Dietary Intake of Sulforaphane-Rich Broccoli Sprout Extracts during Juvenile and Adolescence Can Prevent Phencyclidine-Induced Cognitive Deficits at Adulthood. (2015)

An interesting research direction for ‘prophylactic psychiatry’:

Dietary Intake of Sulforaphane-Rich Broccoli Sprout Extracts during Juvenile and Adolescence Can Prevent Phencyclidine-Induced Cognitive Deficits at Adulthood. (2015)

Oxidative stress and inflammation play a role in cognitive impairment, which is a core symptom of schizophrenia. Furthermore, a hallmark of the pathophysiology of this disease is the dysfunction of cortical inhibitory γ-aminobutyric acid (GABA) neurons expressing parvalbumin (PV), which is also involved in cognitive impairment. Sulforaphane (SFN), an isothiocyanate derived from broccoli, is a potent activator of the transcription factor Nrf2, which plays a central role in the inducible expressions of many cytoprotective genes in response to oxidative stress. Keap1 is a cytoplasmic protein that is essential for the regulation of Nrf2 activity. Here, we found that pretreatment with SFN attenuated cognitive deficits, the increase in 8-oxo-dG-positive cells, and the decrease in PV-positive cells in the medial prefrontal cortex and hippocampus after repeated administration of phencyclidine (PCP). Furthermore, PCP-induced cognitive deficits were improved by the subsequent subchronic administration of SFN. Interestingly, the dietary intake of glucoraphanin (a glucosinolate precursor of SFN) during the juvenile and adolescence prevented the onset of PCP-induced cognitive deficits as well as the increase in 8-oxo-dG-positive cells and the decrease in PV-positive cells in the brain at adulthood. Moreover, the NRF2 gene and the KEAP1 gene had an epistatic effect on cognitive impairment (e.g., working memory and processing speed) in patients with schizophrenia. These findings suggest that SFN may have prophylactic and therapeutic effects on cognitive impairment in schizophrenia. Therefore, the dietary intake of SFN-rich broccoli sprouts during the juvenile and adolescence may prevent the onset of psychosis at adulthood.

“Neurodevelopment during early adolescence is a key stage during maturation, with various structural, neurochemical, and molecular changes taking place in response to genetic and environmental cues. The formation of new neuronal connections during early adolescence also means a high level of vulnerability to pathologic insults ranging from stress to dietary deficiencies. The nutritional status during early adolescence has a great impact on the onset and severity of psychiatric diseases at adulthood. In the past decade, increasing interest in the potential benefits of early intervention for psychiatric diseases, such as schizophrenia, has been seen. Subjects at a high risk of developing psychosis exhibit cognitive impairments, compared with healthy subjects. Approximately one-third of subjects at a high risk develop psychosis within three years, and most are diagnosed as having schizophrenia. In this study, we found that the dietary intake of SFN-rich food during the juvenile and adolescence was capable of preventing PCP-induced cognitive deficits and oxidative stress at adulthood in mice. Although the precise mechanism underlying the preventive effect of SFN-rich food is currently unclear, the dietary intake of SFN-rich foods may be capable of regulating gene expression through epigenetic mechanisms. Since SFN has potent antioxidant and anti-inflammatory effects, SFN may prevent the onset of psychosis in subjects at a high risk and who exhibit oxidative stress and inflammation. Therefore, a randomized, double-blinded, placebo-controlled study of the dietary intake of SFN-rich foods in subjects at a high risk of psychosis is of great interest.”

“In the present study, we found that SFN exhibited prophylactic and therapeutic effects in a PCP-induced cognitive deficits model. Very recently, we found that supplementation with SFN-rich broccoli sprout extract for 8 weeks was effective for the treatment of cognitive impairment in medicated patients with schizophrenia, although other scores (such as psychotic symptoms) were not altered. Furthermore, a recent randomized, double-blinded, placebo-controlled study demonstrated that treatment with SFN-rich broccoli sprout extract significantly improved social interaction, abnormal behavior, and verbal communication in young men with autism spectrum disorder. Glucoraphanin (GF), a glucosinolate precursor of SFN, is widely consumed in cruciferous plant-rich diets; therefore, SFN is considered to have a low toxicity, and its administration in humans is well tolerated. It is reported that SFN readily crosses the blood-brain barrier of mouse after i.p. administration, suggesting that SFN in the brain can improve PCP-induced cognitive deficits. Together, these results suggest that SFN-rich broccoli sprout extract could have a potential therapeutic effect in patients with a number of psychiatric diseases including schizophrenia and autism spectrum disorder, since patients with these psychiatric diseases exhibit cognitive impairment”

As covered in Natural products for schizophrenia :

A small study found benefits from sulforaphane administration [1]: “Sulforaphane (SFN) is a molecule belonging to the isothiocyanate group of organosulfur compounds found in broccoli sprouts. It is known to have potent anti-oxidant and anti-inflammatory activity. Previously, we reported that SFN attenuated behavioral abnormalities in mice after administration of methamphetamine or phencyclidine, suggestive of a potential therapeutic potency in schizophrenia. Recently, we found that SFN improved cognitive deficits in phencyclidine-treated mice”.


See also:

New Targets for Prevention of Schizophrenia: Is it Time for Interventions in the Premorbid Phase? (2015)

Stage specific and prophylactic treatments?

