A focus on nAChRs

While I have the ability to focus for short periods (and jump from thing to thing well!), sustained attention and general cognitive inflexibility are things that I really struggle with, leading to further problems in sustaining goal-directed activity.  I’m trying to work on them non-pharmacologically but that is easier said than done…

I believe there are avenues worthy of further exploration:

  • In a recent trial, encenicline (an α7 nAChR partial agonist) was generally well tolerated and demonstrated clinically meaningful improvements in cognition and function in patients with schizophrenia [1].
  • Preliminary findings with CDP-choline (citicoline) [Examine] in a healthy, schizophrenia-like surrogate sample are consistent with a α7 nAChR mechanism and support further trials with it as a pro-cognitive strategy [2]. Healthy adolescent males receiving 28 days of citicoline showed improved attention and psychomotor speed and reduced impulsivity [3].
  • Galantamine, a potent allosteric potentiating ligand of nAChRs, has produced neurocognitive benefits in only one study with schizophrenia patients. Buchanan et al. found that galantamine improved working memory and verbal learning over placebo in 86 schizophrenia patients while no other study has found good evidence of its procognitive benefits [4]. That said, “cholinergic agents, in particular galantamine and nicotine, appear to have the most promising cognitive enhancing effects in schizophrenia patients” [5].
  • DMXB-A:

    “3-(2,4-dimethoxy-benzylidene)-anabaseine (DMXB-A) is an a-7 nicotinic receptor partial agonist that demonstrated positive benefits on neurocognitive functions—particularly attention—in a proof of-concept study that used a randomized, double-blind, cross-over design to study 12 schizophrenia patients. However, in the phase II study, Freedman et al. found no benefits of DMXB-A over placebo on neurocognition in 31 patients with schizophrenia. They attributed the failure of the phase II trial to the possibility that strong practice effects across the study arms may have obscured any DMXB-A benefits on neurocognition.” [4]

Some recent articles:

Positive allosteric modulators of alpha 7 nicotinic acetylcholine receptors reverse ketamine-induced schizophrenia-like deficits in rats.

Alpha 7 nicotinic acetylcholine receptors (α7-nAChRs) have generated great interest as targets of new pharmacological treatments for cognitive dysfunction in schizophrenia. One promising recent approach is based on the use of positive allosteric modulators (PAMs) of α7-nAChRs, which demonstrate several advantages over direct agonists. Nevertheless, the efficacy of these newly introduced α7-nAChR agents has not been extensively characterised in animal models of schizophrenia. The aim of the present study was to evaluate the efficacy of type I and II PAMs, N-(5-chloro-2,4-dimethoxyphenyl)-N’-(5-methyl-3-isoxazolyl)urea (PNU-120596) and N-(4-chlorophenyl)-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide (CCMI), respectively, and galantamine, an acetylcholinesterase inhibitor (AChE) that also allosterically modulates nAChRs, against ketamine-induced cognitive deficits and social withdrawal in rats. The orthosteric α7-nAChR agonist octahydro-2-methyl-5-(6-phenyl-3-pyridazinyl)-pyrrolo[3,4-c]pyrrole (A-582941) was used as a positive control. Additionally, the antipsychotic activities of the tested compounds were assessed using the conditioned avoidance response (CAR) test. PNU-120596, CCMI, galantamine and A-582941 reversed ketamine-induced cognitive inflexibility, as assessed in the attentional set-shifting task (ASST). The tested compounds were also effective against ketamine-induced impairment in the novel object recognition task (NORT). PNU-120596, CCMI, and A-582941 ameliorated ketamine-induced social interaction deficits, whereas galantamine was ineffective. Moreover, all tested compounds selectively suppressed the CAR. The positive allosteric modulation of α7-nAChRs demonstrates preclinical efficacy not only against schizophrenia-like cognition impairments but also positive and negative symptoms. Therefore, the use of α7-nAChR PAMs as a potential treatment strategy in schizophrenia is supported.

