Evidence-Based Reviews

Negative symptoms of schizophrenia: An update

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Attention is often poor in patients with severe mental illnesses. The patient may have trouble focusing his/her attention or may be able to focus only sporadically and erratically. He/she may ignore attempts to converse with him/her, wander away during an activity or a task, or appear to be inattentive when engaged in formal testing or interviewing.

Clinical relevance of negative symptoms

According to DSM-5, “Negative symptoms are more closely related to prognosis than are positive symptoms and tend to be the most persistent.”18 Research has shown that, compared with positive symptoms, negative symptoms are associated with greater impairment in overall functioning, social interaction, interpersonal relationships, economic functioning, and recreational activities.1,3,5 Negative symptoms also are associated with poorer response to medication and a positive family history of schizophrenia. Research shows that negative symptoms are persistent over time, and, in fact, become more prominent as the patient ages, whereas positive symptoms become less prominent.20

Secondary negative symptoms

Potential secondary causes of negative symptoms should be ruled out before concluding that the negative symptoms are due to schizophrenia.3 What might appear to be a negative symptom of schizophrenia, such as poor motivation or flattened affect, could be due to the presence of major depressive disorder. Such symptoms might resolve with treatment. Alternatively, a patient could have developed pseudoparkinsonism from antipsychotic medication and display unchanging facial expression and decreased spontaneous movements. These symptoms could resolve by adding benztropine or a similar medication to the treatment regimen. Other potential causes of secondary negative symptoms range from chronic substance abuse (eg, leading to poor grooming and hygiene), to paranoia and hallucinations, to sleep apnea inducing anergia and impersistence at work. Causes of secondary negative symptoms are outlined in Table 3.3

Potential causes of secondary negative symptoms

The neuroanatomy of negative symptoms

Although the neuroanatomical basis of negative symptoms has not been determined, neuroimaging studies have provided important clues.3 Structural brain imaging has consistently shown that negative symptoms in patients with schizophrenia correlate with decreased prefrontal white matter volume, anterior cingulate volume, insular cortex volume, left temporal cortex volume, and ventricular enlargement. Interestingly, volume loss starts before the appearance of negative symptoms.21,22 Functional imaging has shown that negative symptoms correlate with reduced cerebral blood perfusion in frontal, prefrontal, posterior cingulate, thalamus, parietal, and striatal regions.21,22 These findings may help explain the apathy, failure to initiate activities, and impaired social relatedness in patients with schizophrenia.

Neurotransmission and negative symptoms

Some experts have hypothesized that lowered cortical dopamine transmission in mesocortical pathways could give rise to negative symptoms, whereas excess transmission in subcortical structures leads to positive symptoms.23 There is also evidence for a noradrenalin deficiency based on the finding that low levels of cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol (MHPG), a noradrenaline metabolite, correlates with greater negative symptom severity.24 The presence of a serotonin deficiency has been proposed based on evidence that negative symptoms might be mitigated by serotonergic agents.25 More recently, some experts have posited that the dopamine D3 receptor might be involved in the etiology of negative symptoms. The dopamine D3 receptor activity is expressed in brain regions thought to control reward, emotions, and motivation.2 Newer medications with novel mechanisms suggest that other neuro­transmitter pathways could be involved.6,7

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