New Targets for Prevention of Schizophrenia: Is it Time for Interventions in the Premorbid Phase? (2015)

New Targets for Prevention of Schizophrenia: Is it Time for Interventions in the Premorbid Phase?

A number of influences have converged that make this Special Theme Issue timely: “A New Direction: Considering Developmentally Sensitive Targets for Very Early Intervention in Schizophrenia”. These factors include: 1. the substantial knowledge about premorbid developmental vulnerabilities to psychosis, especially regarding schizophrenia; 2. the promising results emerging from interventions during the clinical high-risk (CHR) phase of psychosis and; 3. the recognition that the CHR period is a relatively late phase of developmental derailment. These factors have together led to a perspective that even earlier intervention is warranted. This paper briefly summarizes the articles comprising the Special Theme including new data on early neurocognitive development, proposed potential targets for psychosocial and psychopharmacological interventions during the premorbid period as early as pregnancy, and ethical challenges. These thought experiments must be empirically tested, and the ethical challenges overcome as posed by the various interventions, which range from relatively low risk, supportive, psychosocial to higher risk, experimental, pharmacological interventions. All of the interventions proposed require careful study of ethics, safety, potential stigma, feasibility, efficacy and tolerability, and the meaning to the people involved.

Phase specific early intervention & prevention strategies for clinical and familial high risk. Clinical risk symptoms are contrasted with family risk for psychosis by depicting the greater likelihood of conversion to psychosis to occur in the clinical risk group by the larger yellow arrow. Interventions above the line for the clinical risk group begin around the end of elementary school reflecting the earliest period that prodromal symptoms are typically reported, whereas those below the line begin during pregnancy reflecting more of a primary prevention approach.
Phase specific early intervention & prevention strategies for clinical and familial high risk.
Clinical risk symptoms are contrasted with family risk for psychosis by depicting the greater likelihood of conversion to psychosis to occur in the clinical risk group by the larger yellow arrow. Interventions above the line for the clinical risk group begin around the end of elementary school reflecting the earliest period that prodromal symptoms are typically reported, whereas those below the line begin during pregnancy reflecting more of a primary prevention approach.

Perinatal pharmacological intervention with choline

“Ross and Freedman suggest a novel approach toward identifying underlying mechanisms of risk for psychosis through the measurement of endophenotypes during the perinatal period. This is innovative because schizophrenia is a neurodevelopmental disorder, whose onset is the end result of brain changes that begin prenatally, but most endophenotype studies have evaluated adolescents or adults who have entered or passed through the age of risk for the disorder. They suggest a treatment approach that targets a well-known schizophrenia endophenotype, P50 sensory gating. They based a randomized control trial in 76 healthy pregnant women on the hypothesis that perinatal choline supplementation would increase activation of alpha7 nicotinic receptors and normalize developmental defects associated with receptor deficiencies, including deficits in P50 sensory gating. Infants whose mothers had received prenatal choline demonstrated improved infant P50 sensory gating, compared to those whose mothers received placebo. There was an interaction between choline supplementation with infant genotype on CHRNA7 SNP re3087454 on P50 suppression ratio that increased plausibility. At 40 months follow-up, the children had significantly improved attention, which is often impaired in children who later develop schizophrenia. This preliminary work is promising, and if safe, could be considered for a neurobiologically informed primary prevention intervention for pregnant mothers with schizophrenia. Nevertheless, the idea that choline can prevent schizophrenia is quite speculative, and there are many steps needed to confirm this approach including whether improving P50 or accelerating the maturation of P50 can change the vulnerability to schizophrenia.”

See more: Prenatal choline and the development of schizophrenia

Animal studies involving choline supplementation in prenatal/perinatal [1, 2]  and adolescent [3] developmental periods have shown various benefits. A procholine supplement has improved sensory gating and executive function in healthy adults [4]

Targeting oxidative stress, neuroinflammation, NMDAR hypofunction

[researchers] “…suggest that drugs that target the “hub” of oxidative stress and related dysfunctions (neuroinflammation and NMDAR hypofunction) would be candidates for repairing these developmental anomalies, including Omega 3, sulforaphane and N-acetylcysteine (NAC)”

From Targeting of NMDA receptors in new treatments for schizophrenia

  • supplementation with the correct amount of vitamin D in early life could decrease the risk of schizophrenia
  • supplementation of omega-3 fatty acids in the form of fish oils could decrease the onset of psychosis for high-risk subjects
  • supplementation with d-serine during juvenile and preadolescent stages could prevent the onset of psychosis at the adult stage. A natural conclusion would be that supplementation with the endogenous, and therefore safe d-serine, could protect adolescents and young adults at high-risk of developing psychosis.
  • Sulforaphane (SFN) conferred antipsychotic benefits in rodent models of schizophrenia. Interestingly, we found that supplementation with SFN during juvenile stages could prevent the onset of cognitive impairment in the preclinical PCP model of schizophrenia. Therefore, supplementation with SFN-rich broccoli sprout extract during childhood and pre-adolescence may prevent the onset of psychosis in adulthood, assisted by the fact that this extract is widely available as a supplement.
  • The antioxidant N-acetylcysteine (NAC) has the potential to prevent psychosis

“These findings suggest that early intervention with safe supplements could improve cognitive impairment in adolescents and young adults, and possibly prevent the onset of schizophrenia. Finally, we would like to propose a hypothesis that nutrition in childhood and preadolescent stages could have a high impact on subsequent mental health at adolescent and adult stages, particularly the adequate intake of omega-3 fatty acid-rich fish and vegetables (e.g., SFN-rich broccoli sprout), and possibly prevent the onset of psychiatric diseases.”

