Beyond DSM-5: Clinical and biologic features shared by major psychiatric syndromes

Gene/environment interaction. Neurogenetic advances have demonstrated some shared genes among schizophrenia, bipolar disorders, and major depressive disorder (such as the CACNA1C gene).² Also, environmental factors, such as severe childhood maltreatment, lead to high rates of psychosis and mood disorders in adulthood. Risk genes in schizophrenia and mood disorders are likely to be over­expressed with adverse environmental factors and epigenetics.

Shortened telomeres. Patients with psychotic and mood disorders have been reported to have shorter telomeres—proteins that cap the end of chromosomes and shorten with repeated cycles of mitosis and aging—at a younger age, predicting early senescence and mortality. Telomere shortening is associated with multiple factors, including chronic stress, smoking, poor diet, obesity, infections, inflammation, and free radicals, all shared by major psychiatric disorders.

Genetic heterogeneity. Schizophrenia, bipolar disorders, and major depressive disorder are associated with complex genetics (eg, risk genes, mutations, and copy number variants) and various perinatal complications (eg, infections, gestational diabetes, vitamin D deficiency, hypoxia at delivery), which makes them highly heterogeneous syndromes, comprised of hundreds of biotypes. There are many established endophenotypes that a future diagnostic system should adopt.

Elevated cortisol levels. Increased serum cortisol levels are found in depression and schizophrenia related to HPA axis dysregulation as well as life stress. Hypercortisolemia can contribute to neurodegeneration as well as to multiple systemic medical disorders often encountered in mood and psychotic disorders.

Shared clinical features

Psychotic and mood disorders share several key clinical features, including:

• cognitive deficits
• substance use disorders (especially Cannabis and alcohol) as a common comorbidity
• increased suicide risk
• high prevalence of smoking
• premature mortality, by 10 to 20 years
• anxiety as a common comorbidity
• elevated cardiometabolic risk factors, even before pharmacotherapy
• recurrent relapses lead to treatment resistance
• various degrees of fixed false beliefs (delusions)
• perceptional aberrations (various types of hallucinations)
• response to dopamine-serotonin an­­tagonists (atypical antipsychotics) as monotherapy or adjunctive therapy.

While it is fair to say that a diagnostic manual like DSM-5 should focus on the diagnosis of individual psychiatric diseases and syndromes, it is also reasonable to say that focusing primarily on clinical features does not do justice to the biologic complexities of psychiatric disorders and the importance of including biomarkers to increase the validity of psychopathological categories. The shared neurobiologic and clinical features across major psychiatric syndromes, such as schizophrenia, bipolar disorders, and depression, indicate how multifaceted psychiatric diagnosis can be. The same approach is applicable to other psychiatric syndromes, such as anxiety, personality disorders, attention-deficit/hyperactivity disorder, or dementia. Our field should move firmly and steadily toward a diagnostic schema that incorporates ongoing breakthroughs in psychiatric neuroscience as soon as they are replicated.

If psychopathology is a forest, then DSM-5 is a simplistic depiction of each tree’s structure as roots, a trunk, branches, and leaves. Psychiatry needs to move to a far more sophisticated perspective of each tree as an amazingly complex, dynamic, and evolving organism, designed genetically but continuously influenced by its environment. Psychiatry also should keep an eye on the entire forest and detect distinctive patterns as well as idiosyncratic or shared features among the trees. Major insights will ensue about the etiology, course, and management of each diagnostic tree or the mosaic of related trees.