Schizophrenia negative symptoms

Neuroleptics or antipsychotics suppress the positive symptoms of schizophrenia such as combativeness, hallucinations and formal thought disorder. Some also alleviate the negative symptoms such as affective blunting, withdrawal and seclusiveness. Neuroleptics also produce a state of apathy and emotional indifference. Most neuroleptics block dopamine D2-receptors but some, like clozapine, also block dopamine D4-receptors or serotonin 5-hydroxytryptamine2A-receptors. 

The prefrontal cortex (PFQ and in particular the dorsal lateral part (DLPFQ appear to be particularly important in schizophrenia (Kerwin 1992). Lesions there are known to produce functional defects in humans reminiscent of many of the negative symptoms of schizophrenia, such as attention and cognitive defects and withdrawal. Despite this, no specific pathology is seen in the DLPFC in schizophrenics although there is some atrophy and neuronal loss which are normally old and could be congenital. That being so, it is necessary to explain why the symptoms become apparent only in adolescence. 

Reference has been made already to the shortcomings of the term neuroleptic . We now have a situation in which the drugs that are most useful in schizophrenia are regarded as atypical. While the term was introduced to cover those neuroleptics that do not cause EPSs, it has become synonymous with clozapine which has additional advantages over other neuroleptics (e.g. reduces negative symptoms, see text). Thus it is not always clear what is meant or covered by atypical. Hopefully this distinction between the neuroleptics will become unnecessary as better compounds are developed and the older ones become obsolete. 

Figure 17.9 Schematic representation of the proposed activity profile of an ideal neuroleptic. The figure shows DA pathways to the prefrontal cortex, mesolimbic nucleus accumbens and striatum the effects required for an ideal drug on the DA influence and symptoms there and to what extent they are met by most typical and atypical neuroleptics and by clozapine. Note that while all atypical neuroleptics induce few extrapyramidal w side-effects (EPSs) few of them, apart from clozapine, have much beneficial effect in overcoming negative symptoms of schizophrenia ...

It appears that an ideal neuroleptic may need to reduce DA activity in the mesolimbic system (nucleus accumbens) to counter the positive symptoms of schizophrenia, increase it in the prefrontal cortex to overcome negative symptoms and have little or possibly no effect on it in the striatum so EPSs do not arise (Fig. 17.9). No wonder we still await the ideal drug. 

Tandon R., Shipley J. E., Taylos S. et al. (1992). Electroencephalographic sleep abnormalities in schizophrenia. Relationship to positive/negative symptoms and prior neuroleptic treatment. Arch. Gen. Psychiatry 49,... 

D-cycloserine An amino acid analogue of D-serine that has been reported to show benefits in treating the negative symptoms of schizophrenia. 

Roche for their inhibitor RG1678. This trial provides compelling evidence that GlyT-1 inhibitors show promise as a novel class of antipsychotics that are effective at ameliorating the negative symptoms and cognitive dysfunction associated with schizophrenia. 

Schizophrenia is characterized by three partially independent symptom clusters. These symptom clusters are designated positive symptoms, negative symptoms and cognitive impairments [1], The positive symptoms are the most dramatic and are manifestations of psychosis. 

Controlled clinical investigations with careful titration of doses in normal subjects demonstrate that ketamine produces negative symptoms, such as withdrawal and the subtle cognitive impairments associated with schizophrenia [25]. As is the case for schizophrenia, these symptoms occur without clouding of consciousness or frank dementia. Positive symptoms with auditory hallucinations and fully... 

Callicott, J. H., Bertolino, A., Egan, M. F. et al. Selective relationship between prefrontal N-acetylaspartate measures and negative symptoms in schizophrenia. Am. J. Psychiatry 157 1646-1651,2000. 

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