What is new in treatment of negative symptoms? Eur Neuropsychopharmacol. 2014 May.


Negative symptoms of schizophrenia  are  difficult to treat than positive symptoms. There are no medications with specific benefit on these symptoms.Davis MC, Horan WP, Marder SR review current status of our knowledge in developing therapies for these difficult to treat problems.

First generation antipsychotics: originally reported to have benefit on negative symptoms as well. However it is unclear whether this is via effect on positive symptoms ( i. e.g.. improvement in suspiciousness may improve some of the negative symptoms).FGA cause EPS that can mimic negative symptoms.

Second Generation Antispychotics: initially elicited huge expectation that these agents would address negative symptoms. Some studies suggested benefit though many others found no benefit at all. Lower EPS by these agents can mimic  a benefit. Many studies used higher dose of FGA, and when lower doses of FGA were used no difference in benefits were observed. Among SGA, clozapine and amisulpride have attracted attention. Metaanalytic evidence do not support the idea that clozapine has primary anti negative symptom effect. The apparent anti negative effect is likely to be  secondary  to greater anti positive symptom effect. Some studies suggest amisulpride to have effect on  primary negative symptoms, the apparent benefits are most likely attributable to changes in secondary negative symptoms, particularly due to its ability to improve depressed mood. Aripiprazole could theoretically be effective but this has not been studied in trials. Original trials  of Asenapine did not show benefits though pooled analysis of extension study suggested benefit on negative symptoms.

Antidepressants:  Meta analysis support the use of antidepressants ( Singh et al 2010 , Rummel et al 2005).Differentiating between depression primary negative symptom is a serious problem in these studies.

Stimulants: Negative symptoms are thought to be related to  prefrontal hypodopaminergic activity. Cochrane review suggest that amphetamine isomers or methamphetamine to reduce negative symptom . However the included studies did not have appropriate methodology for assessing effects on primary negative symptoms. Modafinil and its enantiomer armodafinil is shown to have limited or no benefits on negative symptoms.

Glutamatergic agents: Different classes of agents like NMDA agonists/partial agonists (D-cycloserine, glycine, D-serine, and D-alanine) ,Glycine transporter-1 (GlyT1) inhibitors (eg sarcosine),N-acetylcysteine (NAC), NMDA uncompetitive antagonist (memantine) &  lamotrigine, which may inhibit glutamate release  are also potential agents.  Though most studies involving these agents show inconsistent results and are troubled by methodological issues this is a promising area.

Cholinergic agents: Recent meta analysis suggest  that adjunct Acetyl choline esterase inhibitors may have benefits over placebo for the treatment of negative symptoms (Singh et al., 2012). Only two RCTs were included and both had problems ( small number of participants and high dropout rates ). Small trials of  cholinergic agonists and nicotinic agonists have  shown to be useful.

Hormones: Small studies supplementing oestrogen and pregnenolone have shown to reduce negative symptoms.

Minocycline:  two RCTs showed this to be effective. Three ongoing trials.

Oxytocin: intranasal spray shown to be of benefit.

Conclusion: Agents that can  enhance NMDA glutamatergic receptor function and  selective nicotinic receptor positive allosteric modulators show the most promise.

Summary of the article:

Psychopharmacology of the negative symptomsCurrent status and prospects for progress.

Davis MC, Horan WP, Marder SR. Eur Neuropsychopharmacol. 2014 May;24(5):788-99

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