Existing treatments for schizophrenia can improve positive symptoms, but it is unclear if they have any impact on negative symptoms. This meta-analysis was conducted to assess the efficacy of available treatments for negative symptoms in schizophrenia. All randomized-controlled trials of interventions for negative symptoms in schizophrenia until December 2013 were retrieved; 168 unique and independent placebo-controlled trials were used. Negative symptom scores at baseline and follow-up, duration of illness, doses of medication, type of interventions, and sample demographics were extracted. Heterogeneity was addressed with the I² and Q statistic. Standardized mean difference in values of the Negative Symptom Rating Scale used in each study was calculated as the main outcome measure. 6503 patients in the treatment arm and 5815 patients in the placebo arm were included. No evidence of publication biases found. Most treatments reduced negative symptoms at follow-up relative to placebo: second-generation antipsychotics: −0.579 (−0.755 to −0.404); antidepressants: −0.349 (−0.551 to −0.146); combinations of pharmacological agents: −0.518 (−0.757 to −0.279); glutamatergic medications: −0.289 (−0.478 to −0.1); psychological interventions: −0.396 (−0.563 to −0.229). No significant effect was found for first-generation antipsychotics: −0.531 (−1.104 to 0.041) and brain stimulation: −0.228 (−0.775 to 0.319). Effects of most treatments were not clinically meaningful as measured on Clinical Global Impression Severity Scale. Although some statistically significant effects on negative symptoms were evident, none reached the threshold for clinically significant improvement.

AUDITORY VERBAL hallucinations (hereafter called auditory hallucinations) are perceptions of external speech in the absence of a stimulus and a cardinal feature of schizophrenia. Functional imaging provides a means of studying their pathophysiology in vivo. Previous neuroimaging studies have sought to "capture" the pattern of activity during auditory hallucinations by asking patients to signal when they occur,^1-3 but the results have been inconsistent. This may reflect the confounding effects of signaling the presence of hallucinations, which can engage areas theoretically implicated in auditory hallucinations,⁴ as well as small numbers of subjects^2,3 and the acquisition of a limited number of images per subject.¹ Most previous studies, with a few exceptions,³ involved single-photon or positron emission tomography (SPET or PET), which, while silent, constrain the number of scans that can be safely acquired. Studies may have also differed in terms of the characteristics of the patients and hallucinations that have been examined. We have developed a method that measures spontaneous neural activity using functional magnetic resonance imaging (fMRI) and permits the acquisition of a relatively large number of images in each subject, without the subject having to signal when auditory hallucinations occur. Moreover, while the scanner noise generated during conventional fMRI can itself activate auditory cortex,⁵ our approach allows activity during auditory hallucinations to be examined in silence. This "random sampling" method can be viewed as a variant of event-related fMRI⁶ that measures the neural correlates of discrete cognitive events, in this case spontaneous hallucinations, rather than the neural response to experimentally presented stimuli.

Background. We used functional MRI to examine the functional anatomy of inner speech and different forms of auditory verbal imagery (imagining speech) in normal volunteers. We hypothesized that generating inner speech and auditory verbal imagery would be associated with left inferior frontal activation, and that generating auditory verbal imagery would involve additional activation in the lateral temporal cortices.Methods. Subjects were scanned, while performing inner speech and auditory verbal imagery tasks, using a 1.5 Tesla magnet.Results. The generation of inner speech was associated with activation in the left inferior frontal/insula region, the left temporo-parietal cortex, right cerebellum and the supplementary motor area. Auditory verbal imagery in general, as indexed by the three imagery tasks combined, was associated with activation in the areas engaged during the inner speech task, plus the left precentral and superior temporal gyri (STG), and the right homologues of all these areas.Conclusions. These results are consistent with the use of the ‘articulatory loop' during both inner speech and auditory verbal imagery, and the greater engagement of verbal self-monitoring during auditory verbal imagery.