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New findings from neuroscience, genetics, and experimental psychology have emerged that provide alternative explanations of many negative symptoms. We review the continuing limitations in treatment and discuss possible sources of heterogeneity among negative symptoms. We also anticipate conceptual uncertainties that may arise with forthcoming treatment developments.
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 rivastigmine,14 and Donepezil15 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.
In addition to modest treatment efficacy, a decade of accumulated data from intervention studies reveals inconsistencies in the pattern of responsiveness among negative symptoms. A review of Clozapine's impact on negative symptoms among refractory patients, for example, demonstrated benefits for negative symptoms restricted to anhedonia.16 By contrast, in a study of Olanzapine among non-refractory patients, benefits for negative symptoms were observed in all factors except anhedonia and asociality.17 Although methodological factors may explain some of the discrepancies, factor analyses of two of the most widely used instruments measuring negative symptoms, the SANS18 and the SDS,19 imply that they may measure more than one domain. If true, the variability in the pattern of treatment responsiveness may reflect differences in etiopathophysiologies among these domains. A number of sources have critically reviewed SANS20–23 and SDS.24
That there are potential sources of heterogeneity among negative symptoms, as suggested by the modest effect size and inconsistent pattern of symptom responsiveness in clinical trials, is consistent with the clinical observation that a variety of patients appear to have ratable negative symptoms. It has long been known, for example, that individual negative symptoms can exist in a variety of neurological disorders. Apathy, for example, is observed in neurodegenerative disorders, including fronto-temporal and Lewy-body dementias, in supranuclear palsy, in Huntington's disease, and is frequently observed in frontal as well as basal ganglia and thalamic disorders. More recently, studies by schizophrenia researchers have established relationships between individual negative symptoms and abnormal frontal lobe circuitry. Among these relationships, abnormalities in neural circuits governing both eye tracking25 and olfaction26 appear impaired in patients with deficit negative symptoms, and olfactory deficits appeared associated with avolitional symptoms.
Apart from specific associations between individual negative symptoms and structural abnormalities, emerging evidence from experimental psychology suggests that inherited temperament phenotypes govern patterns of affiliation, motivation, and perseverance. Probably the best-known and most applicable model to the negative symptom construct is Robert Cloninger's, which used psychometric rating scales, animal research, and genetic studies to construct a model of heritable temperament dimensions including novelty seeking, harm avoidance, reward dependence, and persistence.27 Cloninger's Temperament and Character Inventory,28 a self-report questionnaire that includes questions related on personality traits, also shows areas of important overlap with both the SANS and the SDS, including questions related to an individual's tendency to seek out new things, to feel challenged in unfamiliar social situations, and to perceive an absence of purpose. In work by Akiskal, temperament factors have been shown to influence clinical outcome,29 raising the question of whether temperament variants in patients with schizophrenia—a tendency against novelty seeking, for example—could be a source of variance in treatment for negative symptoms.
Because of the current limitations in treatment responsiveness, it can be expected that the pharmaceutical industry will in the future develop innovative adjunctive treatments targeting negative symptoms to be used in conjunction with antipsychotics. There are indications that new approaches to understanding and treating negative symptoms are emerging. Already, research is underway identifying linkages between temperament traits and gene polymorphisms. The D4 dopamine receptor30 and the 5 HTTLPR transporter gene31 have been linked with abnormalities in novelty seeking and harm avoidance, respectively, although more recent research has not replicated these findings.32 Simultaneously, autism researchers have begun investigating the roles of the pituitary hormones Oxytocin and Vasopressin on affiliative behaviors, based on their apparent role in pair-bonding behaviors among prairie voles.33
For clinicians, meaningful interpretation of any forthcoming data on new adjunctive treatment will depend on a clarification of the nosology of negative symptoms. The current understanding, that negative symptoms are restricted to schizophrenia and form a single domain, appears less certain than previously.
A definitive conceptualization would need to address whether negative symptoms should be considered homogeneous or heterogeneous, categorical or dimensional, and whether and how they are distributed beyond patients with schizophrenia, as suggested by some studies.34,35
Simultaneously, to evaluate patient responsiveness to proposed co-medications, consideration should be given to refining the existing rating instruments. Although the instruments used to measure negative symptoms were designed for research application, they are already used by clinicians, and their use in this context is likely to become more common. Common difficulties experienced in the use of SANS and the SDS relate to the inherent difficulty of rating patients' subjective experience, the vagueness of the anchor points, and the possible influence of secondary causes, including psychosocial and cultural factors. Possible options include refining the anchor points to incorporate more concrete data and the possible inclusion of performance measures.
In its MATRICS initiative supporting the development of pharmacological agents to improve cognition in schizophrenia, NIMH attempted to foster greater collaboration between industry, academia, and regulators. The recent NIMH initiative to address barriers to improved treatment for schizophrenia negative symptoms is encouraging. If progress is to be made in the treatment of negative symptoms, increased collaboration between the basic sciences and clinical research over potential sources of heterogeneity should also be encouraged.