Clozapine discontinuation – some experiences and a new animal model of schizophrenia

It’s four days today since I stopped clozapine (50mg at night). Some rebound insomnia was expected but it’s proving to be more problematic than I’d hoped. That, coupled with the activating effects of aripiprazole (30mg) has left me quite sleep deprived but thankfully not psychotic. It’s a fine line though… one I don’t want to cross yet another time. I attempted to sleep on doxylamine (25mg) but even that was ineffective, giving me a fragmented drowsiness but no proper sleep.

A case of rebound insomnia (on ceasing 75mg) has been reported [1]:

“Rebound insomnia has been reported upon discontinuation of benzodiazepines. We describe the first case of a sleep polygraphically documented rebound insomnia with an unusual somatic fatigue syndrome after long-term use of clozapine in a 30-year-old schizophrenic male. The withdrawal symptoms occurred the first day after drug discontinuation and could be stopped by readministering clozapine. In our opinion, the sudden occurrence of the withdrawal symptoms cannot be explained by a dopaminergic hypersensitivity or a cholinergic rebound, but indicates an involvement of GABAergic and perhaps antiglutamatergic properties of clozapine.”

The whole aim was to avoid getting back on any sedating/weight gaining antipsychotics (which is the next step if I can’t sleep) so I’ll persist with doxylamine for a few nights and maybe see if melatonin can help ‘reset’ things.

Update: Doxylamine (50mg) on the fourth night was slightly more effective but I still only had a broken sleep. Doxylamine (50mg) and melatonin (10mg) on the fifth night resulted in a more solid sleep.

More severe withdrawal symptoms have also been reported  “withdrawal symptoms for clozapine can be severe with rapid onset of agitation, abnormal movements, and psychotic symptoms” [2] The authors in this article concluded: “The severe agitation and psychotic symptoms after clozapine withdrawal in these three patients were due to delirium, perhaps the result of central cholinergic rebound. The withdrawal symptoms and delirium resolved rapidly with resumption of low doses of clozapine. Severe withdrawal symptoms can probably be avoided by slowly tapering clozapine and/or simultaneously substituting another psychotropic with high anticholinergic activity”.

Interestingly:

Diurnal neurobiological alterations after exposure to clozapine in first-episode schizophrenia patients.

Irregular circadian rhythm and some of its most characteristic symptoms are frequently observed in patients with schizophrenia. However, changes in the expression of clock genes or neuropeptides that are related to the regulation of circadian rhythm may influence the susceptibility to recurrence after antipsychotic treatment in schizophrenia, but this possibility has not been investigated. Blood samples were collected from 15 healthy male controls and 13 male schizophrenia patients at 4h intervals for 24h before and after treatment with clozapine for 8 weeks. The outcome measures included the relative expression of clock gene mRNA PERIOD1 (PER1), PERIOD2 (PER2), PERIOD3 (PER3) and the levels of plasma cortisol, orexin, and insulin. Compared with healthy controls, schizophrenia patients presented disruptions in diurnal rhythms of the expression of PER1, PER3, and NPAS2 and the release of orexin, accompanied by a delayed phase in the expression of PER2, decreases in PER3 and NPAS2 expression, and an increase in cortisol levels at baseline. Several of these disruptions (i.e., in PER1 and PER3 expression) persisted after 8 weeks of clozapine treatment, similar to the decreases in the 24-h expression of PER3 and NPAS2. Clozapine treatment for 8 weeks significantly decreased the 24-h levels of PER2 and increased the 24-h levels of insulin. These persistent neurobiological changes that occur after 8 weeks of clozapine treatment may contribute to the vulnerability to recurrence and efficacy of long-term maintenance treatment in schizophrenia.

