Psychiatric Disorders & Schizophrenia

Biopsychosocial Model of Mental Illness

• Psychiatric disorders are psychological disorders severe enough to require treatment by a clinical psychologist or psychiatrist.
• A major challenge in psychiatry is the lack of biological markers for disorders, unlike other medical fields.
• Psychiatric diagnoses rely on behavioral phenomenology (patient symptoms), making accurate diagnosis difficult.
• Diagnoses are guided by the Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association.
• Two main difficulties in diagnosing psychiatric disorders:
  • Substantial heterogeneity in clinical presentation within a disorder.
  • Patients suffering from different disorders often display many of same symptoms, emphasizing the importance of differential diagnosis.

Schizophrenia

• Schizophrenia is a severe psychiatric disorder affecting 1% of the population, with onset in adolescence or early adulthood.
• The current DSM refers to it as Schizophrenia spectrum disorders.
• The term means "splitting of psychic functions".
• Positive symptoms represent an excess of typical function:
  • Delusions
  • Hallucinations
  • Inappropriate affect
  • Disorganized speech or thoughts
• Negative symptoms represent a reduction or loss of typical function:
  • Affective flattening
  • Avolition
  • Catatonia (severe cases)

Schizophrenia Treatment

• Treatment involves antipsychotic drugs.
• Chlorpromazine was discovered accidentally in the early 1950s and calmed agitated patients.
• Reserpine, from the snake root plant, was effective but is no longer used due to the risk of dangerously lowering blood pressure.
• Motor side effects of some drugs mimic those seen in Parkinson’s disease.

Dopamine Theory of Schizophrenia

• The theory emerged in the 1960s that schizophrenia is associated with excessive activity in dopaminergic systems in the brain.
• Antipsychotic drugs exert their effect by decreasing dopamine levels.
• Support for the hypothesis came from the observation that reserpine depletes the brain of dopamine.
• Experiments with chlorpromazine led to a revision of the theory, suggesting high levels of activity at dopamine receptors, not just high dopamine levels.
• In the 1970s, Snyder and colleagues assessed how different antipsychotic drugs bind to dopamine receptors.
• Binding affinity (how strongly a drug binds to a receptor) relates to the potency with which it alleviates symptoms.
• Haloperidol binds weakly to dopamine receptors.
• The discovery of D1 and D2 dopamine receptors led to a revision of the theory: Schizophrenia is caused by hyperactivity specifically at the D2 receptor.
• Limitations of the dopamine theory:
  • Therapeutic effects are not experienced for several weeks.
  • Most medications only alleviate positive symptoms with no effect on negative symptoms.
• The current theory is that excessive activity at D2 receptors is one factor of this disorder but alone cannot explain the disorder.

Current Research in Schizophrenia

• Atypical antipsychotics (second generation) do not bind strongly to D2 receptors.
• Clozapine has affinity for D1 and D4 receptors but only slight affinity for D2 receptor and also binds to some serotonin receptors.
• Hallucinogenic drugs primarily alter perception, emotion, and cognition.
• Lysergic acid diethylamide (LSD) was discovered in 1943.
• Other hallucinogens include dissociative hallucinogens (e.g., ketamine), which is a glutamate antagonist.
• There is renewed interest in hallucinogenic drugs because they mimic positive symptoms.

Genetic & Epigenetic Mechanisms of Schizophrenia

• Schizophrenia has a strong hereditary component.
• The concordance rate in identical twins is about 45%; in fraternal twins, it is about 10%.
• No single gene is responsible for causing schizophrenia; likely, a multitude of genes are involved.
• Several different chromosomes have been implicated.
• Chromosome 22, specifically a deletion at location q11.2, is most implicated.
• Current estimates for lifetime prevalence of schizophrenia are 25% in people with 22q11 deletion syndrome, compared to 1% in the general population.
• Epigenetic mechanisms such as DNA methylation and histone modifications affect genes for synapse-specific proteins in the prefrontal cortex (PFC).
• Environmental risk factors (birth complications, maternal stress, socioeconomic factors) alter the typical course of neurodevelopment, leading to schizophrenia in people genetically predisposed.
• Genetic x environment interactions

