Lessons From Neuropsychiatry

Psychopathology is a parallel manifestation of brain disease to common “neurological” (e.g., motor, sensory, visual) symptoms. Depression in patients with Parkinson’s disease, for example, likely arises from the underlying brain pathology or the consequences of medication treatment, as do the motor symptoms (both the bradykinesias and the dyskinesias) of the disease. Because this likelihood has not come to be appreciated, the understanding of psychopathology in patients with epilepsy has lagged behind that of Alzheimer’s or Parkinson’s disease. Early students of psychopathology associated with epilepsy classified it in relationship to the occurrence of its neurological manifestations (the seizures) instead of by using traditional syndromic approaches to classification, followed by attempts to relate psychopathological syndromes to the brain damage that led to the seizures. To this day, psychiatrists working in the epilepsy area tend to classify psychiatric syndromes as pre-, peri-, or postictal . 12

While this approach provides a temporal explanation of the appearance of psychiatric symptoms, it fails to account for the etiopathogenesis of epilepsy and for the parallel psychiatric phenomena unleashed by the abnormal or damaged brain. Rather than approaching psychiatric phenomena in relation to seizures, the psychiatry of epilepsy would be better served by renewing the effort to understand differences in the brains of epileptic patients with and without psychopathology. Emerging brain-imaging modalities, such as diffusion tensor imaging, show great promise in advancing an understanding of circuit integrity in the living brain and could be used in the epilepsy field.

The taxonomy articulated in DSM-IV only partly fits the psychopathology seen in neurological disease. Some conditions seen in neurological disease, such as post-stroke depression, phenomenologically resemble what is described in DSM-IV as major depression, 13 and the same may be true for depression after traumatic brain injury. 14 However, psychiatric disorders in several other conditions (e.g., Alzheimer’s disease, HIV, Parkinson’s disease, multiple sclerosis, Huntington’s disease) do not fit well into the DSM-IV mold. Further, DSM-IV does not describe well certain other psychopathological conditions seen in neurological disease, such as apathy or executive dysfunction syndrome. 3 And DSM-IV, in its “atheoretical wisdom” that enumerates descriptions without explanations, does not differentiate conditions as physiological consequences of the brain disease versus “reactive” psychological states in brain damaged patients. As we move toward DSM-V, careful attention must be paid to the psychiatric phenomenology of patients with particular neurological diseases and to developing etiologic criteria that may link psychiatric syndromes to brain disease. Such criteria have already been proposed, drawing from clinical epidemiology. 15

In other words, what works to reduce psychiatric symptoms in one neurological disorder may not work in another; replication is necessary. After a stroke, the efficacy of antidepressants for major depression, perhaps specifically of tricyclic antidepressants, is now established 16 and there is evidence that antidepressant therapy may prevent the onset of depression after stroke. 17 However, this is not the case with traumatic brain injury, multiple sclerosis, epilepsy, Alzheimer’s, and Parkinson’s disease. In the latter two, the value of antidepressants has not been unequivocally supported by randomized trials. 18, 19 In fact, in Parkinson’s disease the superiority of antidepressants over placebo for the treatment of depression is unproved, after several randomized trials. 20 In Alzheimer’s disease, the data more clearly support antidepressant efficacy, thanks to refinements in outcome assessment 21 necessary to demonstrate benefit. The lesson here is that what has been learned about symptom-targeted therapy in general psychiatry is not readily transferable to neuropsychiatry. Disease-specific study of treatment is necessary. Ultimately, effective therapy will only come about when disease-specific mechanisms are understood, leading to rational therapeutics.

Existing treatments targeted at psychiatric symptoms in patients with brain disease have failed to reverse the brain damage, in part because they target specific symptoms that result from the loss of brain tissue. In Parkinson’s and Alzheimer’s disease, therapies exist that improve motor ( L -dopa), cognitive (cholinesterase inhibitors), affective (antidepressants), or psychotic symptoms (antipsychotics). These therapies have been applied either empirically or out of evidence that specific symptoms arise with specific neurotransmitter disturbances. None of these treatments addresses the causes of the neurotransmitter deficits, namely progressive neuronal degeneration. In Alzheimer’s disease, treatments that address more fundamental disease mechanisms do not resemble the symptomatic treatments. When brain damage is more severe, most of the mechanism-oriented therapies will likely not be successful after symptoms have started; in order to prevent brain damage, they will have to be applied before symptoms emerge. Generalizing this to schizophrenia means that our best bet to “cure” that disease is to prevent the “brain mis-wiring” that seems to underlie it. The field needs to move to understand the biological manifestations of pre- or early symptomatic phases of brain disease.

Distinctions between neurology and neuropsychiatry are being blurred to the point of extinction. Even if nothing were learned about brain-behavior relationships from neuropsychiatry, we would still learn about the psychopathology of the neurological patients themselves. Psychiatric morbidity affects the great majority of these patients. Dementia, depression, delusions, and hallucinations are most troubling to patients and caregivers, and in general are even more troubling than motor, sensory, or other neurological symptoms. Disability is strongly linked to psychiatric symptoms and functional decline is often a consequence of their persistence. With millions of patients living with chronic neurological diseases (4.5 million Alzheimer’s patients, 500,000 new stroke victims annually, over a million individuals with moderate or more severe traumatic brain injury every year, and millions of others with epilepsy, multiple sclerosis, etc.), the public health significance of caring for the psychiatric aspects of neurological disease is substantial. Developing a better understanding of the emergence of psychiatric disorders in neurological disease, and improving treatments for these conditions should be a major public health priority. Making sure that these millions of patients can access proper psychiatric care is critical to their well-being. As life expectancy after brain damage is steadily lengthened, planning for the growth in the number of cases with such conditions is also needed. Whether or not much is learned about other aspects of psychiatry, caring for these patients better is reason enough for this effort.

As neuroscience and psychology become more applied, as new tools become available to study the living brain, and as translational efforts take off in the next few decades, neuropsychiatry will continue to grow as a field rooted in the interface between neurology and psychiatry, as will caring for the patients seen at that interface. The basic sciences will bring better tools to help facilitate improved understanding of the etiopathogenesis of psychopathology in neurological disease, and continue to reap lessons about brain-behavior relationships. Concurrently, the clinical sciences should make a priority the development and study of treatments for psychopathology in neurological disease, and the educational oversight organizations, such as the American Board of Psychiatry and Neurology, and the Residency Review Commission of the Accreditation Committee for Graduate Medical Education, should modify educational activities, core competencies, and requirements to reflect advances in this area. This effort must also continue to focus on these underserved patients themselves to be sure that what we learn is applied through secondary translation from best practices to widely used practices.

The author is grateful to Drs. Paul McHugh, J. Raymond DePaulo, Peter Rabins, and Hochang (Ben) Lee for their generous comments on earlier drafts of this paper.