It’s interesting to see an animal model of schizophrenia using abrupt clozapine withdrawal, this one implicating changes in GABA release on discontinuation of clozapine [3 [full text]]:

“Schizophrenia disease models are necessary to elucidate underlying changes and to establish new therapeutic strategies towards a stage where drug efficacy in schizophrenia (against all classes of symptoms) can be predicted. Here we summarise the evidence for a GABA dysfunction in schizophrenia and review the functional neuroanatomy of five pathways implicated in schizophrenia, namely the mesocortical, mesolimbic, ventral striopallidal, dorsal striopallidal and perforant pathways including the role of local GABA transmission and we describe the effect of clozapine on local neurotransmitter release. This review also evaluates psychotropic drug-induced, neurodevelopmental and environmental disease models including their compatibility with brain microdialysis. The validity of disease models including face, construct, etiological and predictive validity and how these models constitute theories about this illness is also addressed. A disease model based on the effect of the abrupt withdrawal of clozapine on GABA release is also described. The review concludes that while no single animal model is entirely successful in reproducing schizophreniform symptomatology, a disease model based on an ability to prevent and/or reverse the abrupt clozapine discontinuation-induced changes in GABA release in brain regions implicated in schizophrenia may be useful for hypothesis testing and for in vivo screening of novel ligands not limited to a single pharmacological class.”

Hopefully my experiences will be transient and resolve on their own but management of clozapine discontinuation is an area that needs careful consideration.  If anyone has any experiences with clozapine discontinuation and how they managed any rebound phenomena, please feel free to share.

My trials with supplements for schizophrenia

I’m abandoning my trials with most supplements – they simply have not demonstrated any substantial improvements to my health. I did everything I could to research and try and treat my schizophrenia, believing current antipsychotics were not going to be that effective… Time for a new phase in my life. Wish me luck!

My subjective experiences were:

Longer trials:

L-lysine 6g/day added to clozapine for several months: No decline in auditory hallucinations. No benefits over clozapine alone on total symptomatology. See more
Pregnenolone 100mg/day added to clozapine and aripiprazole for many months: Perhaps a slight improvement in anxiety and negative symptoms. No effect on positive symptoms See here and here [review]
DHEA 100mg/day added to clozapine and aripiprazole for many months: Improvement in negative symptoms. Increase in energy and improvement in depressive symptoms. Some subjective prosocial improvements. Worth further investigation. See here and here [review]
DHEA + Pregnenolone 100mg each added to clozapine and aripiprazole for several months. Perhaps slightly synergistic. Improvement in negative and depressive symptoms.
D-serine 2g bd added to clozapine + aripiprazole for a couple of months: no significant improvement in positive symptoms nor any notable cognitive improvement. Potentially a slight improvement in negative symptoms? There was perhaps a slight decline in cognition, particularly with regard to attention span, on ceasing.
Sodium benzoate + D-serine see here

[A] patient noted rapid improvements in cognition and mood when 1g sodium benzoate tds was added to 2g/day D-serine but this was not trialed for a long period. 500mg sodium benzoate b.d. and D-serine 1g b.d. was as effective as 2g D-serine b.d. but the subjective beneficial effects were minimal in both cases, even on prolonged administration. No subjective improvement in positive symptoms or cognition was noted but there was a slight (?) improvement in negative symptoms.

Sodium benzoate – Slightly activating/mild antidepressant effects at all doses used. see here

One patient with sub-therapeutic levels of clozapine, also taking therapeutic doses of aripiprazole failed to find benefit from 1g sodium benzoate added once daily. Replicating the 2013 study by using 500mg b.d. may be more effective.

