Since the late 1950s, appreciation of
dopamine receptor blockade has played a primary role in understanding the mechanism underlying the
therapeutic effects of
antipsychotic drugs in schizophrenic patients in treating the positive symptoms of
schizophrenia (e.g., delusions and
hallucinations). Development of the second generation of
antipsychotic drugs, otherwise known as atypical
antipsychotic drugs, has resulted in treatments with improved subjective tolerability but relatively modest improvements in the negative symptoms of
schizophrenia such as avolition, flat affect, and
anhedonia. The major current challenge is to develop medications which can further improve negative symptoms treatment and also tackle the intractable clinical problems of
cognitive impairment associated with
schizophrenia. Further advances along these lines with respect to the dopaminergic and serotonergic neurostransmitter systems will be aided by an appreciation of the interaction between
dopamine and
serotonin receptor subtypes in a range of key brain structures, such as the prefrontal cortex, thalamus, striatum, amygdala, hippocampus, and the brain stem nuclei, from which the cell bodies of monoaminergic-containing neurons originate. Increasing emphasis on the use of animal models which are homologous to critical aspects of the pathophysiology in the brains of schizophrenic patients will also be required, especially as negative symptoms and
cognitive impairment become an important focus for generating novel
therapeutics.