While the introduction of second-generation antipsychotics (SGAs) during the 1990s was accompanied by reports suggesting that these agents comprised a breakthrough in the treatment of negative symptoms,1
in current practice, recovery for the patient with negative symptoms has remained elusive. Currently available treatments for negative symptoms appear to have modest benefits, with the result that negative symptoms continue to disproportionately limit patient recovery. Treatment guidelines recommend that to optimize functional outcomes for patients with schizophrenia, psychosocial programs or psychiatric rehabilitation should be combined with pharmacological management.2
Yet for patients with negative symptoms, participation in these programs may not only be more difficult to facilitate, but also less efficacious. According to one study, patients with the more severe “deficit” form of schizophrenia who were enrolled in social skills training experienced less benefit than non-deficit patients.3
That available pharmacological treatments to reduce the burden of negative symptoms have limited benefits is evident from accumulated recent intervention studies consistently showing either small effect sizes or inconsistent results. In particular, the expectation that negative symptoms would show differentially improved responsiveness to SGAs compared with first-generation neuroleptics has not been realized to a degree that is clinically significant. Almost all the large clinical trials of SGAs include analyses of efficacy for negative symptoms, many using statistical procedures to reduce the influence of secondary sources such as extrapyramidal symptoms, demoralization, and sedation. However, the accumulated results from these studies suggest that the effect size of SGAs for negative symptoms is modest.4
Although this is not uniformly true in all studies,5,6
it appears consistent with the experience of many clinicians.
Use of adjunctive agents has likewise yet to emerge as a consistently beneficial strategy for negative symptoms. Although case reports of the efficacy of co-medication strategies with selective serotonin reuptake inhibitors (SSRIs), glutamatergic compounds, and estrogen are available,7
none has convincingly established efficacy, and their use does not appear to have become widespread in clinical practice, with the possible exception of antidepressants. Even within research on the benefits of antidepressants, however, studies have yielded inconclusive results. Almost all have been characterized by small sample size and failure to control for change in secondary negative symptoms.8
Probably the best-studied experimental adjuncts are glutamate modulators, including the NMDA agonists glycine and D-serine, which produced significant reductions in persistent negative and cognitive symptoms when added to antipsychotics in preliminary studies,9,10
but which have not been have not been consistently efficacious in larger subsequent studies.11
Of additional concern, D-Cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor, improved negative symptoms when added to conventional antipsychotics but actually worsened them when added to clozapine.12
Case reports relating to the use of acetyl-cholinesterase inhibitors galantamine,13
have recently been published, but as yet there are no reports from larger prospective studies.
The disappointments in the effectiveness of SGAs and available co-medications do not appear to have been accompanied by a vigorous search by the pharmaceutical industry for new pharmacological approaches for treating negative symptoms. The industry may be reacting to these disappointments by directing their efforts to therapeutic targets that may have a higher likelihood of success.