L-theanine 400mg added to various antipsychotics: improvement in agitation and attention span. Slight anxiolytic effect. Worth further investigation. See more here and here
Sarcosine 2g/day added to various antipsychotics: Dose dependent improvement in concentration (worsening of concentration at higher doses). Acute effects included an improvement in mood. See more here and here
N-acetylcysteine ~3g/day addded to clozapine and aripiprazole: No improvement in positive or negative symptoms. Abnormal LFTs potentially attributed to its use? Really bad flatulence. See more
Acetyl-l-carnitine 5g/day added to clozapine: No notable antidepressant effects despite the claims. Abandoned due to ending up smelling like trimethylamine. See more
Oral lavender oil (80mg +): effective for mild anxiety. See more here
Raw cacao powder 15-30g/day: no notable benefits
Fish oil – 2.7g omega-3 daily ~1 year: No notable benefits?
Combination: Fish oil (2.7g omega-3), aspirin (600mg), curcumin (600mg), coenzyme Q10 (150mg), vitamin E (1000IU), ascorbic acid (2500mg), vitamin D (1000IU), vitamin B12 (1mg), folic acid (5mg), full spectrum multivitamin/B complex and dietary nitrate (8mmol, twice daily) added to aripiprazole 30mg/day resulted in an almost complete attenuation of my auditory hallucinations

Shorter trials:

Sunifiram (20mg acute) added to various antipsychotics: no notable improvements in memory. Slight improvement in attention span and positive symptoms. Improvement in agitation associated with aripiprazole. See more here
Galantamine: 6-20mg nocte: improvement in sustained concentration and memory recall at higher doses. Worth further investigation. See more here
Pregabalin see here
Phenibut 750mg – 1g: Dramatic improvement in the intensity of auditory hallucinations. Acute anxiolytic and antidepressant effects. Worth further investigation. See more here
Agmatine 3g/day added to clozapine and aripiprazole for several weeks: No substantial antidepressant effects. No reduction in total symptomatology. See here
Oxytocin added to clozapine and aripiprazole:

I’ve tried buccal (200IU) and intranasal oxytocin at various doses (exceeding 24IU) and for periods of up to a couple of weeks in the past without noticing anything subjectively. I was more focused on improving negative affect, most particularly relating to loneliness and didn’t specifically try to evaluate improvements in social cognition. My social skills are pretty crappy and I have an autism spectrum condition which adds to my social impairments.

See more [review]

Please note: Most of these trials were done while on a high dose of a SNRI (venlafaxine 375mg/day – I have comorbid TRD). Also note that some trials overlapped.

To conclude, I’d say the most promising leads are galantamine for attention/cognitive symptoms, GABA-B agonism (via phenibut in my case, which also binds to the α2-δ subunit of voltage-dependent calcium channels [1]) for auditory hallucinations, L-theanine for anxiety and activation symptoms, GlyT1 inhibition via sarcosine for attention and depressive symptoms (dose dependent), DHEA for negative and depressive symptoms and pregabalin or oral lavender oil for anxiety. Sunifiram and ampakines deserve further research. I did not notice much improvement from NMDAR glycine site modulation with D-serine or DAAO inhibition with sodium benzoate but recommend further research in the area. D-serine shows encouraging potential, particularly for individuals at high risk for FEP, see here.

30mg of aripiprazole – some experiences. Tackling cravings? The DAergic effects of stress?

It’s interesting to be on a higher (30mg/day) dose of aripiprazole. That said, my mind is all over the place and the agitation is somewhat relieved by a blog post… Time for a bit of ‘catharsis’…

While aripiprazole has high affinity for D2 receptors, it has low intrinsic efficacy (from 25-30% of DA to only about 6% under ‘ideal antipsychotic therapy), acting as a partial agonist. It is also a partial agonist at the 5-HT1A receptor, antagonises 5-HT2A and 5-HT7 receptors and acts as a partial agonist at the 5-HT2C receptor, with high affinity. Aripiprazole has been touted as a “dopamine system stabiliser” because in vivo studies demonstrate that it reduces dopamine release via presynaptic agonism to behave as a functional antagonist of some postsynaptic D2 receptors and as an agonist at others. D2/D3 receptor occupancy ranged from 40% (at 0.5 mg/day) to 95% (at 30 mg/day) and binding rates are high throughout the brain [1, 2].

