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Schizophrenia is, at once, a biological disease, a neuropsychological disorder and a dysfunction of social interactions. This presents clinicians with a series of problems with regards to therapy. In the first section of this article, some of the clinical challenges that face those attempting to develop new drugs, are summarised. Several potential pharmacological therapeutic targets that have been, and are continuing to be used, in the development of new antipsychotic drugs, are then considered. This is followed by an outline of the pharmacological and clinical profiles of some of the newer generation antipsychotics, as well as investigational drugs in the pipeline for schizophrenia. Finally, the implications of the introduction of these new drugs for the management of schizophrenia, are discussed.

Deficits in language comprehension in schizophrenia were examined using event-related potentials (ERPs). Schizophrenic and healthy participants read sentences in which the first clause ended with a homograph, and the second clause started with a target word that was semantically related to the homograph’s dominant meaning (e.g., 1. Diving was forbidden from the bridge because the river had rocks in it. or 2. The guests played bridge because the river had rocks in it.). Processing of the targets (e.g., “river”) was expected to be primarily influenced by the preceding overall sentence context (congruent in 1; incongruent in 2) in healthy participants, but to be inappropriately affected by the dominant meaning of homographs (e.g., the “structure” meaning of “bridge”) in sentences like 2 in schizophrenic patients. The N400 ERP component that is known to be sensitive to contextual effects during language processing confirmed these predictions. This showed that language abnormalities in schizophrenia may be related to deficient processing of context-irrelevant semantic representations of words from the discourse.

Schizophrenia is often associated with cognitive deficits, particularly within the domains of memory and language. Specific cognitive deficits have recently been linked to psychotic phenomena, including verbal hallucinations and disorganized speech. Impairments of working and semantic memory are primarily due to dysfunction of the frontal cortex, temporal cortex, and hippocampus. Cognitive skills in schizophrenia predict social functioning and may serve as outcome measures in the development of effective treatment strategies.

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BACKGROUND: As a group, positively thought-disordered (TD) schizophrenic patients are relatively impaired in their ability to use linguistic context to process sentences online (Kuperberg et al. 1998). This study investigates the heterogeneity in the use of linguistic context both between individual TD patients and within the individual patients as severity of thought disorder changes over time. METHODS: Seventeen TD schizophrenics performed an online word-monitoring task on four separate occasions. In each patient, baseline reaction time (RTs) to target words in normal sentences were subtracted from RTs to target words in pragmatically-, semantically- and syntactically-violated sentences to obtain a measure of online sensitivity to each type of linguistic violation, and these were compared with normative data of a healthy volunteer and a non-TD schizophrenic control group. In addition, the co-variation of severity of thought disorder and sensitivity to linguistic context within all individual TD patients over the four testing sessions, was examined. RESULTS: There was marked heterogeneity between individual TD patients in their sensitivity to different types of linguistic violations: some were selectively insensitive to pragmatic violations, while others were insensitive to semantic and syntactic (subcategorization) violations. There was also an inverse relationship between severity of thought disorder and sensitivity to linguistic violations within individual patients over the four sessions. CONCLUSIONS: It is likely that a single cognitive deficit does not account for all types of schizophrenic thought disorder, but rather that there are multiple deficits affecting specific levels of linguistic processing. In these schizophrenic patients, impairment in the use of linguistic context was related to the state, rather than the trait, of thought disorder.

Extracting meaning from speech requires the use of pragmatic, semantic, and syntactic information. A central question is: Does the processing of these different types of linguistic information have common or distinct neuroanatomical substrates? We addressed this issue using functional magnetic resonance imaging (fMRI) to measure neural activity when subjects listened to spoken normal sentences contrasted with sentences that had either (A) pragmatical, (B) semantic (selection restriction), or (C) syntactic (subcategorical) violations sentences. All three contrasts revealed robust activation of the left-inferior-temporal/fusiform gyrus. Activity in this area was also observed in a combined analysis of all three experiments, suggesting that it was modulated by all three types of linguistic violation. Planned statistical comparisons between the three experiments revealed (1) a greater difference between conditions in activation of the left-superior-temporal gyrus for the pragmatic experiment than the semantic/syntactic experiments; (2) a greater difference between conditions in activation of the right-superior and middle-temporal gyrus in the semantic experiment than in the syntactic experiment; and (3) no regions activated to a greater degree in the syntactic experiment than in the semantic experiment. These data show that, while left- and right-superior-temporal regions may be differentially involved in processing pragmatic and lexico-semantic information within sentences, the left-inferior-temporal/fusiform gyrus is involved in processing all three types of linguistic information. We suggest that this region may play a key role in using pragmatic, semantic (selection restriction), and subcategorical information to construct a higher representation of meaning of sentences.

The use of linguistic context in positively thought-disordered (TD) schizophrenics was investigated through examination of their performance on an on-line word-monitoring task. Controls and non-TD schizophrenics took longer to recognize words preceded by linguistic anomalies compared with words in normal sentences. Compared with both other groups, TD schizophrenics showed significantly smaller differences in reaction time, suggesting that they were relatively insensitive to linguistic violations. TD schizophrenics were also less sensitive to linguistic violations in an off-line version of the task, in which they judged whether the sentences "made sense." Finally, these participants produced more errors on a verbal fluency task than did non-TD schizophrenics or normal controls. These findings are consistent with the theory that schizophrenic thought disorder arises from a deficit in the use of linguistic context to process and produce speech.

We review advances in the treatment of schizophrenia. We begin with an overview of antipsychotic drug development, focusing on the in vitro and in vivo binding profiles of clozapine and a new generation of D2:5HT antagonists. We then consider the main barriers to effective treatment: non-compliance (and side-effects) of medication, recurrent relapse, ’treatment resistance’, negative symptoms and neurocognitive deficits. Within this framework, we review the mechanisms of action and clinical uses of the ’atypical’ antipsychotic drugs. We also show how a variety of psychosocial interventions, particularly those that incorporate cognitive techniques, can be used in combination with pharmacotherapy to overcome the same clinical hurdles.