Donald C. Goff, MD

 published an article that examined the relationship between long-term antipsychotic treatment and brain volume in first-episode schizophrenia patients. That paper triggered considerable media attention. Because it was widely interpreted as showing that antipsychotics damage the brain, it may have caused many people-both patients and family members-to reconsider whether to take their prescribed medication.

As is so often the case, the picture is far from clear.

Ho and colleagues performed structural brain imaging every 3 years for up to 14 years in 211 first-episode patients who had been treated naturalistically. In the beginning, 15% were medication-naive and the majority were treated with first-generation antipsychotics; by the third scan, this had changed to most receiving second-generation antipsychotics and 23% receiving clozapine. On average, each subject was scanned 3 times and had already been treated for 5 months before the first scan.

The investigators found that gray matter volumes of all brain regions except for the cerebellum decreased over time; white matter volume on average was unchanged. Subjects who had received higher average lifetime doses of an antipsychotic had less gray matter at baseline and at all future time points. Neither antipsychotic dose nor type of antipsychotic (first-generation, second-generation, or clozapine) appeared to influence the rate at which gray matter loss progressed over time. In contrast, patients who received a low-dose antipsychotic tended to have modest increases in white matter volume over time compared with modest white matter loss in patients whose lifetime average dose was higher. The only advantage for second-generation antipsychotics over typical antipsychotics was a reduction in parietal white matter loss over time.

If we were to draw conclusions from this study alone, it would appear that gray matter loss can’t be altered by reducing antipsychotic exposure or by switching antipsychotic class-it just happens. The one possible benefit of a low-dose antipsychotic, the preservation of white matter, is of unclear clinical significance, as is the possible increase in parietal white matter with second-generation agents. However, the story gets more complicated as we look earlier in the course of treatment.

 published a report based on roughly half their current sample. In this analysis, they discovered that antipsychotic dose was related to the rate of loss of frontal gray matter, but only in medication-naive patients. Frontal gray matter loss, in turn, corresponded with cognitive decline. These relationships disappeared if subjects had been treated with medication before baseline scanning-in these subjects, brain-derived neurotrophic factor (BDNF) genotype predicted the rate of gray matter loss and the pattern of cognitive deficits. This suggests that gray matter loss associated with antipsychotic dose may have been missed entirely in the recent publication by Ho and colleagues because it may occur very early in treatment-before the baseline scan in the great majority of subjects.

Many additional potential confounds complicate these findings. First, it’s not possible to determine whether higher antipsychotic doses are contributing to the progression of brain loss or are merely a response to it. In the absence of an untreated control group, it’s also not possible to detect neurotoxic effects of drugs that are not related to dose and, without a healthy control group, it is not clear which changes in brain volume are pathological.

Animal studies can begin to address these issues. A study in monkeys conducted by David Lewis’ group prompted concern about antipsychotic neurotoxicity several years ago. Monkeys treated with haloperidol and olanzapine for 17 to 27 months lost roughly 10% of their total brain volume, both gray and white matter, compared with sham-treated controls, with greatest volume loss in frontal and parietal cortex.

 Further examination revealed a reduction in the number of glial cells

; a similar postmortem finding in schizophrenia brains previously had been attributed to the illness. However, this study included only 6 monkeys per treatment group and did not provide information on the time course of neurotoxic changes.

Other studies suggest that antipsychotic effects on brain volume may occur rapidly. For example, Vernon and colleagues

 found a significant loss of frontal cortical volume after only 8 weeks in rats given haloperidol or olanzapine.

Evidence of the rapidity at which antipsychotics can affect brain volume in humans was recently provided by Tost and associates.

 These investigators found a significant, reversible decrease in striatal volume in healthy subjects within 2 hours after they were treated intravenously with haloperidol. Loss of striatal volume powerfully predicted neurological adverse effects.

Taken together, these studies suggest that antipsychotics may contribute to early gray matter loss and, later in the course of treatment, to white matter loss. These effects may be dose-related and probably are not prevented by the use of second-generation agents. This argues for minimizing antipsychotic exposure both acutely and long-term. However, we are left with the additional dilemma that a longer duration of untreated psychosis (DUP) may also be neurotoxic. Longer DUP has been associated with poorer symptomatic and functional outcomes

 Studies of DUP have their own methodological limitations and controversies, but they should serve to warn us that the rapid control of psychosis may also be important.

Psychosis at any phase of the illness can be extremely distressing, disruptive, and potentially dangerous for patient and family. New approaches for early intervention are needed and, with existing drugs, the potential for neurotoxicity must be weighed against short-term and long-term clinical gains. In the meantime, clinicians should avoid using antipsychotics unnecessarily and, when needed, use the lowest effective dose.

 Ho BC, Andreasen NC, Ziebell S, et al. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. 

 Ho BC, Andreasen NC, Dawson JD, Wassink TH. Association between brain-derived neurotrophic factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. 