Aripiprazole: from pharmacological profile to clinical use

 …a strong correlation exists between aripiprazole dose and plasma levels. They state that dopamine receptor occupancy appears to reach a plateau at doses above 10 mg and suggest that, from dose-response studies, the optimal dose of aripiprazole may be 10 mg/day. However, this refers to prolonged treatment with the drug, whereas the point we make here relates to the use of aripiprazole in an acute setting in association with symptom exacerbation, a condition that may be sustained by an overt activation of the dopaminergic system. Hence, as illustrated…, a higher dose of aripiprazole [30mg] will be necessary to compete with dopamine and blunt receptor activation.

Subjective experiences:

The lower doses (5-20mg) were slightly activating but lacked any substantial additional effect on positive symptoms when combined with clozapine (at subtherapeutic levels). One big positive was the effect it seemed to have on clozapine-induced weight gain, as I’ve detailed here. Thankfully, I’m coming off the clozapine and don’t mind a few side effects from the aripiprazole (so far)…

While the higher dose is associated with some pretty activating effects and potentially some slight akathisia, it initially showed promise in treating my auditory hallucinations [3]. Some stress related to study and other challenging situations has precipitated a slight decline in its efficacy towards positive symptoms (and a subjective increase in dissociation [4]). Initially there were some improvements in mood but my affect is quite labile and I’ve sunk into a few really dark places, too. Nothing unmanageable as yet (also on venlafaxine 375mg/day).

Impulsivity is slightly increased and there is slight disinhibition (likely amplified by the acute effects of the increase in pregabalin to 150mg tds).

I can’t rule out a decrease in clozapine as being a factor in these changes, nor can I rule out an increase in pregabalin as another confounding variable. The pregabalin does slightly improve the aripiprazole-induced agitation but if it continues at this intensity, it could soon be problematic.

My attention span is poor, potentially worse than on the lower doses of aripiprazole. Hopefully I can work on that somehow…

Patients with a low striatal D2/3 receptor binding potential (BPp) have a better treatment response than patients with a high BPp. Functioning may decline at high levels of dopamine receptor blockade [including partial agonism] [5].

Substance cravings and self-medication

Being a D2 partial agonist, I’m particularly interested to see how it goes for substance cravings. The activating effect has really increased my desire for nicotine and caffeine (both indirectly DAergic, the latter potentially having an effect on striatal D2/D3 receptor availability [6]) which seem to be calming. Theanine (400mg) is slightly helpful for alleviating the agitation [7, 8].

On that:

Revisiting the ‘self-medication’ hypothesis in light of the new data linking low striatal dopamine to comorbid addictive behavior.

Persons with schizophrenia are at a high risk, almost 4.6 times more likely, of having drug abuse problems than persons without psychiatric illness. Among the influential proposals to explain such a high comorbidity rate, the ‘self-medication hypothesis’ proposed that persons with schizophrenia take to drugs in an effort to cope with the illness and medication side effects. In support of the self-medication hypothesis, data from our earlier clinical study confirmed the strong association between neuroleptic dysphoria and negative subjective responses and comorbid drug abuse. Though dopamine has been consistently suspected as one of the major culprits for the development of neuroleptic dysphoria, it is only recently our neuroimaging studies correlated the emergence of neuroleptic dysphoria to the low level of striatal dopamine functioning. Similarly, more evidence has recently emerged linking low striatal dopamine with the development of vulnerability for drug addictive states in schizophrenia. The convergence of evidence from both the dysphoria and comorbidity research, implicating the role of low striatal dopamine in both conditions, has led us to propose that the person with schizophrenia who develops dysphoria and comorbid addictive disorder is likely to be one and the same.