Stage specific and prophylactic treatments?

Some interesting research has recently been published. Is it time to start to consider a) non-antipsychotic prophylactic interventions and b) stage specific treatments?

There seem to be differing views:

1. Early intervention with pharmacological and social interventions is critical. Under the biomedical model, schizophrenia is a severe, highly disabling and lifelong condition:

Preventing Clinical Deterioration in the Course of Schizophrenia: The Potential for Neuroprotection

An outdated model or important opportunities for early pharmacological interventions?
“Clinicians should be encouraged to treat early to reduce the duration of untreated psychosis, particularly delusions. The emergence of psychosis is a very important time to intervene, and even subtle symptoms could herald future deterioration. The goal is to treat effectively, aiming for full remission of psychotic symptoms. In doing so, clinicians should offer their patients a full armamentarium of interventions to improve their long-term outcome and functioning. This includes combining medication with cognitive-behavioral or other therapies to minimize stress and optimize psychosocial outcome; and using job coaching, cognitive remediation, or other strategies to achieve and retain a full functional recovery.”

“Diagnostic classification and its often stigmatizing effects do not do justice to the uncertainty of prognosis nor the potential inefficiency and risks of routine pharmacological approaches. Prescription of neuroleptics should be cautious and postponed, especially given the availability of sound alternatives with more modest, short-term roles for medication…

Eradicating [symptoms] pharmacologically, even if patients understandably request this, is not always a realistic treatment goal. Limitations in the existing evidence base for neuroleptic medication for voices have been highlighted, and it has been argued that there is not enough robust evidence to support the routine administration of such medication for voice-hearers (who are diagnosed with psychosis)”

⇒ For psychosocial interventions, see Phase-Specific Recovery from Schizophrenia

3. Holistic and spiritual approaches may be effective:

“…some psychiatric states are opportunities for spiritual growth rather than intrinsically destructive psychopathologies”

Interventions for the indicated prevention of psychosis

Accumulating evidence indicates that therapeutic interventions to prevent transition from clinical high risk (CHR) status to fullblown psychosis can be successful (Stafford et al. 2013; Ruhrmann et al. 2010b; Yung et al. 2007). Recent metaanalysis of CHR intervention trials (van der Gaag et al. 2013) found that antipsychotic treatment [number needed to treat (NNT) = 7], cognitive behaviour therapy (CBT) (NNT = 14) and supplementation with omega-3 oils (Amminger et al. 2010) (NNT = 5) are all effective in preventing transition to psychosis at 1-year post-presentation with CHR symptoms (van der Gaag et al. 2013; Fusar-Poli et al. 2013b). These values compare favourably with other interventions in medicine to prevent chronic illnesses, for example in pre-diabetes (metformin NNT = 14 and lifestyle changes NNT = 7 at 3 years), or prodromal cardiovascular disease (anticoagulant therapy NNT = 25 at 2 years) (Fusar-Poli et al. 2014a). However, there is a high rate of at-risk individuals who maintain CHR status for long periods of time before either transitioning to psychosis or remitting spontaneously.

Based on a meta-analysis, over 60 % of individuals identified as CHR will not have transitioned 3 years after identification (Fusar-Poli et al. 2012a) and at least 30 % identified by basic symptoms criteria will not have transitioned by nearly 10 years (Klosterkotter et al. 2001). This has led to concerns regarding unwarranted diagnostic labelling and resultant distress, stigma and discrimination (Yang et al. 2010; Ruhrmann et al. 2012). For example, intervention with antipsychotic treatment carries the risks of side effect burden and of unknown impact on normal brain development during adolescence and early adulthood (Corcoran et al. 2010), and the use of antipsychotics is associated with the extent of progressive grey matter volume decreases and lateral ventricular volume increases observed in CHR individuals who transition to schizophrenia (Fusar-Poli et al. 2013c).

Together, the concerns regarding the relatively low transition rate of the CHR state and the risk of adverse effects of early antipsychotic treatment have lead to conservative approaches of CHR management. Clinical guidelines focus on careful monitoring, and on the provision of relatively benign interventions such as family therapy and omega-3 supplementation in the first instance, and recommend antipsychotic treatment only for those at the immediate threshold of psychosis (Fusar-Poli et al. 2014a). However, antipsychotic medication still has the strongest cumulative evidence for prevention of transition (van der Gaag et al. 2013), and some CHR individuals may ‘miss out’ on effective treatments because of overly cautious guidelines. Therefore, the field has recognized the need to develop better predictive models, combining clinical findings with evidence from emerging prognostic technologies, to tailor therapies to individual needs, according to a clinically acceptable risk–benefit ratio.