 Dorph-Petersen KA, Pierri JN, Perel JM, et al. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. 

 Konopaske GT, Dorph-Petersen KA, Pierri JN, et al. Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. 

 Vernon AC, Natesan S, Modo M, Kapur S. Effect of chronic antipsychotic treatment on brain structure: a serial magnetic resonance imaging study with ex vivo and postmortem confirmation. 

 Tost H, Braus DF, Hakimi S, et al. Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits. 

 Marshall M, Lewis S, Lockwood A, et al. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. 

 Malla AK, Bodnar M, Joober R, Lepage M. Duration of untreated psychosis is associated with orbital-frontal grey matter volume reductions in first episode psychosis. 

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 Psychosis at any phase of the illness can be extremely distressing, disruptive, and potentially dangerous for patient and family.  

Antipsychotics and the Shrinking Brain

It is a pleasure to introduce this series of 4 special articles on schizophrenia. As industry support has shaped postgraduate psychiatric education, the quantity of educational programs has grown dramatically while the breadth of topics has not. Within the field of schizophrenia, subjects related to the prescribing of newer antipsychotic agents are covered extensively, often with particular emphasis on the critical topic of metabolic complications.

Within these areas we teach what we know best; the preponderance of evidence from clinical trials on which most lectures are based comes from adult patients with chronic disorders and tends to focus on the response of psychosis and the prevention of relapse. Other aspects of clinical care receive less attention. The articles in this collection address some of these comparatively neglected subjects including the role of nicotine in schizophrenia.

 provide us with an update on negative symptoms in schizophrenia. The atypical antipsychotics were introduced with the promise of substantial benefit for negative symptoms, but the reality largely proved disappointing to clinicians and families. While some progress has been made in our understanding and treatment of negative symptoms, they remain a source of significant disability and an important area of unmet therapeutic need.

The authors provide guidance to clinicians on the identification and treatment of potentially reversible causes of secondary negative symptoms, such as depression and the neurological adverse effects of conventional neuroleptics. Educating family members about negative symptoms is also important, because family members are often unaware of this aspect of the illness and so may blame the patient for what they perceive as laziness or a deliberate refusal to engage socially or to accomplish basic tasks of daily living.

The central and often neglected involvement of family members is explored by 

 in their excellent review of family services. Traditional mental health training, based on the individual psychotherapy of higher-functioning individuals, has tended to foster an attitude among some clinicians that family members can be excluded from the treatment plan. This stance is unfortunate and potentially quite counterproductive in the care of individuals with schizophrenia. Family members experience significant feelings of loss and burden, both financial and psychological, but can also experience the satisfaction of fundamentally helping loved ones if given the opportunity.

The authors describe the experience of family members and the diverse benefits of psychoeducation and family involvement. They note the difficulty in disseminating and implementing these programs. Fortunately, alternative educational programs, such as the Family-to-Family Program sponsored by the National Alliance on Mental Illness, can be very effective and are usually quite well received by family members.

 and smoking cessation in patients with schizophrenia. Much attention has been paid to the metabolic adverse effects of antipsychotic agents. Far less attention has been directed at cigarette smoking, which is the single most important modifiable cardiac risk factor and an almost universal problem among patients with schizophrenia. This relative disinterest may reflect, in part, the conviction among clinicians that it is unrealistic to expect patients with schizophrenia to reduce or stop smoking.

As the author makes clear, success rates have steadily improved with new pharmacological and cognitive-behavioral approaches, and these interventions should be made available to all psychiatrically ill patients who smoke. In addition, intriguing links between nicotine receptor function, schizophrenia neurobiology, and the actions of atypical antipsychotics have emerged over the past decade. The authors provide an excellent description of promising therapeutic approaches based on this emerging understanding of nicotine receptor pharmacology.

In their review of antipsychotic prescribing in adolescents, 

 provide a valuable summary of an important area of research that has lagged behind the characterization of these agents in adult patients. They report that atypical antipsychotics are now frequently prescribed for younger patients. The extent to which we can apply lessons learned about efficacy and adverse effects from studies of adult patients remains unclear.

The evidence the authors cite suggests that younger patients may be more vulnerable to metabolic adverse effects. As the authors point out, weight gain can be very stigmatizing at this age and the longer-term consequences of cardiovascular risk factors beginning at an early age are of great concern. They note that recent evidence indicates that endocrine effects may not be as disruptive to development as previously feared. Results from several randomized trials in this area have been published over the past few years, and the NIMH-sponsored Treatment of Early Onset Schizophrenia Disorders Study is currently under way, but much more remains to be done.

Issues in Family Services for Persons With Schizophrenia

Atypical Antipsychotics Treatment of Schizophrenia Spectrum Disorders

It is a pleasure to introduce this series of 4 special articles on schizophrenia. As industry support has shaped postgraduate psychiatric education, the quantity of educational programs has grown dramatically while the breadth of topics has not.

Author | Donald C. Goff, MD

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