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Medical Pharmacology Chapter 16: Pharmacology of Antipsychotics Drugs
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Special Section on Negative Symptoms in Psychosis
Antipsychotics: The Central Disappointment
The mainstay of psychosis treatment, dopamine D2 receptor antagonism, has virtually no direct efficacy against primary negative symptoms.
While second-generation (atypical) antipsychotics were initially marketed as superior in this domain, the evidence upon rigorous re-examination is far less compelling.
The landmark Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study demonstrated that the apparent advantages of atypicals over perphenazine, a first-generation agent were minimal, and likely artefacts of reduced extrapyramidal side-effect burden rather than genuine negative-symptom efficacy.
[Lieberman J Stroup T McEvoy J Swartz M Rosenheck R Perkins D Keefe R Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. Published September 22, 2005.N Engl J Med. Volume 353 Number 12. 1209-1223. https://www.nejm.org/doi/full/10.1056/NEJMoa051688]
Clozapine occupies a special position.
Clozapine remains the only antipsychotic with robust evidence for treatment-resistant schizophrenia as a whole, and some meta-analyses suggest modest superiority over other agents for negative symptoms.
However, its effect on primary deficit-state negative symptoms is modest at best.
Its complex pharmacology, involving serotonin, dopamine, muscarinic, and histaminic receptor activity, may underlie what benefit exists.
[Leucht S Corves C Arbter D Engel R Li C Davis J Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis .The Lancet Volume 373, Issue 9657 P.31-41. January 3, 2009. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61764-X/abstract]
Adjunctive Strategies: Given the limitations of antipsychotics, adjunctive pharmacology has been extensively explored. The most studied agents include antidepressants, glutamate modulators, and anti-inflammatory drugs.
SSRIs and mirtazapine have been trialled, resting on the observation that negative symptoms and depression share phenomenological overlap.
The evidence is mixed.
A Cochrane review found modest benefit from adding antidepressants, but study quality was generally poor, follow-up was short, and publication bias is likely.
Benefits may be explained by secondary-symptom amelioration (treating comorbid depression) rather than direct negative-symptom efficacy.
Mirtazapine shows the most consistent signal in randomised trials, possibly through α-2 adrenoceptor antagonism and histamine H1 receptor activity.
[Helfer B Samara M Huhn M Klupp E Leucht C Zhu Y Engel R Seucht S Efficacy and Safety of Antidepressants Added to Antipsychotics for Schizophrenia: A Systematic Review and Meta-Analysis. American Journal of Psychiatry. Volume 173. Number 9. https://psychiatryonline.org/doi/10.1176/appi.ajp.2016.15081035]
Hypofunction of N-methyl-D-aspartate (NMDA) glutamate receptors is among the best-supported neurobiological hypotheses for negative (and cognitive) symptoms. D-serine, glycine, and sarcosine, all NMDA co-agonists, have shown benefit in small trials, but large Phase III trials have generally failed to replicate these results.
The mGluR2/3 agonist approach similarly disappointed in pivotal trials.
These failures have tempered initial optimism, though the glutamate pathway remains a credible target for future drug development.
[Coyle J NMDA Receptor and Schizophrenia: A Brief History. Schizophrenia Bulletin, volume 38, Issue 5, September 2012. 920-926. https://academic.oup.com/schizophreniabulletin/article-abstract/38/5/920/1902055?redirectedFrom=fulltext]
Aripiprazole, brexpiprazole, and cariprazine act as partial agonists at D2/D3 receptors.
Cariprazine has generated particular interest: its preferential affinity for D3 receptors (dense in reward and motivational circuitry) provides a mechanistic rationale for addressing avolition and anhedonia.
A pivotal RCT demonstrated superiority over risperidone specifically on negative symptoms, though effect sizes were modest (standardised mean difference approximately 0.3).
This finding remains one of the more credible pharmacological advances for primary negative symptoms in recent years.
[Nemeth G Laszlovsky I Czobor P Szalai E Szatmari B Harsanyi J et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomized, double-blind, controlled trial. The Lancet volume 389, Issue 10074 1103-1113. March 18, 2017. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30060-0/abstract]
Elevated neuroinflammatory markers are consistently found in schizophrenia, and several trials have examined celecoxib (a COX-2 inhibitor), aspirin, and omega-3 fatty acids as adjuncts.
Results are intriguing but insufficiently powered.
The neuroinflammation hypothesis is compelling at a mechanistic level but awaits translation into clinically meaningful treatment gains.
[Muller N Inflammation in Schizophrenia: Pathogenetic Aspects and Therapeutic Considerations. Schizophrenia Bulletin Volume 44, Issue 5, September 2018. 973-982. https://academic.oup.com/schizophreniabulletin/article-abstract/44/5/973/4965841?redirectedFrom=fulltext]
Psychological Interventions Psychological treatments for negative symptoms have historically been underfunded and understudied, partly reflecting a long-standing and empirically unwarranted assumption that these symptoms are purely biological and therefore inaccessible to psychosocial intervention.
Cognitive Behavioral Therapy for Psychosis (CBTp)
CBTp has a robust evidence base for positive symptoms but its effects on negative symptoms are more contested.
Traditional CBTp protocols were not designed with negative symptoms as the primary target.
Recent meta-analyses suggest modest but significant effects on negative symptoms when CBTp is delivered competently, but several high-quality RCTs including the large ISREP and NIHCE trials have shown no statistically significant benefit on negative symptom scales at follow-up.
The field is now developing targeted CBTp approaches that specifically address the cognitive and emotional drivers of avolition and anhedonia, such as low anticipated pleasure and negative expectancies about effort.
[Turner D van der Gaag M Karyyotaki E Cuijpers P Psychological Interventions for Psychosis: A Meta-Analysis of Comparative Outcome Studies. The American Journal of Psychiatry. Publication date May 1, 2014. https://psychiatryonline.org/doi/10.1176/appi.ajp.2013.13081159]
Motivational Approaches and Behavioral Activation
Behavioral activation rooted in the understanding that avolition involves disruption of the anticipatory reward system has shown promise in pilot trials.
By systematically scheduling graded, meaningful activities and addressing the cognitive barriers to initiating them, this approach targets avolition more directly than generic CBTp.
Preliminary evidence from the Positive Emotions Programme for Schizophrenia (PEPS) and related interventions suggests that directly enhancing hedonic capacity and anticipated pleasure is a tractable goal.
These are among the most theoretically coherent contemporary psychological treatments for primary negative symptoms
[Favrod J Ngyuyen A Fankhauser C Ismailaj A Hasler J-D Ringuet A Rexhaj S Bonsack C Positive Emotions Program for Schizophrenia(PEPS): a pilot intervention to reduce anhedonia and apathy. BMC Psychiatry. Volume 15, article number 231, Published September 29, 2015. https://link.springer.com/article/10.1186/s12888-015-0610-y]
Impaired social cognition, particularly theory of mind, emotion recognition, and attributional bias, both drives and perpetuates asociality and affective blunting.
Social Cognition and Interaction Training (SCIT) and the Metacognitive Training (MCT) programme have produced measurable improvements in social cognitive performance.
The translation to real-world social engagement is variable, but training social cognition directly addresses a key mechanism sustaining negative symptoms in their social domain.
[Roberts D Penn D SCIT) Social cognition and interaction training ((SCIT) route patients with schizophrenia: A preliminary study. Psychiatry Research. Volume 166, Issues 2-3, April 30, 2009. 141-147. https://www.sciencedirect.com/science/article/abs/pii/S0165178108000565?via=ihub]
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