Negative symptoms in schizophrenia
The negative symptoms of schizophrenia include symptoms such as deficiencies in emotional responsiveness, spontaneous speech and volition. Around a half to three-quarters of people with chronic schizophrenia exhibit some features of negative symptoms of schizochizophrenia. Primary negative symptoms are shown in flattening of affect, poverty of speech, lack of volition and drive, loss of feeling, social withdrawal and decreased spontaneous movement.
Negative syndrome in schizophrenia is a distinct dimension of psychopathology. The core negative symptoms such as flattened affect and poverty of speech may be particularly stable over time and less responsive to treatment. Negative symptoms occur in those with bipolar disorder and major depression as well as those with schizopbrenia.
Primary and secondary negative symptoms
There is an overlap between negative symptoms, depressive features and neuroleptic side-effects, particularly somnolence and the bradykinesia due to drug-induced parkinsonism. It may be very difficult to distinguish between persistent, primary negative symptoms that are component of the illness, and negative symptoms secondary to depressive features, drug side-effects or positive symptoms.
Duration of untreated psychosis
There is some evidence from follow-up
studies of schizophrenia that a delay in initiating treatment with
antipsychotic medication may lead to worse clinical and social outcomes. There
is an active morbid process at the onset of schizophrenia that may be
ameliorated by antipsychotic drugs. An alternative notion is that illness with
an inherently poor prognosis in terms of negative symptoms may be identified
later.
Association with social functioning
One study of first episode schizophrenia found that the severity of negative symptoms at first admission was a stronger predictor of poor quality of life at two years than was severity of positive psychotic symptoms. The extent to which negative symptoms may account for; or predict, poor social functioning is still unclear. Certainly, patients with schizophrenia may show poor social functioning in the absence of negative symptoms. Moreover; some studies reported that drug treatment with clozapine improved social and occupational functioning despite a lack of efficacy for negative symptoms.
Neurocognitive correlates of negative symptoms
Schizophrenic patients perform at a lower level than normal controls across a wide range of neuropsychological tests. The symptoms of schizophrenia can be described in terms of three syndromes (reality distortion, disorganisation and psychomotor poverty), each of which may be associated with a different pattern of cognitive impairment. On balance, recent evidence suggests that cognitive impairment in schizophrenic patients is largely independent of positive symptoms, particularly delusions and hallucinations. With regard to negative symptoms, associations have been described with impairment of general intellectual ability and executive function, including verbal fluency and performance in working memory tasks such as the Wisconsin Card Sorting Test.
Structural neuroimaging
Computerised tomography (CT) and magnetic resonance imaging (MRI) in schizophrenia have produced convincing evidence of increased ventricular volume, although the magnitude of these changes is small. With more recent MRI methods, studies have shown that negative symptoms may correlate with temporal lobe volume on the leftor bilaterally. Enlargement of the cerebrospinal fluid (CSF) spaces implies a loss of cortical tissue. Many MRI studies suggest that widespread decreases in grey matter are present even in first episode psychosis. However; few studies have shown significant correlation between regional cerebral volume and negative symptoms. Thus, there is the implication that this anatomical abnormality may underlie the functional abnormality described earlier.
Functional neuroimaging of negative symptoms
Functional neuroimaging can be broadly divided into two techniques:
· Brain mapping - measures cerebral blood flow (rCBF) or metabolism as an index of local neural activity.
· Neurochemical imaging - measures the specific uptake and binding of radiolabelled tracer compounds.
Brain mapping studies
At rest
Ingvar and Franzen first described
‘hypofrontality’ in their group of markedly underactive and withdrawn patients
with schizophrenia. However; in subsequent discussion of this highly influential
study, clinical status of the patients was relatively neglected and the results
were frequently generalised to all schizophrenic patients. Many rCBF studies,
in particular those examining acute unmedicated patients, have since failed to
find hypofrontality, and it seems likely that only patients with marked
negative symptoms may exhibit resting hypofrontality. Liddle et aI. were
able to relate loadings for psychomotor poverty to decreased blood flow in the
left dorsolateral prefrontal and left superior parietal association cortices,
and increased blood flow in the caudate nuclei. These results were later
partially replicated in unmedicated patients. Negative features such as poverty
of speech can also be seen in depression, and may predict lower prefrontal
cortex activity irrespective of diagnosis.
Neurochemical imaging
Some studies have correlated D2-receptor
number with bradykinesia in Parkinson’s disease. This hypothesis led to
attempts to relate indices of neurochemical imaging to negative symptoms of
schizophrenia. Studies suggest that decreased dopaminergic function may mediate
negative symptoms. In contrast, although schizophrenic patients have an
exaggerated release of dopamine in response to the administratioin of
amphetamine, changes in positive but no negative symptoms correlate
with this index of phasic dopamine neurotransmission. No relationship has been
described between negative symptoms and 5 HT2-receptors,
which are target for most atypical antipsychotics.
Response to antipsychotic medication
Negative symptoms are generally considered to show a poor response to conventional anti-psychotics. Although acute studies with such drugs have tended to demonstrate improvemeni in both positive and negative symptoms, the apparent response of negative symptoms may be at least partly a consequence of the successful treatment of positive symptoms and relief of associated depressive features. The newer; atypical, antipsychotic drugs also treat both positive and negative symptoms in acute schizophrenia, but have a lower liability for acute extrapyramidal symptoms (parkinsonism, akathisia and dystonia). The atypical anti-psychotic agents vary in their affinities across dopamine, 5-HT, adrenergic, muscarinic, and histaminic receptors, but how such activity might contribute to differences in their therapeutic and side-effect profiles remains largely a matter for speculation. There is some tentative evidence that 5-HT2 receptor antagonism or relative activity at alpha2-adrenoceptors may underlie a therapeutic action on negative symptoms. The combination of potent blockade of 5-HT-receptor subtypes and relatively weaker dopamine D2 antagonism seen with drugs such as clozapine, risperidone, olanzapine, quetiapine and ziprasilone has also been suggested as a relevant mechanism although efficacy in treating negative symptoms has been demonstrated for some selective D2-antagonists, such as remoxipride.
It is claimed that these new drugs are
superior to conventional antipsychotics for the treatment of negative symptoms.
The key question is whether the demonstration that a drug is effective in
reducing negative symptoms in acute, short-term studies is any indication that
it will have a direct benefit on persistent deficit symptoms in patients during
a more stable phase of illness. To test this will require studies of selected
patients with predominantly negative symptomatology, a strategy adopted by some
recent investigators, such as Speller et al. However; such patients may
represent only a small proportion of patients with schizophrenia. At present,
primary negsymptoms show only a modest response to pharmacotherapy at best, and
current therapeutic strategies aim to minimise secondary negative symptoms
through rationalisation of drug regimens as well as to pursue preventive and
rehabilitative work through psychological and social interventions
Summary:
· For many people with schizophrenia, negative symptoms are the most disabling and persistent component of the illness.
· Negative symptoms are classified as primary (enduring features considered inherent to the Illness) or secondary (to depressive features, drug side-effects or positive symptoms).
· Neurochemical imaging provides some evidence that decreased dopaminergic function may mediate negative symptoms.
· There are claims that some of the new, atypical antipsychotics have a direct, modest benefit on negative symptoms, but evidence is tentative.