“…we have experimentally induced neuroleptic dysphoria, following dopamine depletion using α-methylparatyrosine (AMPT) in a group of medication-free persons with schizophrenia who have consistently experienced dysphoria upon administration of antipsychotic medications [Voruganti et  al. 2001]. Our dopamine depletion single photon emission computed tomography (SPECT) study proved to be the first to link emerging dysphoria to striatal dopamine binding ratio. Details of the study design, as well as complete results, are outlined in a previous publication [Vorguanti et al. 2001]. Additionally, observations over the subsequent 48 hours allowed us to note the cascade of subjective and behavioral events that followed dopamine depletion, which served as the experimental equivalent of dopamine blockade by antipsychotic. The severity of dysphoric responses inversely correlated with the incremental changes in D2 receptor binding ratios (r=-0.82, p< 0.01). Such observations provided for the first time an explanation of why not every patient receiving antipsychotic medications develops neuroleptic dysphoria. Only those patients who have lower dopamine receptor functioning to start with seem to be more vulnerable to the blocking effect of potent dopamine D2 antagonists which, in turn, further impairs striatal dopamine functioning. A number of other neuroimaging studies added more confirmation to our findings in support of the role of low striatal dopamine in the genesis of dysphoric responses [de Haan et al.2006; Mizrahi et  al. 2009]. Additionally, observing the cascade of events that followed dopamine depletion over the next 48 hours, the earliest behavioral change noted was the altered subjective state, which was experienced just a few hours after ingestion of the medication [Voruganti and Awad, 2006]. Such an experimental finding is consistent with clinical observations of patients experiencing dysphoric response as early as a few hours after ingesting the medication [Awad and Hogan, 1985]. Additionally, our data revealed that the phenomenon of neuroleptic dysphoria is not simply an affective change, but is more complex and includes motor, cognitive and motivational components.”

  • Reduction in dopamine D2 receptor binding has also been associated with enhanced impulsivity in rats, a mechanism implicated in the genesis of addictive behavior

“…recent data suggest that persons with schizophrenia and comorbid drug abuse suffer from combined dysfunction: increased dopamine sensitivity in the area of the striatum more responsible for psychotic symptoms and the reduced sensitivity to dopamine-release in the striatal region associated with reward and enforcement. The interpretation of such important findings is that such alterations in dopamine release could initiate a vicious circle of using drugs to self-medicate, which in turn can only worsen the psychotic symptoms. Such reported blunting of dopamine release in all striatal regions in persons with schizophrenia and comorbid drug abuse can also explain the reported frequent association of vulnerability to addictive behavior and the development of neuroleptic dysphoria, as we reported earlier”

“Such new information also has implications for the choice of the antipsychotic medication used for treatment of psychosis with comorbid drug abuse. The preference for choosing an antipsychotic in such a situation needs to be based on the pharmacological properties of medications, selecting an antipsychotic which has low potency for dopamine D2 antagonism or an antipsychotics that does not stay long on the dopamine receptor, so as not to further impair striatal dopamine functioning [Samaha, 2014; Awad, 2012]. Chronic dopamine blockade can lead to postsynaptic upregulation, which in turn enhances the reinforcement properties of drugs of abuse. Such new information can explain the reported beneficial effects of medications such as clozapine [Green et al. 2008] or other new atypical antipsychotics, such as olanzapine [Littrell et  al. 2001] and risperidone [Smelson et al. 2002]. Aripiprazole being an agonist/antagonist is expected theoretically to be a useful antipsychotic in such situations; however, results from the ongoing clinical trials are not yet available.”

“Based on recent data demonstrating the role of low striatal dopamine in the genesis of neuroleptic-induced dysphoria as well as comorbid vulnerability for addictive states, we propose that the person with schizophrenia experiencing negative subjective and dysphoric responses can be one and the same who develops vulnerability to comorbid addictive states. Such a new formulation not only adds basic clarification about the link between both conditions, but provides neurobiological support of the ‘self-medication hypothesis’. As subjective and dysphoric neuroleptic responses are the earliest experiences following ingestion of the antipsychotic medication, it is possible that such subjective negative responses can serve as an early clinical marker for potential development of vulnerability to addictive states. Similarly, it underscores the importance of choosing an antipsychotic appropriate to such clinical situations ( i.e. an antipsychotic which is not a strong dopamine D2 blocker) in order to not further compromise dopamine striatal functioning. Such a new understanding also clarifies why not many patients with schizophrenia and comorbid drug abuse treated with the potent dopamine D2 blockers, such as haloperidol, have been rarely able to exert adequate control over their addictive behavior. It also highlights the urgent need to re-examine the process of development of new antipsychotics by establishing comorbid substance abuse in schizophrenia as possibly a new indication for medication development.”

