Matcheri Keshavan, Harvard University

I have always been interested in the nature of the self- questions such as who we are, and how an optimum knowledge of the self is critical for defining our health and happiness.  As I began learning to learn about the brain in medical school, I began asking- what in our brain determines our ability to distinguish the self from others. The young woman in my psychiatry rotation, diagnosed with schizophrenia, who was troubled by thoughts being stolen by, and feelings of her actions being controlled by an alien power, reflecting a blurred boundary between the self and other. This brilliant engineering student also had a substantive decline in her cognitive functions. She had been examined by neurologists, who felt there was no brain dysfunction they could identify; she was diagnosed with a “functional” psychosis. She questioned the diagnosis of schizophrenia, and I had no answer to her question as to how I can confirm her diagnosis. Her psychosis got better with medications, though she remained functionally impaired. Working with her crystallized my passion to study this illness. The fact that psychiatry was a field in which we could help change lives but still knew so little (which is true even now) drew me to pursue research.

It is hard to pinpoint a single mentor, but many remarkable individuals with illness, teachers and institutions were formative for my subsequent development as a clinician, teacher and researcher. Successive training experiences led me to learn about the various tools of understanding the brain, including imaging, EEG, neuroendocrine, genetic and cognitive neuroscience approaches. In parallel, as I began working with patients with a first psychotic episode, it became clear to me that studies in the early course is the best way to understanding these illnesses. It was also clear that treating psychosis was only part of the solution, and that addressing cognitive, and functional impairments early in the illness is critical. A series of controlled trials of cognitive enhancement therapy led to promising results for individuals in the early course of schizophrenia, and represents one of the most gratifying aspects of my work thus far.

As I continued to work with people with serious mental illnesses, it also became clear that no two individuals the same type of illness. Our symptom-based diagnostic labels were not neatly mapping on to what we saw in the clinic, with substantive overlaps in clinical presentation, treatment response and biomarkers across several psychotic illnesses, including bipolar disorders and schizophrenia. On the other hand, there appeared to be distinct groups of psychosis patients that appeared to differ in regard to the severity of cognitive impairments. This led us, as part of the bipolar-schizophrenia network for intermediate phenotypes (BSNIP) consortium, to propose a novel approach classification of psychotic disorders using cognition and electrophysiological biomarkers agnostic to DSM diagnoses.   This suggests that we may be in a position to predict outcomes in individuals in the early course of psychosis disorders, and also to identify which patients might respond best to specific psychosocial, or pharmacological interventions.  These questions shape my ongoing research which seek to translate research insights into clinical practice.

Looking back, it appears that understanding cognition and its impairments in psychoses, as well as improving these deficits is a theme that “connects the dots” in my career. It has also become clear that cognition may be the royal road to understanding this brain disease. More work needs to be done, that will hopefully steer our field toward a more precise way to understand, diagnose, and treat these highly enigmatic, and disabling illnesses.