Comprehensive Study Notes on Psychiatric Disorders: Anxiety, Affective Disorders, and Schizophrenia

Classification and Definitions of Psychiatric and Anxiety Disorders

Psychiatric disorders are broadly categorized into three major classes: Anxiety disorders, Affective disorders, and Schizophrenia. Anxiety disorders themselves are defined by specific emotional states and physiological responses. Fear is an emotional state associated with the desire to escape from an immediate threat; it is considered innate and species-specific. In contrast, anxiety is a general feeling that something bad is going to happen in the absence of an immediate threat, often described as "worry." Anxiety disorders are the most common of all psychiatric disorders. Notable examples include Panic disorder, Agoraphobia, Generalized anxiety disorder, Specific phobias, and Social phobia. Additionally, the term "AQ" is associated with these categorizations.

Disorders Characterized by Increased Anxiety: OCD and PTSD

Other disorders involve increased levels of anxiety but have distinct symptomatic profiles. Obsessive-compulsive disorder (OCD) is defined by obsessions—which are recurrent, intrusive thoughts, images, ideas, or impulses—and compulsions, which are repetitive behaviors performed to reduce anxiety. Posttraumatic Stress Disorder (PTSD) involves symptoms that must last for at least one month following a trauma. These symptoms include flashbacks, nightmares, irritability, emotional numbness, the avoidance of reminders of the traumatic event, and an exaggerated startle response.

Biological Bases and the Physiological Stress Response

There is a genetic predisposition for many anxiety disorders. A stressor is defined as a threatening stimulus that evokes fear. The resulting stress response involves a sequence of physiological events: Sympathetic activation, Adrenal activation, and eventually Exhaustion. The stimulus-response relationship can be strengthened or weakened by experience. Bruce McEwen defines stress as "events interpreted as threatening to an individual [that] elicit a physiological response." Sources of stress can be negative, such as trauma or illness, or positive, such as the birth of a child or a job promotion. Regardless of the stimulus, the physiological response remains the same.

Neural Circuitry of Fear: Amygdala and Related Structures

The amygdala is centrally involved in fear and anxiety processing. It projects to three primary regions to coordinate the stress response: the Hypothalamus, which manages the peripheral stress response including increased heart rate and the release of stress hormones; the Prefrontal cortex, which controls the behavioral approach to or avoidance of fearful stimuli; and the Pons, which mediates the tensing of neck and trunk muscles during a startle response. The human amygdala shows activation when individuals view faces with emotional expressions such as fear or anger. People with specific phobias exhibit hyperactivation in the amygdala when presented with stimuli related to their phobia. Neurochemically, this circuitry involves a balance between CCK (cholecystokinin) and GABA within the prefrontal cortex and amygdala.

The Hypothalamic-Pituitary-Adrenal (HPA) Axis and Regulation

The HPA axis is the primary pathway for the physiological stress response. The process begins when the Hypothalamus releases corticotropin-releasing hormone ($CRH$). This triggers the Anterior pituitary gland to release adrenocorticotropic hormone ($ACTH$), which travels through the blood to the Adrenal gland (located near the Kidney). The Adrenal gland then releases Cortisol, which effects physiological changes supporting fight-or-flight responses. The HPA axis is regulated by a "push-pull" mechanism involving the Amygdala and the Hippocampus. Both regulate $CRH$ neurons: the Amygdala activates the HPA axis, while the Hippocampus deactivates it. The hippocampus contains glucocorticoid receptors that participate in a feedback loop to inhibit the HPA axis.

Impact of Chronic Stress and PTSD Physiology

Chronic stress leads to impaired immune system function. Elevated Cortisol causes atrophy of the hippocampus characterized by an increased rate of neuronal death and a decreased rate of neurogenesis (the addition of new neurons). Because the hippocampus normally inhibits the HPA axis, its atrophy creates a cycle of dysregulation. PTSD patients exhibit unique physiological markers: they often have lower than normal baseline cortisol levels but show an exaggerated cortisol increase when exposed to trauma-related stimuli. Studies of combat veterans with PTSD and their identical twins without combat experience show that both have smaller than average hippocampi, suggesting a possible genetic vulnerability.

Pharmacological Treatments for Anxiety

Treatments for anxiety disorders include therapy and anxiolytic medications. Benzodiazepines work by targeting the $GABA_A$ receptor, specifically the GABA-gated $Cl^-$ channel. These receptors have binding sites for GABA, Benzodiazepines, and Ethanol. Serotonin-selective reuptake inhibitors (SSRIs) are also utilized, particularly for OCD. New targets for drug research include $CRH$ receptors and $CCK$.