Disruptions of executive function, including attentional deficits, are a hallmark of a number of diseases. Acetylcholine in the prefrontal cortex (PFC) regulates attentive behaviour; however the role of α7 nicotinic acetylcholine receptor (α7nAChRs) in attention is contentious. In order to probe attention we trained both wild type and α7nAChR knockout mice on a touchscreen based 5-choice serial reaction time task (5-CSRT). Following training procedures we then tested sustained attention using a probe trial experiment. To further dissect the role of specific nicotinic receptors in attention we then tested the effects of both α7nAChR and β2nAChR agonists on the performance of both wild type and knockout mice on the 5-CSRT task. At low doses, α7nAChR agonists improved attentional performance of wild-type mice, while high doses had deleterious effects on attention. α7 nAChR knockout mice displayed deficits in sustain attention that were not ameliorated by α7nAChR agonists. However, these deficits were completely reversed by the administration of a β2nAChR agonist. Furthermore, administration of a β2nAChR agonist in α7 nAChR knockout mice elicited the same biochemical response in the prefrontal cortex as the administration of α7nAChR agonists in wild type mice. Our experiments reveal an intricate relationship between distinct nicotinic receptors to regulate attentional performance and provide the basis for targeting β2nAChRs pharmacologically to decrease attentional deficits due to α7nAChR dysfunction.

Other cholinergics

  • Rivastigmine and donepezil have similarly failed to demonstrate benefits as neurocognitive enhancers in schizophrenia in several placebo-controlled trials. In a 12-week open-label trial, Chung et al. found that 28 schizophrenia patients who received up to 10 mg/day of donepezil as an adjunct to atypical antipsychotics demonstrated improvements in attention, memory, psychomotor speed, and mental set-shifting. [4].

See more here


Metabolic syndrome and obesity among users of second generation antipsychotics: A global challenge for modern psychopharmacology (2015)

Having experienced weight gain side effects from clozapine, it’s nice to see some progress being made towards ameliorating them… I’m particularly impressed by the authors in depth discussion of the potential use of phytochemicals. I’ve included some highlights.

Metabolic syndrome and obesity among users of second generation antipsychotics: A global challenge for modern psychopharmacology

Second generation antipsychotics (SGAs), such as clozapine, olanzapine, risperidone and quetiapine, are among the most effective therapies to stabilize symptoms schizophrenia (SZ) spectrum disorders. In fact, clozapine, olanzapine and risperidone have improved the quality of life of billions SZ patients worldwide. Based on the broad spectrum of efficacy and low risk of extrapyramidal symptoms displayed by SGAs, some regulatory agencies approved the use of SGAs in non-schizophrenic adults, children and adolescents suffering from a range of neuropsychiatric disorders. However, increasing number of reports have shown that SGAs are strongly associated with accelerated weight gain, insulin resistance, diabetes, dyslipidemia, and increased the cardiovascular risk. These metabolic alterations can develop in as short as six months after the initiation of pharmacotherapy, which is now a controversial fact in public disclosure. Although the percentage of schizophrenic patients, the main target group of SGAs, is estimated in only 1% of the population, during the past ten years there was an exponential increase in the number of SGAs users, including millions of non-SZ patients. The scientific bases of SGAs metabolic side effects are not yet elucidated, but the evidence shows that the activation of transcriptional factor SRBP1c, the D1/D2 dopamine, GABA2 and 5HT neurotransmitions are implicated in the SGAs cardiovascular toxicity. Polypharmacological interventions are either non- or modestly effective in maintaining low cardiovascular risk in SGAs users. In this review we critically discuss the clinical and molecular evidence on metabolic alterations induced by SGAs, the evidence on the efficacy of classical antidiabetic drugs and the emerging concept of antidiabetic polyphenols as potential coadjutants in SGA-induced metabolic disorders.

“…we summarized the results of 20 clinical studies and three preclinical studies, assessing the efficacy of pharmacological interventions (i.e. metformin, nizatadine, orlistat, ranitidine, topiramate, etc.) against SGA-induced metabolic side effects. This summarized evidence shows that one out of five studies with metformin resulted in negative results. The other four positive studies concluded that weight gain, insulin resistance can be efficiently controlled, but lipid profile may even worsen. Metformin reduced body weight in clozapine-treated patients, but its beneficial effects disappeared after discontinuing this medication. Orlistat in overweight/obese clozapine-or olanzapine-treated patients failed to prevent obesity and lipid accumulation, which suggest that the intestinally absorbed lipids may not be relevant for SGAs-induced obesity. Atomoxetine, a selective norepinepherine reuptake inhibitor with appetite suppressant activity, was not effective in preventing obesity in patients treated with olanzapine and clozapine.”