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

Antipsychotic drugs have thus far focused on dopaminergic antagonism at the D2 receptors, as counteracting the hyperdopaminergia in nigrostriatal and mesolimbic projections has been considered mandatory for the antipsychotic action of the drugs. Current drugs effectively target the positive symptoms of psychosis such as hallucinations and delusions in the majority of patients, whereas effect sizes are smaller for negative symptoms and cognitive dysfunctions. With the understanding that neurocognitive dysfunction associated with schizophrenia have a greater impact on functional outcome than the positive symptoms, the focus in pharmacotherapy for schizophrenia has shifted to the potential effect of future drugs on cognitive enhancement. A major obstacle is, however, that the biological underpinnings of cognitive dysfunction remain largely unknown. With the availability of increasingly sophisticated techniques in molecular biology and brain imaging, this situation is about to change with major advances being made in identifying the neuronal substrates underlying schizophrenia, and putative pro-cognitive drug targets may be revealed. In relation to cognitive effects, this review focuses on evidence from basic neuroscience and clinical studies, taking two separate perspectives. One perspective is the identification of previously under-recognized treatment targets for existing antipsychotic drugs, including myelination and mediators of inflammation. A second perspective is the development of new drugs or novel treatment targets for well-known drugs, which act on recently discovered treatment targets for cognitive enhancement, and which may complement the existing drugs. This might pave the way for personalized treatment regimens for patients with schizophrenia aimed at improved functional outcome. The review also aims at identifying major current constraints for pro-cognitive drug development for patients with schizophrenia.

Myelination/structural alterations

When can interventions be started? Is prodromal intervention a realistic aim?

Recently, differing results with regard to structural changes have been published:

” …there is minimal evidence of an association between untreated psychosis and brain structure in first episode psychosis (FEP)” [a]

” [there are] extensive white matter tracts anomalies in patients with schizophrenia, more specifically, in drug-naïve FEP patients. The results also indicate that a small number of white matter tracts share common FA anomalies that relate to deficit symptoms in FEP patients. Our study adds to a growing body of literature emphasizing the need for treatments targeting white matter function and structure in FEP patients.” [b] [See review]

“…results suggest that the progression of brain abnormalities in first episode psychosis subjects is restricted to those with a poor outcome and differs between diagnosis subgroups. Antipsychotic intake is associated with a different pattern of grey matter reductions over time.” [c]

Neuroinflammation in gray and white matter in schizophrenia has recently been studied via PET with a TSPO radioligand:
“The lack of significant difference in neuroinflammation in treated patients with SCZ in the midst of a psychotic episode and healthy volunteers suggests that neuroinflammatory processes may take place early in disease progression or are affected by antipsychotic treatment.” [d]

Neuroimmune biomarkers in schizophrenia

Schizophrenia is a heterogeneous psychiatric disorder with a broad spectrum of clinical and biological manifestations. Due to the lack of objective tests, the accurate diagnosis and selection of effective treatments for schizophrenia remains challenging. Numerous technologies have been employed in search of schizophrenia biomarkers. These studies have suggested that neuroinflammatory processes may play a role in schizophrenia pathogenesis, at least in a subgroup of patients. The evidence indicates alterations in both pro- and anti-inflammatory molecules in the central nervous system, which have also been found in peripheral tissues and may correlate with schizophrenia symptoms. In line with these findings, certain immunomodulatory interventions have shown beneficial effects on psychotic symptoms in schizophrenia patients, in particular those with distinct immune signatures. In this review, we evaluate these findings and their potential for more targeted drug interventions and the development of companion diagnostics. Although currently no validated markers exist for schizophrenia patient stratification or the prediction of treatment efficacy, we propose that utilisation of inflammatory markers for diagnostic and theranostic purposes may lead to novel therapeutic approaches and deliver more effective care for schizophrenia patients.

Abnormal immune system development and function in schizophrenia helps reconcile diverse findings and suggests new treatment and prevention strategies

“…the hypothesis of abnormal immune system development presented here helps to unify and explain a broad range of findings from diverse fields, including epidemiology, genetics, immunology, neurophysiology, and pharmacology. It suggests that early immune system programming influenced by the disruptive effects of pre- and perinatal adversity combines with abnormal central nervous system (CNS) development to produce schizophrenia. While complementing neurodevelopmental theories of schizophrenia, it offers a more complete integration of key findings on schizophrenia and helps explain the growing set of research findings linking schizophrenia to numerous immune abnormalities, including altered immune cell activities, inflammation, immune-related genes, infections, and auto-immune disorders.

These findings on patients with schizophrenia are complemented by a large and growing body of evidence from experiments with laboratory animals. These experiments have shown that prenatal exposure to adverse environmental conditions such as infection can disrupt development of both the immune and nervous systems, with effects on immune function, behavior, and brain structure that can be manifested much later in development, during puberty and adulthood.

One interesting feature of our hypothesis is that it suggests several novel approaches to treatment and prevention of schizophrenia. A number of these approaches appear to be ones that could be readily tested, and could be implemented in ways that are ethical and relatively economical.”

New treatment strategies

Bolstering immune function

“One treatment strategy suggested by the hypothesis would be to employ practices that bolster immune function, by helping schizophrenia patients to follow procedures that have been shown to reduce inflammatory responses and improve defense against infection. These include, for example, insuring a balanced diet and ample levels of sunlight exposure, to insure adequate levels of vitamin D. A complementary approach would insure that patients practice regular moderate exercise and stress management—a regimen that some controlled experiments have found to reduce inflammation and improve resistance to infectious diseases.”