Stress and Dopamine

A recent review has been published:

The Dopaminergic Response to Acute Stress in Health and Psychopathology: A Systematic Review

“Stress-induced dorsal striatal DAergic activity may reflect the somatosensory experience induced by the stressor, but also involvement in active avoidance behavior or cognitive aspects of stress. The experience of stress, however, seems to be more directly related to mPFC DAergic activity, serving as a threat evaluation system, and ventral striatal DAergic activity, possibly related to expectations about the stressor. In dysregulated stress-systems, preliminary results indicate a blunted striatal DAergic response in pain-related disorders and cannabis use and an augmented striatal DAergic response in psychosis. However, the scarcity of studies, modest sample sizes and inconsistent findings prevent any firm conclusions.”

Some areas covered:

  • The healthy ventral striatal response: Whereas the dorsal striatal DA response seems to be associated with the sensory and affective properties related to the stressor itself, DAergic activity in the ventral striatum varies with subjective expectations about the stressor. Only when controlled for pain-specific components does an increase in ventral striatal DAergic activity become apparent, which correlates with pain, stress-related negative affect and fear
  • The healthy extrastriatal response: DAergic activity here was positively associated with subjective stress ratings and heart rate, directly relating this response to experiential and physiological measures of stress. As with the striatal response, DAergic activity in the mPFC might be valence-unspecific
  • In individuals who reported low maternal bonding, and are assumed to be at risk for a broad range of psychopathology, psychological stress increased DAergic activity in the ventral striatum.
  • Results partly affirm increased stress-related dorsal striatal DAergic activity in the psychosis spectrum. The mixed results within the striatum are unexpected considering the solid evidence for aberrant striatal DAergic functioning in psychosis in combination with the well-validated putative link between stress and psychosis
  • In cortical areas, no main effect of stress has been reported in the psychosis spectrum

A recent study [9] found a widespread DAergic deficit extending to many cortical and extrastriatal regions including the midbrain in schizophrenia, with blunted DA release potentially affecting frontal cortical function

Restoring a healthy gut?

It’s becoming more apparent that my gastrointestinal system is about as healthy as my mental health. Clozapine has worsened already problematic constipation and the high protein diet that I’m using to combat weight gain certainly hasn’t helped that, nor the excessive (highly malodourous) flatulence. A month on a general probiotic initially seemed promising but it seems I need to further modify my diet. Even on the high protein diet, once again, I’m gaining weight. Food cravings are extreme and I wake up in the middle of the night – essentially on autopilot aka ‘clozapined’ – to eat…

I would say I’ve never really had a well functioning GI system and with all the research pointing to the role of the microbiome and brain-gut axis in health and illness, it’s time to see if I can change that with some simple and safe dietary modifications.

Basically, I’m considering continuing the probiotic and adding prebiotics, additional soluble fibre and enriching my diet with polyphenols to align with a more ancient and traditional one:

“Comparisons of the modern Western-style diet (WSD) with more ancient and traditional diets are helping to redefine the paradigm of malnutrition. Malnutrition is no longer restricted to the lack of certain essential nutrients, but also encompasses over nutrition and aberrant nutrient ratios and profiles. The WSD is typified by altered fat profiles with elevated saturated fats and synthetic trans-fatty acids compared to essential fatty acids and unsaturated fatty acids (mono- and polyunsaturated) and low availability of saturated fats in more traditional diets. The WSD is also defined by high levels of refined carbohydrates or sugars as opposed to traditional diets where foods enriched with complex, lowly digestible highly fermentable carbohydrates (e.g., fiber and prebiotics) form staples and support a saccharolytic, SCFA-producing gut microbiota. For proteins too, major differences occur between WSD and more traditional diets and foods, with amino acid composition and profile of foods being altered by industrial food-processing technologies. The WSD has largely replaced plant polyphenols as preservatives and to a lesser extent flavorings with chemical substitutes and finally, modern foods have substituted the phylogenetically diverse and numerically dense microbial food passengers found on traditional fermented and raw foods with monocultures of strains selected for technological purposes or more commonly, with sterility. Within the human “super-organism,” nowhere are the metabolic consequences of this altered nutritional environment more obvious than in the interactions between the gut microbiome and host energy metabolism and brain function. We have known for a while now that the gut microbiome and its interactions with diet plays a critical role in energy homeostasis and immune tolerance. We have linked aberrant gut microbiota profiles with diseases of immune function or autoimmune diseases and metabolic diseases like obesity, diabetes and non-alcoholic fatty liver disease. However, only very recently has altered brain development been considered a consequence of our closely co-evolved gut microbiome being out of step with our modern diet.” [1]