  • With respect to the serotoninergic hypothesis, the interventions with fluoxetine also failed. The use of sertraline in clozpaine-induced weight gain resulted in cardiac death in rodents.
  • Tetradecylthioacetic acid (TTA), a modified fatty acid, recently showed a minor protective effect against hypertriglyceridemia, but failed to prevent weight gain induced by clozapine in rodents.
  • Berberine, a natural alkaloid, inhibited in vitro adipogenesis and SREBP-1 overexpression induced by clozapine and risperidone in 3T3 adipocytes: “Berberine is an example of an antidiabetic phytochemical with potential protective effect against lipid accumulation induced by clozapine.”
  • Resveratrol and green tea, showed some efficacy in decreasing weight gain and fat mass accumulation induced by olanzapine in rodents.

“Our group and others have demonstrated that specific polyphenols from dietary sources ameliorate insulin resistance, inflammation and obesity.”

  • Anthocyanins, a family polyphenols, have shown significant clinical effect in improving insulin sensitivity in obese, nondiabetic, insulin-resistant patients.

“Polyphenols are family of polar compounds found in fruits and vegetables, they have been popular for their potent antioxidant effect, but in the past 5 years increasing evidence has shown that, anthocyanins, a specific category of polyphenols, are effective in ameliorating obesity and insulin resistance.

The mode of action and pharmacokinetic profile of these compounds is not yet fully elucidated and their bioavailability after oral administration is a matter of continuous controversy. However, there is robust evidence on their efficacy in cardiometabolic problems. Kurimoto et al. reported that anthocyanins from black soy bean increased insulin sensitivity via the activation of AMP-activated protein kinase (AMPK) in skeletal muscle and liver of in type 2 diabetic mice. AMPK, a regulator of glucose and lipid metabolism in liver and muscle cells, is inhibited by olanzapine, which may contribute to the olanzapine-induced hepatic lipid accumulation. Anthocyanins also display insulin-like effects even after intestinal biotransformation.

We have previously demonstrated that anthocyanins ameliorate signs of diabetes and metabolic syndrome in obese mice fed with a high fat diet have. Delphinidin 3-sambubioside-5-glucoside (D3S5G), an anthocyanin from Aristotelia chilensis, is as potent as Metformin in decreasing glucose production in liver cells, and it displays insulin-like effect in liver and muscle cells. The anti-diabetic mode of action of anthocyanins have been associated with the transcriptional down-regulation of the enzymes PEPCK and G6P gene in hepatocytes. Prevention of adipogenesis is also another reported mechanmis for some anthocyanins from Aristotelia chilensis. Anthocyanins also induce significant increase in circulating levels of adiponectin in murine models of MetS. This is relevant, since adiponectin is reduced in clozapine-treated patients and weight reduction is associated with higher circulating levels of adiponectin. In a recent study Roopchand et al., demonstrated that blueberry anthocyanins are as potent as metformin in correcting hyperglycemia and obesity in obese hyperglyceminc mice. Dietary anthocyanins have also proven efficacy in decreasing les of the inflammatory mediators PAI-1 and retinol binding protein 4 in obesity and type 2 diabetes . Recent medical and nutritional studies suggest that anthocyanins from diverse dietary sources are potent anti-diabetic, anti-obesity and cardioprotective molecules. Another fact that makes anthocyanins candidates for preventing clozapine-induced lipogenesis is that they are capable of suppressing the inflammatory response through targeting the phospholipase A2, PI3K/Akt and NF-kappaB pathways. These pre-clinical findings were corroborated by clinical evidence showing the dietary anthocyanins from blueberries improve insulin resistance in young obese, non-diabetic adults. The clinical efficacy of polyphenols in SGAs-induced MetS has not yet been established, but a recent pre-clinical demonstrated that, resveratrol, a polyphenol found in grapes, decreases olanzapine-induced weight gain.”