Diagnosing and treating unrecognized infections and immune disorders

“Because the hypothesis suggests that schizophrenia patients’ symptoms may sometimes be promoted by unrecognized and/or untreated infections, another strategy could involve more careful testing for untreated infections, and trials with targeted anti-viral or antibiotic regimes. Similarly, treating previously unrecognized immune disorders, or investigating medications to reduce high levels of pro-inflammatory cytokines, could be an informative test. As part of their disability, schizophrenia patients are less likely to seek out medical care and/or follow treatment recommendations. Thus, it may become important to regularly screen for infections as part of standard psychiatric care. Of note, adherence to anti-viral, antibiotic, or anti-inflammatory medication regimes may be greater than adherence to antipsychotics, as they tend to be better-tolerated, and carry less illness-related fear and stigma.”

⇒ For more information: Inflammation and immunology in schizophrenia

Inflammatory responses:
Characteristics, sources, and neuronal consequences of activated inflammatory responses in schizophrenia. Abnormal expression of inflammatory genes in monocytes/macrophages (M/M) results in peripheral low-grade inflammation (patients: solid orange and green lines-healthy subjects: dashed lines). Stress and/or pathogen exposure may lead to an over-activation of microglia (MG), which activates astrocytes (AC) and the consequent release of cytokines (IL-6, IL-10, TGF-β) that stimulate the production of kynurenic acid (KYNA). KYNA blocks signaling at the NMDA receptor and the α7 nicotinic acetylcholine receptor (α7nAChR). MGs releases cytokines (IL-1β, IL-12, TNF-α) that weaken the biosynthesis of serotonin and promotes the production of quinolinic acid (QUIN) and 3-hydroxykynurenine (3-OHKY), both neurotoxic substances. Abnormal HPA axis function may further contribute to the development of low-grade inflammation as the normal feed-back exerted by cortisol is not working properly. Furthermore, prenatal immune priming by in utero exposure to infection may provide a developmental source of long-term immune abnormalities to schizophrenia.

⇒ See also: Pro-/antiinflammatory dysregulation in early psychosis: results from a 1-year follow-up study.

Impact of treatment

The impact of antipsychotic treatment has recently been studied:
“Although short-term treatment with antipsychotics was associated with prefrontal cortical thinning, treatment was also associated with better cognitive control and increased prefrontal functional activity.” [d]
“… antipsychotic drugs significantly reduce the secretion of TNF-α, nitric oxide, IL-1β, and IL-2 from activated microglia. Furthermore, some drugs were found to have stronger inhibitory effects, e.g., risperidone, which inhibited the secretion of several cytokines from activated microglia more than haloperidol, and indications of clozapine-specific effects have also been reported. Moreover, in the context of the kynurenine pathway, one animal study demonstrated that chronic treatment with antipsychotic drugs reduces brain KYNA. Meyer et al. reviewed the influence of antipsychotic treatment on peripheral cytokines in clinical populations and found that antipsychotics reduced the level of proinflammatory cytokines (IL-1β, IL-6, sIL-6R, TNF-α) while increasing peripheral production of anti-inflammatory substances such as (sIL-1RA, sIL-2R and IL-10). Here, SGAs seemed to have the most pronounced effects and a possible relation between the ability to normalize immune function and clinical effects were identified.” [e]

The rest of this post will focus on pharmacological interventions.

Schematic diagram depicting opportunities for anti-inflammatory drug interventions in schizophrenia. A) Current monotherapy with antipsychotics after disease onset. B) Future treatment based on patient stratification and targeting the inflammatory status at early onset and throughout the disease progression. This is based on the premise that treatment of schizophrenia patients with anti-inflammatory drugs in combination with antipsychotics will lead to symptom improvement. This evidence has come from adjunctive treatment studies using aspirin (Laan et al, 2010 and Weiser et al, 2012), the selective COX-2 inhibitor celecoxib (Muller et al, 2004, Muller et al, 2010, and Akhondzadeh et al, 2007), N-acetylcysteine ( Berk et al., 2008 ) and minocycline, an antibiotic with anti-inflammatory and neuroprotective properties targeting microglia (Sommer et al., 2014 ).

Aspirin, estrogen, EPO, minocycline, N-acetylcysteine, neurosteroids, melatonin, lipoic acid, omega-3 PUFAs, other anti-inflammatory interventions and antioxidants have all been suggested as early interventions [1, 2]

N-acetylcysteine shows promise as a relatively safe intervention. One study found a mediator effect of duration of illness on response/treatment outcome:

Towards stage specific treatments: effects of duration of illness on therapeutic response to adjunctive treatment with N-acetyl cysteine in schizophrenia.

Schizophrenia is a chronic and often debilitating disorder in which stage of illness appears to influence course, outcome, prognosis and treatment response. Current evidence suggests roles for oxidative, neuroinflammatory, neurotrophic, apoptotic, mitochondrial and glutamatergic systems in the disorder; all targets of N-acetyl cysteine (NAC). A double blind, placebo controlled trial suggested NAC to be beneficial to those diagnosed with schizophrenia. The current manuscript aims to investigate duration of the illness as a key factor that may be modulating the response to NAC in the participants who took part in the study. A sample of 121 participants were randomised in a double fashion to 24 weeks (placebo=62; NAC=59). Clinical and functional variables were collected over the treatment period. Duration of the illness at baseline was grouped into <10 years, 10-<20 years and >20 years. Mixed Model Repeated Measures Analysis was used to explore the effect of illness duration on response to treatment with NAC. A significant interaction between duration of the illness and response to treatment with NAC was consistently found for positive symptoms and functional variables, but not for negative or general symptoms or for side effect related outcomes. The pattern of changes suggests that this mediator effect of duration of illness in response to treatment is more evident in those participants with 20 years or more of illness duration. Our results suggest a potential advantage of adjunctive NAC over placebo on functioning and positive symptoms reduction in those patients with chronic schizophrenia. This has potential for suggesting stage specific treatments.

