Biology of Psychiatric Disorders¶
Chapter 462 | Harrison's 22e · Part 13 – Neurologic Disorders · Chapter 462
Key Clinical Points¶
- Psychiatric disorders are heterogeneous syndromes currently lacking well-defined neuropathology and specific biological markers; diagnosis relies on clinical observation via DSM-5 criteria.
- The Research Domain Criteria (RDoC) framework addresses the limitations of categorical nosology by focusing on core behavioral abnormalities (e.g., psychosis, anhedonia) and underlying brain circuitry.
- Neurogenetics provides critical insights into pathogenesis; germline risk alleles are key for distinguishing etiological factors from compensatory responses.
- Autism Spectrum Disorders (ASD) are highly heritable (60–90% monozygotic twin concordance) and characterized by polygenic inheritance ('conspiracy of alleles').
- Opioid action in the locus coeruleus (LC) involves μ-opioid receptors, G_i/G_o proteins, and the cAMP-PKA-CREB pathway; chronic use leads to homeostatic upregulation of AC isoforms, PKA subunits, and tyrosine hydroxylase.
- Advanced tools like GWAS, high-throughput sequencing, and patient-derived iPSC-derived brain organoids are accelerating the study of psychiatric pathophysiology.
DEFINITION & CLASSIFICATION¶
• Current Clinical Status: Psychiatric disorders are broad, heterogeneous syndromes. ◦ Pathology: Currently lack well-defined neuropathology and bona fide biological markers. ◦ Diagnosis: Based solely on clinical observations using criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). • Alternative Framework: Research Domain Criteria (RDoC). ◦ Purpose: Addresses limitations of categorical nosology by focusing on core behavioral abnormalities shared across several syndromes. ◦ Key Domains: Includes psychosis (loss of reality) and anhedonia (decreased ability to experience pleasure) and the associated brain circuitry controlling these behaviors.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Neurogenetics: Essential for identifying molecular clues since the human brain can only be examined indirectly during life. ◦ Germline Risk: Identification of germline risk alleles/mutations allows distinction between etiological factors and compensatory responses (germline risk is present before the brain develops). ◦ Methodologies: Progress driven by genome-wide association studies (GWAS), high-throughput sequencing, and patient-derived pluripotent stem cells (iPSCs) to create brain organoids. • Genetics of Autism Spectrum Disorders (ASD): ◦ Heritability: Highly heritable; monozygotic twin concordance is 60–90% (a 4- to 6-fold increase compared to dizygotic twins). ◦ Inheritance Pattern: Polygenic; characterized by a "conspiracy of alleles" that are common in the population but carry small individual effects. ◦ Molecular Findings: Enrichment of pre- and postsynaptic molecules and chromatin modifiers. ◦ Developmental Convergence: Identified in deep layer (V and VI) excitatory neurons in mid-fetal human cortex; also noted in glutamatergic neurons in mid-fetal prefrontal cortex.
CLINICAL FEATURES¶
• Course and Prognosis: ◦ Severity: Ranges from mild/moderate (varying degrees of pre-illness function) to severe (patients essentially homebound). ◦ Progression: Most patients experience some improvement; however, return to prior level of function is unusual. ◦ Warning Signs: A continued decline in function should prompt evaluation for other illnesses. • Specific Risks (e.g., ME/CFS): ◦ Symptoms: Social isolation, loss of hope, serious depression, and increased risk of suicide.
DIAGNOSTIC APPROACH¶
• Clinical Observation: Diagnosis is made based on DSM-5 criteria. ◦ Symptom Monitoring: New or changing symptoms → work up to identify any new illnesses. ◦ Scheduled Intervals: Used to adjust treatments and detect intercurrent disease.
MANAGEMENT & TREATMENT¶
• Supportive Care: Counseling may help patients and their families cope with the long-term consequences of chronic illness. ◦ Rehabilitation: Consultation with physical or occupational therapists to identify energy-saving strategies and necessary accommodations (e.g., wheelchairs for limited mobility).
BIOLOGICAL MECHANISMS¶
• Opioid Action in the Locus Coeruleus (LC): ◦ Acute Mechanism: μ-opioid receptor → G_i/G_o proteins → inhibition of adenylyl cyclase (AC) → reduced cAMP → reduced PKA activity → reduced phosphorylation of CREB. ◦ Chronic Adaptation: Chronic administration leads to homeostatic upregulation of: 1. AC isoforms. 2. PKA catalytic (C) and regulatory (R) subunits. 3. Tyrosine hydroxylase (the rate-limiting enzyme in catecholamine biosynthesis). ◦ Result: Increased excitability of LC neurons due to enhanced cAMP signaling.
Reference Tables¶
TABLE 462-1 Initial Actions of Drugs of Abuse DRUG Opioids Psychostimulants (cocaine, amphetamine, methamphetamine)…¶
Harrison's 22e, p.3656
| DRUG | NEUROTRANSMITTER AFFECTED |
DRUG TARGET (ACTION) |
|---|---|---|
| Opioids | Endorphins, enkephalins |
μ- and δ-opioid receptors (agonist) |
| Dopamine | ||
| Nicotine | Acetylcholine | Nicotinic cholinergic receptors (agonist) |
| GABA | ||
| Glutamate | ||
| Acetylcholine | ||
| Serotonin | ||
| Others | ||
| Marijuana | Endocannabinoids (anandamide, 2-arachidonoylglycerol) |
CB receptor (agonist) 1 |
| Glutamate |