Some  polyphenols showing positive outcomes for diabetes, obesity and metabolic syndrome [see article for more information]:

Purified anthocyanins 160 mg  twice a day
Cinnamon extract 250 mg, twice a day
Whole  blueberries 22.5 g twice a day
Resveratrol 150 mg
Pomegranate juice 1.5 mL/Kg
Raisins (Vitis vinifera) 36 g/day
Green tea extract 375 mg  (270mg catechins) per day

See more:

Attenuating antipsychotic-induced weight gain and metabolic side effects

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.

GlyT1 inhibitors

GlyT1 inhibitors may be useful for the treatment of cognitive dysfunction and the negative symptoms of schizophrenia without having undesirable central nervous system side effects [1]. Similarly, GlyT1 inhibition is a potential therapeutic strategy in addressing the symptom domains of autism spectrum conditions [2].

Based on an animal model (reduced Sp4 expression in mice), GlyT1 inhibition may have promise in treating attentional deficits in neuropsychiatric patients but not learning or motivational deficits [3]:

“…by using this model relevant to schizophrenia, we demonstrated that GlyT-1 inhibition (Org 24598) significantly reversed the attentional but not learning or motivational deficits of these mice. Interestingly, GlyT-1 inhibition impaired the attention of WT littermate mice without affecting their learning or motivation. These data support GlyT-1 inhibition as a potential treatment for attentional but not positive valence deficiencies (negative symptoms) related to schizophrenia as well as a U-shape dose response of optimal synaptic glycine levels for attentional performance.”

That said:

“…the inability of GlyT1-inhibition to remediate behaviors relevant to negative symptoms is surprising given that: (1) lower plasma and cerebrospinal fluid glycine level of patients with schizophrenia is linked to negative symptoms (Hashimoto et al, 2003); and (2) glycine treatment (although chronic) modestly lowers negative symptom ratings (Heresco-Levy et al, 1999; Javitt et al, 1994). However, such positive findings have not always been reproduced (Buchanan et al, 2007). In fact, Roche recently stopped trials testing a GlyT-1 inhibitor for the improvement of negative symptoms in schizophrenia, perhaps due in part to the sole reliance on clinical rating scales rather than objective translational laboratory tests as primary outcome measures. Testing negative symptoms using laboratory-based measures with relevance to those presented here may provide more relevant cross-species findings (Barnes et al, 2014; Der-Avakian et al, 2013; Young et al, 2013b) and greater sensitivity to the effects of GlyT-1 inhibitors. Constitutively reducing Sp4 expression in mice resulted in impaired attention that was remediated by GlyT-1 inhibition. The finding that this treatment did not remediate motivational deficits suggests that the attentional deficits of Sp4 mice are unlikely a result of altered motivation or learning. The lack of effect on motivation could be because of a requirement of longer treatment duration, although it improved attention acutely. Alternatively, more direct NMDAR1 activation may be required. Furthermore, the mechanism(s) underlying impaired motivation and learning resulting from reduced Sp4 expression have yet to be delineated. As SP4 regulates the transcription of NMDA receptor subunits GluN1, GluN2A, and GluN2B (Priya et al, 2014; Priya et al, 2013), further investigation of other mechanisms using these mice is warranted.

In conclusion, reduced Sp4 expression in mice largely recreates the attentional deficits observed in patients with schizophrenia as measured by the 5C-CPT (Young et al, 2013a). These data support pairing attentional assessment with evidence of reduced SP4 levels in peripheral blood mononuclear cells, as seen in first-episode patients with schizophrenia (Fuste et al, 2013). Such an approach might provide a useful personalized biomarker for predicting whether GlyT-1 inhibition may remediate attentional deficits in individual patients. However, such treatment would unlikely treat impaired positive valence related to reward anticipation. SP4 rare copy number variations and reduced protein levels are linked to several psychiatric disorders that exhibit attentional deficits including schizophrenia, bipolar disorder, and major depressive disorder (Pinacho et al, 2011; Shi et al, 2011; Tam et al, 2010; Zhou et al, 2009). Hence, identifying the mechanism(s) of how reducing Sp4 levels negatively affect attention and the neurobiology underlying GlyT-1 inhibition-induced reversal of these effects will prove vital. Importantly though, the present work using this model organism provides opportunities for personalized medicine for the treatment of attentional deficits in neuropsychiatric patients having low SP4 levels (McMahon and Insel, 2012).”