“In accordance with the staging model, progressive neurobiological abnormalities occur over the course of schizophrenia. Our results are consistent with the broader theoretical model of neuroprogression, potentially mediated by free radical-mediated neurotoxicity, inflammation, apoptotic pathways, mitochondrial dysfunction or neurogenesis in schizophrenia on which antioxidant therapeutic strategies such as NAC may counteract some of the effects which contribute to persistent schizophrenic symptomatology and complications of its treatment In that regard NAC has been shown to potentially impact on oxidative biology, both by increasing glutathione levels and directly scavenging free radicals. It has also shown to decrease pro-inflammatory cytokines, reverse models of
mitochondrial toxicity, reduce apoptosis and enhance neurogenesis, factors also pertinent to the persistent pathophysiological progression of schizophrenia .The effects derived from chronicity in terms of the progression of oxidative stress imbalance may provide a substrate on which NAC may be more effective with its correspondent implications for response. Interestingly results from this study provide new insights into the plausible underlying mechanisms which may help to clarify the outcomes of the main trial, which improved global measures of psychopathology (including total, general and negative components of the PANSS) but failed to report beneficial effects on positive symptoms for the group of patients as a whole  Beneficial effects of NAC, particularly in positive symptoms, might be mediated by the duration of the illness. NAC may replenish GSH, counteracting oxidative stress and modulating glutamate receptors which have been linked to thepresence of negative symptoms thus diminishing its severity over the course of the illness. Positive symptoms have been related to dopaminergic dysfunction which according to the immune-inflammatory-glutamate dysfunction hypothesis would be more persistent on relapse or chronic states. Stage of illness may thus have an impact on treatment response to adjunctive treatment with antioxidants such as NAC.With regard to the staging paradigm, our results add to the notion that differential treatment response may occur in the different stages of the illness. With conventional antipsychotics, patients in the earlier stages of the illness appear to have a better response to treatmentEven though this raises the possibility that the primary reason for the higher efficacy of NAC in late stages of SZ might be that antipsychotics are relatively effective at alleviating the symptoms in early-stage patients, thereby obscuring any beneficial effects of NAC in this subgroup. That treatment with NAC seems to be more effective in individuals with long-standing symtoms suggests that it might be operating on the pathways to neuroprogression rather than the primary dopaminergic abnormality that antipsychotics target. This might be due to the reviewed evidence of greater damage secondary to oxidative stress with greater chronicity, which might suggest a greater substrate on which NAC might work.Results derived from this study may thus shed light on the plausible biological substrate that underlies illness progression and on the use of potential adjunctive treatments such as NAC that may counteract functional outcomes at different stages. Although more research on specific metabolic pathways on which NAC may interact is required, our data supports thehypothesis that NAC may have an impact on the pathways to neuroprogression in schizophrenia. The results derived from this study bring us closer to both more personalised approaches by defining a clinical pathological model of staging in psychosis by shedding light on the biological impact of adjunctive treatment with NAC on symptomatological and functional outcomes of the illness.

In our sample NAC has shown to be an effective treatment at an advanced stage of the disorder when response to treatment may be hard to be observed constituting an ideal and safe treatment option to reverse long-term disability of chronic patient”

On potential prophylactic interventions with N-acetylcysteine:
Early detection and intervention are key principles in clinical medicine and psychiatry. In this issue of Neuron, Cabungcal et al. (2014) demonstrate that prophylactic treatment with antioxidants in adolescence prevents adult deficits in a rat model relevant to schizophrenia.

Abnormal development can lead to deficits in adult brain function, a trajectory likely underlying adolescent-onset psychiatric conditions such as schizophrenia. Developmental manipulations yielding adult deficits in rodents provide an opportunity to explore mechanisms involved in a delayed emergence of anomalies driven by developmental alterations. Here we assessed whether oxidative stress during presymptomatic stages causes adult anomalies in rats with a neonatal ventral hippocampal lesion, a developmental rodent model useful for schizophrenia research. Juvenile and adolescent treatment with the antioxidant N-acetyl cysteine prevented the reduction of prefrontal parvalbumin interneuron activity observed in this model, as well as electrophysiological and behavioral deficits relevant to schizophrenia. Adolescent treatment with the glutathione peroxidase mimic ebselen also reversed behavioral deficits in this animal model. These findings suggest that presymptomatic oxidative stress yields abnormal adult brain function in a developmentally compromised brain, and highlight redox modulation as a potential target for early intervention.