Neural Mechanisms of Schizophrenia

• Structural imaging of individuals at risk for schizophrenia shows reduced hippocampal volume and enlarged lateral ventricles.
• Volume loss is often greatest in the hippocampus and prefrontal cortex.
• Alterations to different areas of the brain develop at different rates.
• Functional imaging studies have implicated changes in the nigrostriatal pathway (dopamine) in schizophrenia.
• Resting-state connectivity studies are used to see if connectivity predicts treatment response to antipsychotic medications.

Depressive Disorders

• Major Depressive Disorder (MDD), or clinical depression, is characterized by intense feelings of despair, hypoactivity, sleep problems, withdrawal, lack of appetite, and an inability to care for oneself.
• The global prevalence of MDD is 2-5%.
• MDD is twice as common in women as in men.
• MDD is highly comorbid with other conditions (anxiety, diabetes, heart problems)
• Associated with myriad of negative long-term outcomes including reduced quality of life, marital dissatisfaction, job loss, and suicide (4-15%).
• DSM criteria of MDD

Neural Basis of Depression

• Depression is one of the most widely studied psychiatric disorders.
• Functional imaging studies of depression implicate fronto-limbic neural circuits as being primarily involved.
• Prefrontal activity and connectivity is altered in depression
• Amygdala activation is altered in depression
• Recent functional connectivity studies show that depression is affected by altered connectivity in intrinsic networks.
• Most consistent evidence for alterations in the default mode network and ventral attention network.

Treatment: The History of Antidepressants

• Monoamine oxidase inhibitors (MAOIs) inhibit the breakdown of monoamines (serotonin, catecholamine dopamine, adrenaline and noradrenaline) in the cytoplasm.
• In the 1950s, Iproniazid, developed for tuberculosis treatment, was found to have antidepressant effects, leading to its use in treating clinical depression.
• MAOIs have side effects: in combination with tyramine-rich foods (e.g., cheese, wine, or pickles), can cause life-threatening surges in blood pressure.
• Tricyclic Antidepressants (TCAs) have a chemical structure that includes 3 rings of atoms.
• In the 1950s, Imipramine, the first TCA, was thought to be an antipsychotic drug. Had little effect on schizophrenia patients, with some antidepressant effects.
• TCAs block the reuptake of serotonin and norepinephrine, increasing levels in the brain.
• TCAs are safer to use than MAO inhibitors.
• Selective Serotonin-Reuptake Inhibitors (SSRIs) are a variation of TCAs that selectively block serotonin uptake, with a slightly different chemical structure.
• In the 1980s, Prozac (fluoxetine) became one of the most commonly prescribed drugs for the treatment of MDD, obsessive-compulsive disorder, anxiety, premenstrual dysphoric disorder, and eating disorders.
• Other SSRIs include paroxetine and sertraline.
• SSRIs are not more effective than imipramine in treating depression but are very popular because of fewer side effects compared to TCAs and because they treat a variety of psychological disorders.
• Selective norepinephrine-reuptake inhibitors (SNRIs) are just as effective as SSRIs in the treatment of depression.
• The choice of antidepressant drug (SSRI vs. SNRI) often comes down to clinical judgment based on the patient’s history, side effect profile, and trial-and-error.
• Atypical antidepressants do not neatly fit into existing classifications of antidepressants.
• Bupropion blocks the reuptake of dopamine and norepinephrine and blocks nicotinic acetylcholine receptors.
• Agomelatine is a melatonin receptor agonist.
• NMDA-receptor antagonists (glutamate)
• In the 1990s, Ketamine was shown to have a powerful effect on reducing depression after a single low dose but has undesirable side effects.

Treatment of Severe Depression

• Brain stimulation in the form of repetitive transcranial magnetic stimulation (rTMS) can treat severe depression.
• High-frequency (5 pulses per second) and low-frequency rTMS (less than one pulse per second) to the dorsolateral prefrontal cortex (DLPFC) can alleviate symptoms.
• Deep brain stimulation involves implanting an electrode into an area of the white matter of the anterior cingulate cortex.
• Some studies show 60% substantial improvement in depression symptoms from deep brain stimulation.