1. The probiotic

I’m using a clinically tested 26 billion CFU probiotic (Bifidobacterium lactis HOWARU HN019 5 billion CFU, BI-04 10.5 billion CFU; Lactobacillus acidophilus La-14 10.5 billion CFU).

“There are some studies showing effects of probiotics on brain function in healthy humans. For example, women who had taken a fermented milk product containing four probiotics (Bifidobacterium animalis subsp. lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp. lactis) showed reductions in brain responses to an emotional task, particularly in sensory and interoceptive regions that were measured with functional magnetic resonance imaging. Moreover, in another study, global psychological distress and anxiety symptoms, as measured by the Hospital Anxiety and Depression Scale, were improved in the group taking a Lactobacillus and Bifidobacterium-containing probiotic compared with those taking a matched control product. Importantly, probiotic supplementation of the mother during and after pregnancy has been shown to alter the infant’s microbiota. There is a need for future trials focusing on the best combinations of probiotic strains, the timing of administration, and whether these probiotics are more efficacious in conjunction with prebiotics. Also the mechanisms of action of probiotics are understudied and further investigating why certain bacterial strains have positive effects on brain health will be an important area into the future.” [1]

Recently, a randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood provided “…the first evidence that the intake of probiotics may help reduce negative thoughts associated with sad mood” [2]

Gut microbiota modulation and implications for host health: Dietary strategies to influence the gut–brain axis
Gut microbiota modulation and implications for host health: Dietary strategies to influence the gut–brain axis

2. The prebiotic

“Prebiotics are nondigestible food ingredients that selectively stimulate the growth of probiotic bacteria such as Lactobacilli and Bifidobacteria in the gut. Increasing the proportion of these bacteria with prebiotics such as galactooligosaccharides or fructooligosaccharides has many beneficial effects on the gut, the immune system, and on brain function, specifically, increased BDNF expression and NMDA receptor signaling, providing initial support for further investigations of the utility of prebiotics in mental health and potential treatment of psychiatric disorders. Recently, a human study has shown that subjects supplemented with galactooligosaccharides displayed a suppression of the neuroendocrine stress response and an increase in the processing of positive versus negative attentional vigilance, showing an early anxiolytic-like profile. Inulin-type fructans and lactulose modulate gut transit, decrease putrefactive activity within the gut lumen, prevent GI infections, and mitigate inflammatory responses” [3]

I’m using inulin:

“Inulin and oligofructose are considered as functional food ingredients since they affect the physiological and biochemical processes in rats and human beings, resulting in better health and reduction in the risk of many diseases. Experimental studies have shown their use as bifidogenic agents, stimulating the immune system of the body, decreasing the pathogenic bacteria in the intestine, relieving constipation, decreasing the risk of osteoporosis by increasing mineral absorption, especially of calcium, reducing the risk of atherosclerosis by lowering the synthesis of triglycerides and fatty acids in the liver and decreasing their level in serum. These fructans modulate the hormonal level of insulin and glucagon, thereby regulating carbohydrate and lipid metabolism by lowering the blood glucose levels; they are also effective in lowering the blood urea and uric acid levels, thereby maintaining the nitrogen balance. Inulin and oligofructose also reduce the incidence of colon cancer.” [4]

Even at doses as low as 2.5 g twice a day, inulin can exert a prebiotic effect in healthy volunteers by stimulating bifidobacteria growth. [5] Doses of 5-40g have been used for therapeutic purposes: 10 g per day for lowering triglycerides to upward of 40 g per day for relieving constipation. It has been reported that prehistoric foragers in the Chihuahuan Desert ate a diet which contained upward of 135 grams of inulin-like fructans [6].