In an animal model myelin maturation, glutathione level and redox regulation deficits were “reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors” [2]

Activation of the HPA-axis may mediate oxidative stress via glucocorticoids

Minocycline administration carries a more extensive side-effect profile and is unlikely to be a recommended intervention during prodromal stages (where transition to psychosis is uncertain) . It is likely best left as an intervention for first-episode psychosis:
“…minocycline may protect against gray matter loss and modulate fronto-temporal areas involved in the pathophysiology of schizophrenia. Furthermore, minocycline add-on treatment may be a potential treatment in the early stages of schizophrenia and may ameliorate clinical deterioration and brain alterations observed in this period.” [3].
“Treatment with the antibiotic minocycline (3mg/kg/day) normalized microglial cytokine production in the hippocampus and rescued neurogenesis and behavior. We could also show that enhanced microglial TNF-α and IL-1β production in the hippocampus was accompanied by a decrease in the pro-proliferative TNFR2 receptor expression on neuronal progenitor cells, which could be attenuated by minocycline. These findings strongly support the idea to use anti-inflammatory drugs to target microglia activation as an adjunctive therapy in schizophrenic patients.” [3b]

Perhaps the safest intervention is omega-3 PUFAs:
“In a clinical randomized controlled trial (RCT) by Amminger et al., a markedly decreased progression rate to psychosis was found in at risk subjects receiving high-dose polyunsaturated fatty acids (PUFAs). PUFAs are involved in the myelination process, and peripheral PUFA levels have been found to be decreased in schizophrenia. A recent DTI study in early-phase psychosis patients found an association between level of PUFAs in peripheral erythrocytes and white matter integrity. Possibly, PUFA distribution is altered in patients at risk for psychosis, with a link between PUFA levels and white matter integrity. Free radicals can damage membrane PUFAs, and disturbances in fatty acids and membrane phospholipid identified in patients with schizophrenia may be caused by increased oxidative stress according to a review by Yao and Keshavan. The same authors point to disruption of antioxidative systems related to schizophrenia, with reduced amounts of non-enzymatic plasma antioxidant components [e.g., albumin, bilirubin, uric acid, ascorbic acid (vitamin C), α-tocopherol (vitamin E)], see also the recent clinical study by Zhang et al. demonstrating a reduced plasma total antioxidant status in a sample of schizophrenia patients. Interestingly, PUFAs also have mild anti-inflammatory effects”
“Compared to placebo, ω-3 PUFAs’ significant effects on the amplitude of the reduction in General and Total PANSS scores are evident after the first four weeks of treatment; a reduction of positive symptoms and a lower mean PANSS positive score were apparent after eight weeks, whereas the significant drop in negative symptoms and the significant change and higher mean scores in global functioning occur later at 12weeks. The delay of onset of ω -3 PUFAs seems comparable to that of antipsychotics and antidepressants.” [4]
On the contrary, a combination of omega-3 PUFAs and α-lipoic acid was not found to be a suitable alternative to antipsychotics in the longer term prevention of relapse after first episode psychosis:
“We found no evidence that ω-3 PUFAs+α-LA could be a suitable alternative to maintenance antipsychotic treatment in relapse prevention, in this small study. Antipsychotic discontinuation after a single episode of schizophrenia carries a very high risk of relapse, and treatment guidelines endorsing this practice should be revised.” [5]
That said, adjunct treatment with omega-3 PUFAs alongside antipsychotics may have benefits:
“…supplemental omega-3 might increase efficacy of conventional antipsychotics in decreasing symptoms of schizophrenia. Low price, rare adverse reactions and availability of omega-3 made this substance a potential supplement in improved treatment of schizophrenia” [6]

Initial research indicates that pregnenolone may be a promising option. Pregnenolone is relatively safe but more research is needed to confirm whether it is an effective approach as an early intervention therapy.
“Neurosteroids perform a variety of actions that impact critical brain functions such as modulation of inhibitory GABAergic and excitatory glutamatergic neurotransmitter systems, myelination, reduction of apoptosis, and reduction of inflammatory responses. Pregnenolone and its metabolite pregnenolone sulfate, belong to the group of neurosteroids found in high concentrations in certain areas in the brain which positively modulate excitatory glutamatergic NMDA receptors. Pregnenolone administration results in elevations in downstream neurosteroids, such as allopregnanolone, a molecule with neuroprotective effects that also increases neurogenesis, decreases apoptosis and inflammation (thus its downstream anti-inflammatory function), modulates the hypothalamic-pituitary-adrenal axis, and markedly increases GABA (A) receptor responses. Pregnenolone and its sulfate ester are under investigation for their potential to improve cognitive and memory functioning. Emerging preclinical and clinical evidence suggests pregnenolone may be a promising novel therapeutic candidate in schizophrenia.” [7]

⇒ For a review of microglial abnormalities in schizophrenia and therapeutic interventions:

Microglial Abnormalities in the Pathophysiology of Schizophrenia

The etiology of schizophrenia remains unclear while, in many aspects, the neuropathology of schizophrenia has recently been reported to be closely associated with microglia dysfunction. Microglia, which are the major players of innate immunity in the CNS, respond rapidly to even minor pathological changes in the brain and contribute directly to neuroinflammation by producing various pro-inflammatory cytokines and free radicals. Recent human studies have revealed microglial activation in schizophrenia using postmortem brains or in vivo neuroimaging techniques. We and other researchers have recently shown the inhibitory effects of some antipsychotics on the release of inflammatory cytokines and free radicals from activated microglia, both of which have recently been known to cause the synaptic pathology, a decrease in neurogenesis, and white matter abnormalities often found in the brains of patients with schizophrenia. In addition, recent evidence strongly suggests a neurodevelopmental role of microglia in regulating synapse formation/function by their interaction with synapses and phagocytotic activity. It is not known whether microglia dysfunction and microglia-orchestrated neuroinflammation are the primary cause of schizophrenia but they are closely related to the progression and outcomes of schizophrenia. Understanding microglial pathology may shed new light on the therapeutic strategies for schizophrenia.

