Disease modifying effects of antipsychotic drugs in schizophrenia: a clinical and neurobiological perspective

Only in psychiatry would the benefits of one of the great pharmacological breakthroughs in the history of medicine be questioned over a half century after its introduction to clinical practice. When H. Laborit, a French Naval Surgeon stationed in Tunisia, serendipitously realized that chlorpromazine, a compound synthesized by the chemist P. Charpentier, could be used for the treatment of schizophrenia, and brought it to the attention of J. Delay and P. Deniker, psychiatrists at St. Anne's Hospital, a chain of events ensued that changed the course of psychiatry and ushered in the age of psychopharmacology1. The advent of this antipsychotic prototype was of comparable significance to other therapeutic milestones like the discovery of insulin, antibiotics and L‐dopa.

In the ensuing years, numerous studies by eminent researchers in many countries documented the therapeutic efficacy of chlorpromazine, and the other antipsychotics that followed, in relieving the acute psychotic symptoms of schizophrenia and preventing their recurrence2. And while neurological side effects were prevalent, and in many cases problematic, in most instances they could be managed with dose adjustment or adjunctive medications. Second generation (“atypical”) medications in turn provided comparable or (in clozapine's case) superior efficacy, and fewer neurological but more metabolic side effects. However, in both cases, the therapeutic benefits of antipsychotics, when used properly, more than offset their side effects3.

In addition to symptom suppression, longer term studies of patients in their first episode or early stages of illness suggested that antipsychotic drugs, by virtue of their ability to limit the duration and number of psychotic episodes, could impact the clinical deterioration which Kraepelin considered the defining feature of what he termed dementia praecox4. In other words, antipsychotics might not just be symptom suppressing, but could mitigate the progression of schizophrenia. If confirmed, this would mean that psychiatry had treatments that could modify the course of the illness, something that had not been achieved with other brain diseases, such as Alzheimer's, Parkinson's and Huntington's.

The evidence for this aspirational therapeutic effect is somewhat circumstantial, but nevertheless compelling, and includes the following.

Treatment studies of first episode patients have consistently found associations between the duration of psychosis prior to treatment and outcome5. Specifically, these studies have found that longer periods of active psychotic symptoms prior to first treatment were associated with poorer outcome. What is remarkable is that this relationship was present for outcomes measured in multiple ways, including the time to or level of recovery from the first episode, the time to or likelihood of relapsing after recovery from the first episode, and long‐term outcomes measured globally for up to five years after entering treatment for a first episode. Moreover, maintenance treatment studies have demonstrated the prophylactic effect of antipsychotic drugs in preventing relapse; treatment, then, may be responsible for mitigating the course of the illness and producing more favorable outcomes.

Furthermore, numerous investigations of brain morphology (post‐mortem and neuroimaging) have demonstrated structural abnormalities in various anatomic regions in schizophrenia patients compared to control subjects. These abnormalities primarily involve volume reductions of gray matter in soft tissue structures (e.g., hippocampus, temporal and frontal cortices, superior temporal gyrus, thalamus) and volume enlargements of fluid containing structures (e.g., ventricular system, subarachnoid space); but they also include shape anomalies and neurodevelopmental anomalies like cavum septum pellucidum, callosal agenesis and gray matter heterotopias. To the extent that some of these pathomorphologic features represent an atrophic process associated with illness progression, they are a target for therapeutic intervention. Various studies have demonstrated gray matter volume changes consistent with progression in specific anatomic regions, and an association between cumulative intake of atypical antipsychotic medication and less pronounced cortical thinning has been reported6. While the correlations of treatment and volume change cannot be confirmed as neuroprotective or disease modifying, they are certainly consistent with that interpretation.

Finally, since the introduction of antipsychotic medications into clinical practice, the frequency of the phenomenologic subtypes has changed. Historically, it was postulated that the less severe forms of schizophrenia were characterized by formed delusions, hallucinations and affective symptoms, and paranoid subtype diagnoses, while the more malignant forms exhibited negative, disorganized and motor symptoms and received hebephrenic and catatonic diagnoses. If there is indeed a continuum of severity in illness subtypes, a unidirectional pattern of change in patients' symptoms and diagnoses should reflect progression of the illness. Studies which have found an association between longer periods of untreated psychosis and a greater number of exacerbations and greater likelihood of developing negative, hebephrenic and catatonic symptoms are consistent with this interpretation. However, since antipsychotics came into use, the proportion of patients with predominant negative symptoms and hebephrenic and catatonic symptoms has decreased4.

Given the obvious acute and prophylactic benefits of antipsychotics, and the possibility that they may be disease modifying, it is hard to understand why there would still be questions as to their effectiveness. In fact, I cannot think of another medication class in other disease areas which has faced similar challenges to its effectiveness after longstanding use and voluminous supportive evidence. Classic “debunking” studies like the Cardiac Arrhythmia Suppression Trial (CAST)7 and the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)8 were either rigorous tests of clinical lore or comparative effectiveness studies. Given the number and consistency of studies, and numerous meta‐analyses, I wonder why reviews like that of Correll et al9 still need to be written for antipsychotics.

It is my contention that the enduring skepticism and distorted views of the clinical effects of antipsychotic drugs are mostly due to the stigma of mental illness and prejudice toward psychiatry, the medical specialty which is focused on their study and care10. The stigma historically associated with mental illness is currently perpetuated by lay and professional groups, who oppose the use and deny the efficacy of medication on ideological grounds. They are anti‐psychiatry or anti‐medical in their ideological orientation, and motivated by biased beliefs. Some lay persons challenge the notion of mental illness, the validity underpinning psychiatric nosology and the evidence supporting the therapeutic basis of psychotropic medications. Some professionals are motivated by factional disputes in mental health care between medical and psychosocial approaches. The latter seek to deny or diminish the evidence that mental disorders have biological bases and are effectively treated with somatic (medications, brain stimulation) forms of treatment, in favor of psychological explanations and psychotherapeutic approaches.

It is certainly appropriate, indeed warranted, to require hard evidence for the efficacy and safety of medical treatments as justification for their clinical use, but it is prejudicial and disingenuous to keep moving the threshold of proof higher and higher because of dogmatically held views. While we seek and hope for future scientific breakthroughs that will yield better drugs and even greater therapeutic advances, we must recognize and be grateful for what we have, and put them to the best use for our patients11.

Jeffrey A. Lieberman
Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York State Psychiatric Institute, New York, NY, USA