Tackling negative/cognitive symptoms and other novel treatments

See other reviews:

From the schizophreniaresearch.org.au library:

Table 1
New Targets to Help Different Symptom Domains:  Current treatments for schizophrenia, although effective for positive symptoms, have not proven as effective for negative symptoms and cognitive dysfunction. Additional strategies, such as combining antipsychotics or adding adjunctive agents to antipsychotics, have also yielded disappointing results in both negative and cognitive symptom domains. However, the N-methyl-d-aspartate (NMDA) receptor hypofunction hypothesis, with its focus on the glutamate system’s effect on dopamine, can explain the positive, negative, and cognitive symptoms in schizophrenia. Therapeutic targets are being explored that focus on NMDA receptors (eg, glycine, d-serine), glycine reuptake inhibition (such as sarcosine and bitopertin), and, through a different pathway, α-7 nicotinic acetylcholine receptor agonism (eg, encenicline).

Wikipedia: Adjunctive agents in Schizophrenia

The Role of Cognitive Enhancement in Schizophrenia

Putative neuroprotective agents in neuropsychiatric disorders

Molecular Targets for Treating Cognitive Dysfunction in Schizophrenia

Psychopharmacological Treatment of Neurocognitive Deficits in People with Schizophrenia: A Review of Old and New Targets

Addressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options.

Augmentation strategies in patients with schizophrenia who show partial response to clozapine treatment

Management of Negative Symptoms in Schizophrenia: Looking Positively

Pharmacotherapy of cognitive deficits in schizophrenia

Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment.

cognitive enhancement schizophrenia.JPG


Efficacy of Anti-inflammatory Agents to Improve Symptoms in Patients With Schizophrenia: An Update

“Of these components, aspirin (mean weighted effect size [ES]: 0.3, n = 270, 95% CI: 0.06-0.537, I(2) = 0), estrogens (ES: 0.51, n =262, 95% CI: 0.043-0.972, I(2) = 69%), and N-acetylcysteine [NAC] (ES: 0.45, n = 140, 95% CI: 0.112-0.779) showed significant effects. Celecoxib, minocycline [a, b, review and meta-analysis], davunetide, and fatty acids showed no significant effect. Conclusion: The results of aspirin addition to antipsychotic treatment seem promising, as does the addition of NAC and estrogens. These 3 agents are all very broadly active substances, and it has to be investigated if the beneficial effects on symptom severity are indeed mediated by their anti-inflammatory aspects.”


One review concluded that “the benefits with NSAID augmentation are, perhaps, too small to be clinically meaningful

Is there evidence for any clinical benefits of anti-inflammatory medications?

“Moderate to high quality evidence suggests small to medium benefits of adjunctive non-steroidal anti-inflammatory medications for reducing symptoms of schizophrenia.”

Adjunctive treatment with lisdexamfetamine dimesylate [1] or modafinil [2] is promising for improving negative symptoms but in some cases, may worsen positive symptoms. A systematic review and meta-analysis of randomized controlled trials for modafinil or armodafinil augmentation of antipsychotics found some small-sized benefits, concluding that augmentation with these agents: “reduces negative symptoms with a small effect size; the absolute advantage is also small, and the advantage disappears when chronically ill patients or those with high negative symptom burden are treated. Ar/mod does not benefit or worsen other symptom dimensions in schizophrenia.”

Lisdexamfetamine-Structural Formula V.1.svg        Modafinil2DACS.svgCompounds such as amphetamine or modafinil may exert their reward-related effects on behavior in part via a dopamine D1 receptor mechanism: D1 receptor agonists may have beneficial effects.

Reward learning as a potential target for pharmacological augmentation of cognitive remediation for schizophrenia: a roadmap for preclinical development

– The MAO-B inhibitor selegiline has some potential benefit for the treatment of negative symptoms.


CDP-choline, a procholine supplement, may improve executive functioning and sensory gating.

Citicoline.svgOther cholinergics (particularly cholinesterase inhibitors) may also be beneficial:

“High quality evidence suggests a medium effect of adjunctive donepezil or galantamine for improving overall and negative symptoms compared to placebo.

High to moderate quality evidence from pre-post comparisons of memory, attention and motor function showed some improvement following administration of adjunctive cholinesterase inhibitors (single- and dual-action); however, there was no significant benefit of adjunctive cholinesterase inhibitors compared to placebo for improving motor function, language or executive function. Evidence suggested possible benefit of cholinesterase inhibitors compared to placebo for improving visual learning and memory and visual attention (trail making task).

High quality evidence suggests single-action cholinesterase inhibitors alone (donepezil) may confer some benefit for attention and short-term memory.”

Oxytocin has a role in the treatment of social/emotional deficits [3]. While current research is still unveiling its effect on social domains, initial research is promising. Likewise, intranasal desmopressin is a promising adjunctive treatment for negative symptoms.