Sarcosine, a simple GlyT-1 inhibitor, has demonstrated some promising potential [4, 5]. Some worsening of symptoms has been noted at doses in excess of 2000mg [6] and a case of hypomania has been reported [7]. Antidepressant effects have also been reported [8].

Regulation of GlyTs:

BDNF, acting on TrkB receptors, inhibits glycine uptake in astrocytes by promoting GlyT internalization through a Rho-GTPase activity dependent mechanism [9]. GSK3β is important for stabilising and/or controlling the expression of functional GlyTs on the neural cell surface [10].

A soon to be published article may be of interest:

Inhibition of glycine transporter 1: The yellow brick road to new schizophrenia therapy?

While pharmacological blockade of dopamine D2 receptor can effectively suppress the psychotic or positive symptoms of schizophrenia, there are no satisfactory medication for the negative and cognitive symptoms of schizophrenia in spite of the proliferation of second generation antipsychotic drugs. Excitements over a new class of third generation antipsychotics that might possibly fill this urgent medical need have been prompted by the recent development of glycine transporter 1 (GlyT1) inhibitors. The impetus of this novel pharmacological strategy stems directly from the prevailing hypothesis that negative and cognitive symptoms are attributable to the hypofunction of glutamatergic signalling via the N-methyl-D-aspartate (NMDA) receptor in the brain. Inhibition of GlyT1 reduces clearance of extra-cellular glycine near NMDA receptor-containing synapses, and thereby increases baseline occupancy of the glycine-B site at the NR1 subunit of the NMDA receptor, which is a prerequisite of channel activation upon stimulation by the excitatory neurotransmitter glutamate. Pharmacological inhibition of GlyT1 is expected to boost NMDA receptor function and therefore alleviate persistent negative and cognitive symptoms without excessive risk of excitotoxicity associated with direct NMDA receptor agonists. The recently completed phase III clinical trials of the Roche compound, bitopertin (a.k.a. RG1678 or RO-4917838) had initially raised hope that this new class of drugs might represent the first successful translation of the glutamate hypothesis of schizophrenia to the clinic. However, the outcomes of the multi-centre bitopertin clinical trials have been disappointing. The present review seeks to examine this promise through a critical survey of the latest clinical and preclinical findings on the therapeutic potential of GlyT1 inhibition or down-regulation [link out]

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

Levothyroxine Augmentation in Clozapine Resistant Schizophrenia: A Case Report and Review (2015)

Levothyroxine Augmentation in Clozapine Resistant Schizophrenia: A Case Report and Review

There are many reports that show different thyroid abnormalities in schizophrenia without clear establishment of their role in etiology and treatment outcome of schizophrenia. Among these reports, there are only a few that consider a role for thyroid hormones as augmenting agents in the treatment with antipsychotic drugs. This case report outlines symptom subsidence of a patient with clozapine refractory paranoid schizophrenia and normal thyroid function who added levothyroxine to clozapine and found that symptoms of psychosis returned once levothyroxine was discontinued. Although this observation needs to be confirmed in controlled clinical trials, we aimed to discuss possible hypothesized mechanisms underlying this observation.

“The patient was hospitalized with a confirmed diagnosis of refractory paranoid schizophrenia, and clozapine was administered with a gradually increasing dose, up to 600 mg per day. After six weeks, she was significantly calmer with lower anxiety and aggression, her sleep quality had improved, and her appetite had increased. However, she was still experiencing social withdrawal, persecutory and reference delusions, and visual hallucinations. Despite good drug adherence, psychosis continued four months after discharge. Afterwards, without our knowledge, the mother, who had hypothyroidism, advised the patient to use levothyroxine (at a dose of 0.1 mg per day) in addition to clozapine. After two weeks with this treatment, hallucinations and delusions completely subsided, and the patient’s social relations improved. When we were informed, discontinuation of levothyroxine was advised, given her normal thyroid tests. About three weeks after the removal of levothyroxine, psychosis symptoms gradually reappeared (despite still taking clozapine). The patient was again experiencing hallucinations and delusions.”

