GLUTAMATERGIC
  • AMPA glutamatergic receptor
  • NMDA glutamatergic receptor
  • Metabotropic glutamate receptor
  • Glycine reuptake
OTHER
  • α2 adrenergic receptor
  • GABAA R subtype

See more:

Pharmacological Treatment of Cognitive Symptoms

The Magic of Movement; the Potential of Exercise to Improve Cognition (2015)

Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials. (2015)

Cognitive enhancing agents in schizophrenia and bipolar disorder (2015)

Drug repurposing and emerging adjunctive treatments for schizophrenia (2015)

Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review (2015)

Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms (2015)

A critical review of pro-cognitive drug targets in psychosis: convergence on myelination and inflammation

Psychopharmacological treatment of neurocognitive deficits in people with schizophrenia: a review of old and new targets.