“An inulin dose of 5–8 g/d should be sufficient to elicit a positive effect on the gut microbiota. One possible side effect of prebiotic intake is intestinal discomfort from gas production. However, bifidobacteria and lactobacilli cannot produce gas as part of their metabolic process. Therefore, at a rational dose of up to 20 g/d, gas distension should not occur. If gas is being generated, then the carbohydrate is not acting as an authentic prebiotic. This is perhaps because dosage is too high and the prebiotic effect is being compromised, i.e., bacteria other than the target organisms are becoming involved in the fermentation.” [7]

In overweight adults, treatment with galactooligosaccharides induced “favorable” changes in gut microbial composition, increased secretory IgA levels, and reduced inflammation and measures of the metabolic syndrome [8]

10g of inulin tastes fine mixed in with a protein shake.

3. Polyphenols etc:

I’m using raw cocoa [cacao] powder. It is known to be rich in polyphenols, such as catechin, epicatechin, procyanidin B2 (dimer), procyanidin C1 (trimer), cinnamtannin A2 (tetramer), and other oligometric procyanidins [9] It has numerous health benefits and provides caffeine and theobromine [10]. I’m using a dose of 30g/day [380kJ, 6.4g protein, 7.6g carbohydrate]

“Cocoa is a food relatively rich in polyphenols, which makes it a potent antioxidant. Due to its activity as an antioxidant, as well as through other mechanisms, cocoa consumption has been reported to be beneficial for cardiovascular health, brain functions, and cancer prevention. Furthermore, cocoa influences the immune system, in particular the inflammatory innate response and the systemic and intestinal adaptive immune response. Preclinical studies have demonstrated that a cocoa-enriched diet modifies T cell functions that conduce to a modulation of the synthesis of systemic and gut antibodies. In this regard, it seems that a cocoa diet in rats produces changes in the lymphocyte composition of secondary lymphoid tissues and the cytokines secreted by T cells. These results suggest that it is possible that cocoa could inhibit the function of T helper type 2 cells, and in line with this, the preventive effect of cocoa on IgE synthesis in a rat allergy model has been reported, which opens up new perspectives when considering the beneficial effects of cocoa compounds. On the other hand, cocoa intake modifies the functionality of gut-associated lymphoid tissue by means of modulating IgA secretion and intestinal microbiota.” [11]

4. Supplemental dietary fibre

NOTE: In case of medication-induced constipation, caution is required when increasing fibre intake.

“Dietary fibers pass through the upper intestine and are fermented by large-bowel anaerobic microbiota to produce SCFAs. SCFAs promote gut epithelial integrity and exert immune effects, including stimulation of G protein–coupled receptors, promotion of innate (Toll-like receptor 2) immune responses, and induction of regulatory T cells” [8]

I’m sticking with psyllium husk in divided doses. I’ve found it has better effects for alleviating constipation when it’s mixed with water and a macrogol 3350 sachet.

I’ll see how it goes!


See also:

A role for the microbiome in schizophrenia?

Dietary glycemic index as a modulator of behavioral and biochemical abnormalities?

Immunomodulatory Effects of Probiotic Supplementation in Schizophrenia Patients: A Randomized, Placebo-Controlled Trial.

The gut microbiota and inflammatory noncommunicable diseases: Associations and potentials for gut microbiota therapies

Gut microbiota modulation and implications for host health: Dietary strategies to influence the gut–brain axis

Host microbiota constantly control maturation and function of microglia in the CNS