“About 30–36% of patients with chronic schizophrenia have abnormal thyroid tests, but, in clinical terms, they are euthyroid. These abnormalities may disappear following successful treatment of schizophrenia and may also have a correlation with treatment response to antipsychotics. For instance, it has been observed that higher T3 serum levels in patients with chronic schizophrenia are related to their better cognitive functions and lower extrapyramidal drug side effects. It has also been seen that high basal TSH is associated with poorer response and blunted TSH response to thyrotropin releasing hormone (TRH) and a high level of T4 before treatment with better response to treatment. T4 levels before treatment are also positively correlated with severity of the disorder. Although the results of studies are contradictory, they mostly cite increased total and free T4 in patients with schizophrenia before treatment and their normalization after treatment”

Augmentation with pregabalin in schizophrenia

Augmentation with pregabalin in schizophrenia.

Anxiety is a core symptom of schizophrenia that elicits significant subjective burden of disease and contributes to treatment resistance in schizophrenia. Anxious syndromes might be attributed to incompletely remitted delusions, the negative syndrome, depressive episodes, panic attacks, social phobia, avoidance after hospitalization, and down-tapering of benzodiazepine medication. Pregabalin, an antagonist at the alpha2delta subunit of voltage-gated Ca channels, modulates several neurotransmitter systems and was found to alleviate anxiety in different mental disorders. In schizophrenia, this treatment option has not been evaluated before.Here, we report a case series of 11 schizophrenic patients who had treatment-resistant anxiety and received augmentation with pregabalin. This observational analysis reveals that the strategy was able to significantly reduce scores on the Hamilton anxiety scale; furthermore, we observed improvements of psychotic positive and negative symptoms and mood as assessed by Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, and Calgary Depression Scale for Schizophrenia. After augmentation, both a complete discontinuation of concomitant benzodiazepine treatment as well as a dose reduction of antipsychotics could be achieved. We did not observe pharmacokinetic interactions or adverse events.These observations suggest that treating anxious syndromes in schizophrenia with pregabalin can be effective and tolerable. Further investigations should differentiate schizophrenic subsyndromes of anxiety and evaluate benefits and risks of pregabalin in comparison to placebo and active competitors.


panss pregabalin

Pregabalin was started with 75 mg/d and raised according to clinical necessity to a mean dose of 313.6 mg/d after a mean observation period of 6.7 weeks. Serum levels were assessed in a subgroup of 5 patients (mean dose, 375 mg/d; mean serum level, 1.7 mg/L). We observed improvements of anxiety (HAMA: P = 0.007, t16.9 = 3.041, effect size = 1.2) and mood (CDSS P = 0.002, t17.3 = 3.754, effect size = 1.6) (Fig. 1A). In addition, psychotic positive (PANSS positive: P = 0.009, t16.1 = 2.962, effect size = 1.3), negative (PANSS negative: P = 0.093, t17.7 = 1.773, effect size = 0.8; and SANS: P = 0.076, t19.1 = 1.875, effect size = 0.8), and global psychopathology (PANSS global psychopathology: P <= 0.000, t19.526 = 4.948, effect size = 2.1) responded, resulting in significantly decreased total PANSS scores (P <= 0.000, t16.6 = 4.326, effect size = 1.8) (Fig. 1B). In particular, partially remitted formerly treatment-resistant psychotic symptoms responded to the add-on of pregabalin.

Pregabalin may also be effective in treating alcohol dependence [1] Rarely, pregabalin-associated elevation of clozapine serum levels have been reported [2, 3]

I’d like to hear from anyone who has used pregabalin as an augmentation strategy in schizophrenia.

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

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


Sex differences in incidence, onset and course of schizophrenia suggest sex hormones play a protective role in the pathophysiology. Such a role is also proposed for oxytocin, another important regulator of reproduction function. Evidence on the efficacy of sex hormones and oxytocin in the treatment of schizophrenia is summarized.