Theories of Depression

• The monoamine theory of depression suggests underactivity at serotonergic and noradrenergic synapses.
• This theory is based on the observable effects of MAO inhibitors (all agonists).
• Autopsy findings in deceased depressed patients show upregulation of serotonin and norepinephrine receptors who never received treatment implicating a deficit in monoamine release.
• The monoamine theory has been challenged.
• The neuroplasticity theory of depression suggests that depression symptoms are due to change occurring downstream from the synaptic changes, an increase in neuroplasticity.
• Stress and depression lead to a decrease in neuroplastic processes, which leads to neuron loss (hippocampus).
• Antidepressants increase synaptogenesis (increase in BDNF)
• Many genes have been implicated in depression.
• Genetic x environment interactions through epigenetic mechanisms, contribute to depression.

Anxiety Disorders

• 1 in 5 people in their lifetime will experience an anxiety disorder.
• Twice as many females suffer from an anxiety disorder compared to males.
• Four anxiety disorders:
  • Generalized anxiety disorder: Extreme feelings of anxiety and worry without a precipitating stimulus.
  • Specific phobia: Strong fear of objects/situations (e.g., spiders, enclosed spaces) out of proportion to real danger.
  • Agoraphobia: Pathological fear of public places and open spaces - distinct diagnosis in DSM-V
  • Panic disorder: Recurrent, rapid-onset attacks of extreme fear and severe symptoms of stress (e.g., heart palpitations).

Anxiety Disorders Treatment

• Benzodiazepines (Diazepam/Valium) are muscle relaxants, anticonvulsants, and sleep-inducing drugs that have agonistic effects on GABA A receptors but are addictive.
• Antidepressants (monoamine agonists and TCAs) are effective in treating anxiety disorders due to high comorbidity with depression.
• Pregabalin is a new drug being used to treat anxiety disorders, acting on voltage-gated calcium channels.

Animal Models of Anxiety Disorders

• Elevated plus maze: rats placed on a 4-armed plus-sign-shaped maze elevated (50cm above floor). Proportion of time rats spend in enclosed arms is a measure of anxiety.
• Defensive-burying test: Rodents are shocked by a wire-wrapped wooden dowel. The amount of time the rats spend spraying bedding material at the source of the shock is a measure of anxiety.
• Risk assessment test: Induce fear via exposure to a cat. The time the animal spends doing risk assessment is a measure of anxiety.
• Tests are validated by the observation that benzodiazepines reduce indices of anxiety, whereas nonanxiolytic drugs do not.

Genetic and Neural Mechanisms of Anxiety

• Researchers are unable to definitively locate genes related to anxiety disorders, and research into epigenetic factors is still in its infancy.
• The limbic system (amygdala) is primarily implicated (because is overly responsive to stimulation).
• Activation of the HPA axis- corticotropin RH
• Medial prefrontal cortex fails to down-regulate.

Diathesis-Stress Model

• Originated in the 1950s and is used to explain the etiology of depression.
• Psychiatric disorders occur due to an interaction between vulnerability (e.g., genetic predisposition) and stressful life events (e.g., the onset of a disease).
• The degree or intensity of stress required for the development of a disorder is dependent on an individual’s vulnerability.
• An individual with greater vulnerability will require a smaller amount of stress to trigger a psychological disorder.

Early Experience of Stress

• Early exposure to severe distress has an adverse impact on development.
• Individuals exposed to traumatic experiences in childhood exhibit differences in their brain compared to individuals without trauma exposure.
• Early exposure to stress increases the intensity with which future stress responses are experienced.
• This may increase the vulnerability for a disease (i.e., act as a diathesis) or precipitate the onset of a disease due to the experience of a stressful event.
• Examples: depression (Saleh et al 2017), schizophrenia (Cannon et al 2022), PTSD (McKeever and Huff, 2003)