It does not adequately inform psychiatric practitioners about the many clinical and biologic features shared across the various diagnostic categories. It does not do justice to the galloping advances in the neurobiology of psychiatric brain disorders and the wealth of potential biomarkers that will eventually endow psychiatry with an objective and ultimately more valid, not just reliable, diagnostic model that is compatible with a future of precision medicine.

The Research Domain Criteria (RDoC) Project¹ is a valiant attempt to transcend the DSM’s “Chinese menu” approach to diagnosis. It was championed by the former director of the National Institute of Mental Health (NIMH), who used his authority to encourage investigators applying for federal grants to employ the RDoC principles in their research programs. Who does not recall the awkward moment, a few weeks before the official baptism of DSM-5 as psychiatry’s latest diagnostic Bible in May 2013? The NIMH director’s unflattering portrayal of the incipient DSM-5 was a well-publicized shot across the bow. The kerfuffle was later resolved, but its effects linger among clinical researchers who relentlessly hope for neuroscience advances to translate into a more objective diagnostic approach to psychiatric diagnoses. The neurobiological foundations of psychopathology are bound to guide us to a more valid set of diagnostic categories, yet the pace remains painfully slow.

However, the copious advances in brain research are providing other dividends beyond a better diagnostic forest. Many intriguing insights are emerging about the connectedness among major psychiatric “trees,” including schizophrenia, bipolar disorders, and major depressive disorder. The following are examples of neurobiology, clinical, and treatment commonalities across those psychotic and mood disorders.

Shared neurobiology

Progressive brain tissue loss/neurodegeneration.Numerous studies have established that abnormal neuroplasticity is a common theme during psychotic, manic, and depressive episodes. These findings have demonstrated that the more recurrent the episodes, the more prominent the atrophy in either overall brain volume or specific brain regions, especially in the hippocampus, prefrontal cortex, and cerebellum as measured on MRI.

White matter pathology. Multiple studies have reported a loss of myelin integrity in psychotic and mood disorders. Abnormalities are detected by using diffusion tensor imaging and measuring anisotropy and diffusivity of water flow in white matter traits. White matter pathology can be associated with intra- and inter-hemispheric disconnectivity and impairment of brain functional integration that may contribute to positive, negative, and cognitive symptoms.

Neuroinflammation. Acute psychotic and mood episodes have been shown to be associated with significant elevation in inflammatory cytokines in CSF and serum, including interleukins (such as interleukin-6), tumor necrosis factor-alpha, interferon gamma, and C-reactive protein. Those inflammatory biomarkers subside when the acute episodes are treated. It is believed that activation of the microglia leads to a release of proinflammatory cytokines.

Mitochondrial dysfunction. Many studies document various dysfunctions of the mitochondria in schizophrenia, bipolar disorders, and major depressive disorder. The consequences include oxidative stress due to a decrease in the antioxidant glutathione, produced in the mitochondria, which is vital for neutralizing the reactive oxygen and nitrogen species referred to as free radicals. There is a substantial increase of free radicals during acute psychotic and mood episodes, which contributes to neurodegeneration.

Glutamate pathway abnormalities. A large body of literature has focused on the glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction as a key pathophysiology in schizo­phrenia and mood disorders. Interestingly, the NMDAR appears to be hypo­active in schizophrenia as evidenced by the schizophrenia-like effects of potent NMDAR antagonism by phencyclidine and hyperactive in unipolar and bipolar depression as evidenced by the remarkably rapid improvement of treatment-resistant depression with the NMDAR antagonists ketamine or nitrous oxide. Glutamate pathways may ultimately shed light on the neurochemical pathology underpinning psychotic and mood disorders. The NMDAR is also likely linked to both neuroplasticity and cognitive impairments in the major psychiatric disorders because both are related to calcium passing through the NMDAR ion channel.

A large study of 4,444 consecutive patients in Taiwan found that those with low total cholesterol (<160 mg/dL) had higher scores of anxiety, phobia, psychoticism, and aggressive hostility.¹⁷ In the same study, women with low high-density lipoprotein cholesterol (<35 mg/dL) had significantly higher scores for depression, phobia, anxiety, interpersonal sensitivity, somatization, and aggressive hostility.¹⁷

Not surprisingly, low cholesterol has been proposed as a biomarker for mood dysregulation, depression, and suicidality,¹⁸ as well as a predictor of the depression severity and increased suicide risk.¹⁹ Clinical recovery in depression may be accompanied by a significant increase of total cholesterol²⁰ but, interestingly, a decrease in cholesterol levels after treatment of mania. High cholesterol was reported to predict poorer response to selective serotonin reuptake inhibitors, and total cholesterol levels >200 mg/dL were associated with lack of response to fluoxetine and nortriptyline.² Interestingly, clozapine, which elevates lipids, exerts a strong anti-suicide effect in schizophrenia and schizoaffective disorder, but that may not be the main reason for its efficacy in preventing suicide in patients with psychosis.

Cholesterol is an important lipid for brain function. At lower levels, it appears to be associated with depression, suicide, violence, anxiety, schizophrenia, and severe personality disorders (including antisocial personality disorder and borderline personality disorder). However, at high levels, it may improve cognition in schizophrenia and ameliorate the pace of AD and neurodegeneration. Psychiatrists should monitor patients for hypercholesterolemia and hypocholesterolemia, both of which are common among psychiatric patients. High levels may be genetic or the result of weight gain, hypercortisolemia, diabetes, or immune or inflammatory processes. Similarly, low levels may be genetic or secondary to statin therapy.

The bottom line: As psychiatric physicians, we should protect both the hearts and brains of our patients