Role of Microglial M1/M2 Polarization in Relapse and Remission of Psychiatric Disorders and Diseases

Psychiatric disorders such as schizophrenia and major depressive disorder were thought to be caused by neurotransmitter abnormalities. Patients with these disorders often experience relapse and remission; however the underlying molecular mechanisms of relapse and remission still remain unclear. Recent advanced immunological analyses have revealed that M1/M2 polarization of macrophages plays an important role in controlling the balance between promotion and suppression in inflammation. Microglial cells share certain characteristics with macrophages and contribute to immune-surveillance in the central nervous system (CNS). In this review, we summarize immunoregulatory functions of microglia and discuss a possible role of microglial M1/M2 polarization in relapse and remission of psychiatric disorders and diseases. M1 polarized microglia can produce pro-inflammatory cytokines, reactive oxygen species, and nitric oxide, suggesting that these molecules contribute to dysfunction of neural network in the CNS. Alternatively, M2 polarized microglia express cytokines and receptors that are implicated in inhibiting inflammation and restoring homeostasis. Based on these aspects, we propose a possibility that M1 and M2 microglia are related to relapse and remission, respectively in psychiatric disorders and diseases. Consequently, a target molecule skewing M2 polarization of microglia may provide beneficial therapies for these disorders and diseases in the CNS.

Possible roles of the cannabinoid receptors in M1/M2 polarization of microglia. 2-AG released from M1 microglia promotes production of pro-inflammatory cytokines and mediators by M1 microglia via CB1 and then induces down-regulation of CB1. On the other hand, 2-AG stimulates M2 polarization of microglia via CB2. Subsequently, M2 microglia can produce IL-10 and anti-inflammatory/pro-resolving lipid mediators (resolvin D1 and lipoxin A4). – See more at:
 CB2 receptor agonism may provide a novel approach as an early intervention to target schizophrenia-related pathology [8, 9, 10] and protect the CNS from deleterious immune alterations [11]. This may be an approach that is devoid of significant side effects and deserves further investigation.

L-type voltage-gated calcium channels have been found to modulate microglial pro-inflammatory activity and may be an attractive target for therapeutics [12]

Microglial intracellular Ca2+ signaling as a target of antipsychotic actions for the treatment of schizophrenia

Microglia are resident innate immune cells which release many factors including proinflammatory cytokines, nitric oxide (NO) and neurotrophic factors when they are activated in response to immunological stimuli. Recent reports show that pathophysiology of schizophrenia is related to the inflammatory responses mediated by microglia. Intracellular Ca2+ signaling, which is mainly controlled by the endoplasmic reticulum (ER), is important for microglial functions such as release of NO and cytokines, migration, ramification and deramification. In addition, alteration of intracellular Ca2+ signaling underlies the pathophysiology of schizophrenia, while it remains unclear how typical or atypical antipsychotics affect intracellular Ca2+ mobilization in microglial cells. This mini-review article summarizes recent findings on cellular mechanisms underlying the characteristic differences in the actions of antipsychotics on microglial intracellular Ca2+ signaling and reinforces the importance of the ER of microglial cells as a target of antipsychotics for the treatment of schizophrenia.

Pharmacological MAGL inactivation may be an effective protective strategy:

“…monoacylglycerol lipase (MAGL) inactivation robustly preserved myelin integrity and suppressed microglial activation in the cuprizone-induced model of T-cell-independent demyelination. These findings suggest that MAGL blockade may be a useful strategy for the treatment of immune-dependent and -independent damage to the white matter.” [13]

Vitamin D

Vitamin D may play a role in the pathogenesis of psychiatric illness [14]. Multiple relevant neurotransmitter pathways, immune function and inflammation are all influenced by vitamin D status [15] Developmentally vitamin D deficient animals show increased behavioural deficits in a NMDA antagonist model of schizophrenia and “a transient vitamin D deficiency has a long-lasting effect on NMDA-mediated signalling in the rodent brain and may be a plausible candidate risk factor for schizophrenia and other neuropsychiatric disorders. [16] Clinical trials are underway to determine if antipsychotic induced weight gain may be related to a vitamin D deficiency [17]

1,25(OH)2D3 has a direct effect on neural stem cell proliferation, survival, and neuron/oligodendrocyte differentiation, thus representing a novel mechanism underlying its remyelinating and neuroprotective effect.

Controlling hyperhomocysteinemia

In patients with hyperhomocysteinemia, adjunctive administration of B Vitamins [a complex of folic acid, cobalamin (B12), and pyridoxine (B6)] produced improvements in neurocognitive outcomes over placebo.

See more:

Dietary and nutritional therapies for schizophrenia

Biomarker Symptom Profiles for Schizophrenia and Schizoaffective Psychosis (2015)

Role of Inflammation in Psychiatric Disease (2015)