Double-blind, placebo-controlled, randomized studies were included, examining augmentation with estrogens, selective estrogen receptor modulators (SERMs), testosterone, dehydroepiandrosterone (DHEA), pregnenolone, and oxytocin. Outcome measures were total symptom severity, positive and negative symptom subscores, and cognition. In meta-analyses, combined weighted effect sizes (Hedges’ g) per hormone were calculated.


Twenty-four studies were included, examining 1149 patients. Significant effects were found for estrogen action (k = 10), regarding total symptoms (Hedges’ g = 0.63, p = 0.001), positive (Hedges’ g = 0.42, p < 0.001), and negative symptoms (Hedges’ g = 0.35, p = 0.001). Subgroup analyses yielded significant results for estrogens in premenopausal women (k = 6) for total, positive, and negative symptoms, and for the SERM raloxifene in postmenopausal women (k = 3) for total and negative, but not positive symptoms. Testosterone augmentation in males (k = 1) was beneficial only for negative symptoms (Hedges’ g = 0.82, p = 0.027). No overall effects were found for DHEA (k = 4), pregnenolone (k = 4), and oxytocin (k = 6). Results for cognition (k = 12) were too diverse for meta-analyses, and inspection of these data showed no consistent benefit.


Estrogens and SERMs could be effective augmentation strategies in the treatment of women with schizophrenia, although potential side effects, partially associated with longer duration use, should be taken into account. Future trials are needed to study long-term effects and effects on cognition.

Meta-analysis of estrogen action augmentation on total symptom severity. Studies above the red line used estrogens (in premenopausal women, and in one study in men), and studies below the red line used raloxifene (in postmenopausal women).

Meta-analysis of dehydroepiandrosterone (DHEA) augmentation on total symptom severity

Meta-analysis of pregnenolone augmentation on total symptom severity.

Meta-analysis of oxytocin augmentation on total symptom severity.

“Cognitive results were available for studies on estrogens, DHEA, pregnenolone, and oxytocin, with most studies describing several cognitive domains. Raw data per domain or composite scores were sparse, therefore meta-analyses could not be performed. Memory was most frequently tested (ten studies), significant effects were observed in three studies: raloxifene improved verbal learning more than placebo (Huerta-Ramos et al., 2014), pregnenolone improved visual memory (Ritsner et al., 2010), and verbal memory was higher in the oxytocin versus placebo group (Feifel et al., 2012). Executive function, attention, and processing speed were each examined in seven studies. Significant improvements relative to placebo were found in executive functioning after pregnenolone (Kreinin et al., 2014), in visual attention after DHEA (Ritsner et al., 2010) and pregnenolone (Kreinin et al., 2014), and in processing speed after pregnenolone (Ritsner et al., 2010). Five studies examined visuospatial, constructional, and movement skills; significant effects were found only for DHEA (Ritsner et al., 2006a and Ritsner et al., 2006b). One study examined verbal fluency and found a significant effect of raloxifene on phonemic fluency (Huerta-Ramos et al., 2014). Social cognition was examined in five studies; two studies on oxytocin found significant effects for second order false belief identification (Pedersen et al., 2011) and fear recognition and perspective taking (Gibson et al., 2014).”

“In conclusion, hormonal augmentation strategies are an interesting direction in the development of new treatment methods for schizophrenia. Especially estrogen augmentation in women warrants further investigation, as beneficial effects on total, positive and negative symptom severity were found. However, risks of side effects of estrogens, partially associated with longer duration use, should be taken into account. For this reason, SERMs may serve as a favorable alternative for estrogens that is also appropriate for use in men. Testosterone could be effective in reducing negative symptom severity in men, but this finding needs replication. The precursors DHEA and pregnenolone do not seem to be of therapeutic value for schizophrenia, neither does oxytocin. Regarding cognition, some promising results were found for each of the studied hormones. Future research is needed to carefully examine the therapeutic effects of hormone augmentation, especially in the long term and effects on cognition, as new treatment strategies could emerge from which patients with schizophrenia may benefit.”

See also:

Neurosteroids as therapeutics