Affective Disorders: Depression and Bipolar Disorder

Affective disorders are mood disorders. Recurrent depression includes Major depression, which has a $10\%$ lifetime prevalence, and Dysthymia. Bipolar disorder, or manic-depressive disorder, has a $1\%$ lifetime prevalence and involves recurrent episodes. Type I Bipolar is characterized by mania, while Type II is characterized by hypomania. Mania involves inflated self-esteem or grandiosity, a decreased need for sleep, increased talkativeness, racing thoughts, distractibility, increased goal-directed behavior, and excessive involvement in pleasurable activities like gambling or sex. It can also include psychotic features such as delusions and paranoia and is often severe enough to require hospitalization.

Biological Theories and Genetic Links for Mood Disorders

The monoamine hypothesis suggests depression results from a deficit in central diffuse modulatory systems (DA, NE, 5-HT). Levels of monoamine metabolites are reduced in the CSF of depressed patients. While drugs like Reserpine, MAO inhibitors, and Imipramine increase monoamine levels and relieve symptoms, there is a "catch": medications increase monoamine levels immediately, yet it takes $2$ to $3$ weeks for symptoms to improve. The diathesis-stress hypothesis posits that a genetic predisposition ($diathesis$) combines with early life stress to make the HPA axis hyperactive. Regarding genetics, Caspi et al. (2003) found that individuals with at least one copy of the short ($s$) allele of the serotonin transporter gene who also had a history of stressful events were at a higher risk for depression. Furthermore, chronic stress leads to decreased $BDNF$ (Brain-Derived Neurotrophic Factor) in the Hippocampus, while antidepressants increase monoamines and enhance neurogenesis and neuronal survival via $BDNF$.

Neural Activity and Clinical Interventions for Affective Disorders

Resting-state metabolic activity in the anterior cingulate cortex is increased in depression. Bipolar disorder is at least partly hereditary, with a $50\%$ concordance rate in monozygotic twins, and is associated with increased activity in the amygdala and orbitofrontal cortex. Treatment options include Electroconvulsive therapy (ECT), which provides quick relief in the temporal lobe but can cause memory loss; Psychotherapy for mild to moderate cases; and Antidepressants (MAO inhibitors, tricyclics, and SSRIs like Fluoxetine). Lithium is the standard treatment for Bipolar disorder. Deep Brain Stimulation (DBS) of the anterior cingulate cortex is used as a last resort for severe depression. In terms of efficacy, antidepressants and psychotherapy both show $50-60\%$ improvement rates (compared to $30\%$ for placebo), and combining them is slightly more effective than either alone.

Sleep, Circadian Rhythms, and Depression

Disordered sleep is a prominent symptom of depression. Patients exhibit reduced REM latency (entering REM sleep sooner) and increased REM periods throughout the night. Total or selective sleep deprivation (waking a patient whenever they enter REM) is a highly effective treatment for about $2/3$ of patients. Like medications, these effects accumulate over several weeks.

Schizophrenia: Symptoms and Biological Markers

Schizophrenia is a severe mental disorder characterized by a loss of contact with reality. Positive symptoms include auditory hallucinations, delusions of grandeur or persecution, disordered thought processes, and bizarre behaviors. Negative symptoms include social withdrawal, flat affect (blunted emotions), anhedonia (loss of pleasure), reduced motivation, alogia (reduced speech), and catatonia (reduced movement). Biological markers include a larger ventricle-to-brain size ratio and disorganized pyramidal cells in the hippocampus, parahippocampus, and entorhinal cortex. This cellular disorder correlates with symptom severity and may be linked to maternal influenza during the second trimester of pregnancy.

Neurochemical Hypotheses and Treatment of Schizophrenia

The Dopamine Hypothesis suggests psychosis is triggered by the activation of dopamine receptors, as high doses of amphetamines can cause delusions and paranoia. Conventional neuroleptics like chlorpromazine and haloperidol block $D_2$ receptors and reduce positive symptoms, but they cause side effects like Parkinson’s disease symptoms and tardive dyskinesia. The Glutamate Hypothesis is based on the effects of PCP and Ketamine, which inhibit NMDA receptors to mimic schizophrenic symptoms, suggesting the disorder reflects diminished NMDA activation. Hallucinogens like LSD act on serotonin ($5-HT$) but produce visual hallucinations, whereas schizophrenic hallucinations are mainly auditory; thus, serotonin is likely not the primary mechanism. Modern drug research is focusing on the NMDA receptor. Treatments typically combine drug therapy with psychosocial support.

Concluding Perspectives on Psychiatry and Neuroscience

Mental illness is increasingly recognized as pathologic modifications of the brain where genes and environment interact. While drugs affect chemical synaptic transmission, the delay in therapeutic effect remains unclear. Furthermore, the exact mechanism of how psychosocial treatments act upon brain structures is less understood than pharmacological interventions.