Several years ago, a research group from the United Kingdom announced in the prestigious scientific journal Nature that a gene for schizophrenia had been located. This was greeted with widespread applause. Even the editors of Nature believed that a major piece of the puzzle for schizophrenia had at last been found.

Sadly, the bubble soon burst. Despite many attempts, no one was able to replicate the initial finding, and it is now widely felt to have been a mistake. This is no longer surprising. Use of the restriction fragment length polymorphism approach to finding genes for complex disorders like schizophrenia has been notably unsuccessful. Currently, journal editors are alerted to the receipt of claims that a gene for some disorder has been found, only to be burnt by the next dozen failures to replicate the finding. The schizophrenia “finding” was a great disappointment.

The number of graduating psychiatry residents who choose a career in academic medicine is remarkably small, and the percentage who become National Institutes of Health (NIH)-funded investigators is even smaller. Although this trend for a reduced number of physician-scientists is true in all branches of medicine and has reached criticialproportions, the perception is that this shortage is even more severe in psychiatry. The purpose of this essay is to increase awareness of the problem and begin a discussion of the reasons why the field finds itself in this problematic situation.

First, however, it is important to more clearly define the nature of the problem. At the current time, NIH funding for research and training grants (Research Career Development Awards) has attained unprecedentedly high levels, with the percent of submitted applications that are funded higher than ever thought possible. Physicians who submit NIH grant applications are as successful as their PhD colleagues, dispelling the myth that physicians cannot compete with PhDs for such funding. Others have raised the question as to whether physicians are necessary or even desirable as investigators. In other words, the entire concept of a clinician-scientist is considered by some to be simply passé.

Rumor has it that the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) is on the way. Apart from giving the American Psychiatric Association an enormous financial boost, this should be an opportunity to improve on some of the terrible intellectual lapses of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Revised (DSM-IV-R), to bring DSM and the International Classification of Diseases (ICD) schemes closer together, and to expand on biological and other markers as diagnostic components in the classificatory process. It is hoped that more than the first of these possibilities will be realized.

Since the publication of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, (DSM-III), the DSM manuals have brought a measure of good sense to clinical practice and have improved communication among researchers, so that at least in theory schizophrenia is similar on both sides of the Atlantic, and most probably is similar on both coasts of the United States. The slavish adherence to listed criteria has developed a sense of renewed interest in phenomenology of a practical kind, and exclusion criteria mean that not all individuals who visit a psychiatrist's office can be guaranteed a diagnosis. The distinction between Axis 1 and Axis 2 categories and the removal of any psychoanalytic taints was a stunning acceptance of Jaspers pace Freud.

The medical records of 110 patients receiving conventional antipsychotics at two geographically distinct Veterans Administration hospitals (Syracuse, New York and Omaha, Nebraska) were reviewed. The most common reasons for continuation of conventional antipsychotics were good response and patient or physician choice. Frequently, physicians did not discuss the reasons for continuing conventional antipsychotics or the availability of alternative therapies with their patients. Geographic differences in physicians' prescribing practices of conventional antipsychotics were apparent.

Individuals with schizophrenia are known to demonstrate cognitive and behavioral difficulties, particularly alterations in executive functions, including working memory. It is unclear whether these deficits reflect trait-related vulnerability to schizophrenia indicators and can be assessed by studying nonpsychotic relatives of patients with schizophrenia. In this study, we used an oculomotor delayed response (ODR) paradigm to examine spatial working memory in 37 “high-risk” child and adolescent offspring and siblings (age range=6–25 years) of patients with schizophrenia or schizoaffective disorder. Compared with 37 age- and sex-matched healthy controls (age range=6–23 years), high-risk subjects showed nonsignificantly greater errors in the ODR task at longer delay intervals. Statistical analyses suggested that performance improved with age in healthy control subjects, whereas it worsened with age in high-risk subjects. In both groups, the ODR errors were generally associated with poorer sustained attention (Continuous Performance Test: visuospatial d prime), some-what poorer executive function (Wisconsin Card Sorting Test), and elevated Heinrichs-Buchanan neurological soft signs scores. These findings indicate the presence of spatial working memory abnormalities in individuals at risk for schizophrenia. Furthermore, these abnormalities may be progressive in nature. The ODR task is a valuable indicator of prefrontal cortical function and spatial working memory and may be a potentially valuable marker for familial risk of schizophrenia.

Use of augmenting agents in schizophrenia is a common practice in response to resistant symptoms or comorbid illness. Increasingly, clinicians are combining more than one antipsychotic agent, despite a lack of evidence from controlled studies to support this approach. A rationale can be made for adding higher-potency agents to clozapine in an attempt to optimize D2 dopamine receptor blockade, but this strategy requires further study before it should be adopted in clinical practice. Older reports have explored the use of antidepressants, mood stabilizers, and anxiolytics as augmenting agents. These agents appear to improve comorbid affective or anxiety symptoms, but earlier evidence of improvement in psychotic or negative symptoms has not been replicated consistently. Glutamatergic agents acting at the glycine coagonist site of the N-methyl-D-aspartate receptor, including glycine, D-cycloserine, and D-serine, have demonstrated impressive therapeutic effects for negative symptoms when added to conventional neuroleptic agents, but do not appear to enhance clozapine efficacy. Given the high rates of symptom persistence and disability associated with schizophrenia, the need for augmentation strategies is great, but no approach has clearly emerged as effective for a substantial portion of patients. Although certain approaches may prove helpful for individual patients, augmentation should not be used unless monotherapy has been optimized, and should not be continued long-term unless benefits are clear.

Since the introduction of clozapine, several novel antipsychotic agents have been introduced and more are in Phase II/III studies. Because these agents are used clinically as first-line treatment, we need to be more familiar with their side-effect profiles. This manuscript reviews the cardiovascular side effects of currently available novel antipsychotics. The medications reviewed include clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. Guidelines are suggested for the use of these medications in clinical practice.

Treatment of acute mania has been greatly influenced by loading strategies. Loading has potential benefits, including rapid symptom reduction in mania and a shortened length of stay. Disadvantages include an increased likelihood of adverse effects of the medications. Loading strategies for lithium, valproic acid (divalproex sodium), carbamazepine, oxcarbazepine, olanzapine, and haloperidol decanoate in the treatment of acute mania are discussed. Recent studies high-light this treatment option for selected patients. It is the unique properties of the medications that influence their use in loading. Issues in patient selection for loading strategies with each medication are also considered.