5-HT₃ antagonist augmentation is associated with significant reduction in negative symptom (SMD = 1.10), general psychopathology (SMD = 0.70), and total symptom (SMD = 1.03) ratings without reduction in positive symptom ratings. [4]

– Famotidine: “In the 1990s, the effect of an H2R antagonist, commonly used in the treatment of peptic ulcer, was evaluated in patients with SCH. During 3 weeks, in an open-label trial, ten patients received 20 mg twice a day of famotidine without interrupting their treatment with conventional antipsychotics. Famotidine led to significant reduction in the scores of Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI), suggesting its administration as a useful alternative for SCH treatment. Later, another open-label trial was performed with 18 patients receiving 100 mg of famotidine daily, during 3 weeks. Significant improvements were found after measurements with BPRS, CGI, and the Schedule for the Assessment of Negative Symptoms (SANS). Recently, a randomized clinical trial for famotidine was performed with 30 patients with SCH, 16 patients received 100 mg of famotidine twice daily and 14 received placebo. Famotidine caused no significant adverse effects, and it led to great reduction in symptoms for both the Positive and Negative Syndrome Scale and CGI”.[5]Famotidine.svg

– Augmentation with naltrexone (50mg bid) has demonstrated efficacy in treating some symptoms [6] A later study (doses of 200mg/day) failed to find any clinical benefit [7]

Testosterone augmentation may be a potential therapeutic strategy in patients with schizophrenia [8]

Selective estrogen receptor modulators (SERMs) like raloxifene have been proposed as treatments for negative symptoms [9] A recent study found that adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia.

Allopurinol has rapidly resolved psychotic symptoms in some patients [10]

Methylene blue, which blocks NO-dependent soluble guanylate cyclase-mediated intracellular signalling, has been shown to exert therapeutic effects as an adjuvant to established antipsychotics in the treatment for schizophrenia. Caution is required due to potent MAO-A inhibition by methylene blue with cases of serotonin syndrome being reported after combination with other serotonergic agents. [11]

Methylene blue

Tocilizumab, a IL-6 receptor antibody, is undergoing clinical trials [12] IL-6 has broad relevance in psychiatric illness, including an intriguing modulatory action on 5-HT2a receptors [13]

Cyproheptadine, a first-generation antihistamine with additional anticholinergic and antiserotonergic properties is available over-the-counter in Australia and may augment some antipsychotics: “According to a small study, cyproheptadine hydrochloride has been found to improve sleep, calmness, as well as mood and energy levels, and to improve both negative and (sometimes even) positive psychotic symptoms in a subgroup of chronic schizophrenics who do not respond (either completely or sufficiently) to other therapies.

In clinical trials in which cyproheptadine was used as an adjunct to antipsychotic treatment for patients with schizophrenia, an improvement in negative symptoms was seen.” [14]Cyproheptadine.svg

7,8-dihydroxyflavone shows promise [15] It is considered to be orally active, BBB permeable, metabolised into active O-methylated metabolites and produces sustained activation and internalisation of TrkB receptors with an affinity of ~10nM [16]. Unfortunately, it has a relatively short half-life (~9 min with 1 mg/kg oral administration in rats). 4′-dimethylamino-7,8-dihydroxyflavone has improved properties that may make it better suited as a drug candidate.7,8-dihydroxyflavone.svg

6R-l-erythro-5,6,7,8-tetrahydrobiopterin (BH4) may be of benefit [17].

– Enhanced GABAB signalling, preferably by positive allosteric modulation, improves PPI deficits in animal models [17] Anecdotally (from a single case study), acute administration of either baclofen or phenibut resulted in a reduction in the intensity of auditory hallucinations in a patient with clozapine resistant schizophrenia and further studies are warranted.

“Harte and O’Connor (2005) demonstrate that a reduction in the mPFC GABAB receptor-mediated inhibitory tone is associated with a disinhibition of PFC-mediated corticofugal glutamate drive onto both mesolimbic dopamine and GABA-containing neurons in the VTA while local intra-mPFC perfusion with the selective GABAB receptor agonist baclofen reverses this effect. Baclofen has been clinically tested as a possible antipsychotic and while it alone is not beneficial it has been proposed that cortical GABAB receptor activation may be a useful treatment in schizophrenia when co-administered with conventional neuroleptics” [18]

Clonidine, potentially along with other α2-noradrenergic agonists, is capable of significantly increasing sensorimotor gating and normalising levels of P50 gating, which has a potentially high clinical relevance for the medical treatment of schizophrenia. [19]

– Potentially highly relevant to the treatment of negative symptoms, researchers found that “PCP-induced social withdrawal results from deficient endocannabinoid transmission and FAAH inhibition with URB597 reversed these deficits.” [20]

Maprotiline produced the greatest reduction in alogia symptoms with a 50% decrease in severity [21]

– Addition of fluvoxamine to antipsychotics improves verbal memory. It is postulated that the mechanism involves enhanced GABA-A receptor/BDNF-dependent synaptic plasticity in the hippocampus [22]

-Addition of atorvastatin to risperidone was effective in reducing negative sign in schizophrenia although further studies seem to be needed [23]

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