From the Editor

Depression and schizophrenia: Many biological and clinical similarities

Current Psychiatry. 2023 February;22(2):3-5 | doi: 10.12788/cp.0331

References

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Clinicians generally regard major depressive disorder (MDD) and schizophrenia as 2 separate and distinct psychiatric brain disorders. However, despite some differences, those 2 psychiatric syndromes have numerous similarities across clinical features and neurobiologic parameters.

Biological similarities

Both disorders share the following variables:

Highly genetic in etiology but with environmental influences and epigenetics
Associated with childhood maltreatment, abuse, or neglect
Disrupted neuroplasticity, especially shrinkage in hippocampal volume
Significant drop in brain-derived neurotrophic factor resulting in decreased neurogenesis
Extensive white matter pathology across interhemispheric and intrahemispheric bundles
Increased levels of serum cortisol, a stress hormone and inflammatory biomarker
Hypofrontal cerebral blood flow during acute episodes of both MDD and schizophrenia
Reduced dendritic spines (in number and size) and impaired experiential neuroplasticity
Neuroinflammation (eg, cytokines, tumor necrosis factor-alpha, C-reactive protein) during acute episodes
Elevated oxidative stress biomarkers, indicating an increase in free radicals
Overactive default mode network associated with ruminations in MDD and “daydreaming” in schizophrenia
Decrease in gamma-aminobutyric acid (GABA) and its inhibitory activity, translating into dysregulation of glutamatergic pathways and other neurotransmitters
Immune dysregulation and comorbid autoimmune disorders

Clinical similarities

Psychotic symptoms, especially delusional thinking such as paranoia in schizophrenia and severe self-deprecation in MDD
Significantly elevated lifetime suicide risk
Cognitive impairment (more severe in schizophrenia across several cognitive functions)
Similarity of depressive and negative symptoms (especially anhedonia, apathy, restricted facial expression, social withdrawal)
Antidepressant medications im-prove depressive and negative symptoms (though not completely in the case of negative symptoms of schizophrenia)
Both have treatment-resistant subtypes that fail to respond to standard therapies
Both are associated with comorbid generalized anxiety disorder
Both are associated with comorbid obsessive-compulsive disorder
Both are associated with serious alcohol and drug use
Early mortality from general medical conditions, especially cardiovascular risks due to obesity, diabetes, hypertension, dyslipidemia
Elevated risk of dementia with aging compared to the unaffected general population
Opioids improve MDD and psychosis (buprenorphine in MDD and morphine in schizophrenia)
Several second-generation antipsychotic medications are approved for both MDD and schizophrenia
Electroconvulsive therapy is effective when pharmacotherapy fails in both MDD and schizophrenia

Biological differences

Glutamate N-methyl-D-aspartate receptor antagonists (eg, ketamine) improve MDD but worsen schizophrenia
Muscarinic agonists improve psychosis but worsen depression
High pain threshold in schizophrenia (pain insensitivity) and low threshold in MDD (in which pain is a common comorbidity)
Cortical thinning more severe in schizophrenia
Hippocampal atrophy is reversible with successful treatment in MDD but not in schizophrenia
Hypofrontality is reversible with remission in MDD but not in schizophrenia

Clinical differences

Auditory and visual hallucinations are more common in schizophrenia than in MDD
Anosognosia is common in schizophrenia but not in MDD
Implausible delusions are more common in schizophrenia than in MDD
Mood-congruent delusions are more common in MDD than in schizophrenia
Sadness, crying, pessimism, and self-deprecation are common in MDD but not in schizophrenia
Achieving full remission is more common in MDD than in schizophrenia
Long-acting injectable medications are available for schizophrenia but not for MDD
Evidence-based psychotherapy, without pharmacotherapy, is more likely to be effective in MDD than in schizophrenia

A transdiagnostic model of psychopathology

The significant overlap between MDD and schizophrenia should not be surprising. They are both generated by the same organ, the human brain, with disrupted neurochemical and physiological circuits in the brain.

The overlap is also consistent with the emerging transdiagnostic model of psychopathology.^1-9 This model proposes that there is a “core” genetic risk for psychopathology with different iterations. The transdiagnostic model is in stark contrast to the prevailing DSM-5, which categorizes psychiatric disorders in “silos,” as if they are completely independent from each other despite many shared features. This is highly debatable according to the substantial evidence that multiple psychiatric disorders share many genes that influence brain development in utero and predispose individuals to a variety of clinical symptoms in adolescence and young adulthood.

The origin of mental illness is being disentangled by emerging research, which is identifying the common links among the various disorders currently listed in DSM-5.¹⁰ However, the evolution of psychiatric diagnosis has come full circle from a single entity before DSM, to multiple entities with DSM, and now back to a unified transdiagnostic model that is rapidly emerging.¹¹ This has implications for the FDA’s persistent dogma that clinical trials for new drugs must be targeted for 1 of the DSM-5 categories, a flawed and narrow assumption. Given the accelerating body of evidence for a unified, transdiagnostic model, it makes much more sense for the FDA to approve medications that target a psychiatric symptom that is shared by multiple psychiatric conditions within a transdiagnostic clinical system. When medications are approved for a symptom regardless of a DSM diagnosis, the term “off-label” and its “stigma” will then fade into history, along with the malignant preauthorization racket that was invented by greedy insurance companies that exploit the off-label use of medications (even when an FDA-approved medication for the patient’s condition does not yet exist) simply to deny coverage, lower their expenses, and fatten their profits.

Subtle cognitive decline in a patient with depression and anxiety