Psychopharmacology Lecture Notes

Core Principles of Psychoactive Drugs and Psychopharmacology

• Definition of Psychoactive Drugs: These are chemicals that interact with the central nervous system (CNS) to produce significant changes in mood, consciousness, perception, and behavior.
• Mechanisms of Action:     * Increasing or decreasing the production or reuptake of neurotransmitters.     * Increasing or decreasing the release of neurotransmitters.     * Facilitating, mimicking, or blocking neurotransmitters at specific receptor sites.
• Drug Effects - Agonists: The effect is similar to the neurotransmitter.     * Direct Agonists: These mimic the effect of a neurotransmitter specifically at a receptor site.     * Indirect Agonists: These attach to a binding site on a receptor cell other than where the neurotransmitter attaches, thereby facilitating the action of the neurotransmitter.     * Inverse Agonists: These bind to the same receptor as an agonist but produce the opposite physiological effect.
• Drug Effects - Antagonists: These reduce or block the effects of an agonist (neurotransmitter).     * Direct Antagonists: These attach to a neurotransmitter’s receptor site to reduce the effect of the agonist.     * Indirect Antagonists: These attach to a binding site on a receptor cell other than the neurotransmitter attachment site and interfere with the action of the neurotransmitter.

Demographic Considerations in Psychopharmacology

• Drugs and Older Adults (Ages 65+):     * Medication-related problems are common in individuals over the age of $65$.     * Reasons for Problems: Use of multiple medications (polypharmacy), noncompliance with regimes, and changes in sensitivity (age-related changes in drug absorption, distribution, metabolism, and excretion).     * Benzodiazepine Sensitivity: Due to lower kidney functioning, the half-life of these drugs increases, leading to a higher risk of toxicity.     * Clinical Rule: The general guideline is to ‘start low and grow slow’ regarding dosage.
• Drugs and Race/Ethnicity (Cross-Ethnic Differences):     * Differences are primarily due to pharmacokinetic factors, specifically how the body metabolizes drugs.     * Asians and African Americans: Tend to have a slower metabolism of certain drugs. Consequently, they are more sensitive to both therapeutic and side effects of neuroleptics, benzodiazepines, lithium, and some antidepressants. Clinical recommendation is to start with a lower dose.
• Prescribers of Psychotropic Drugs:     * Settings: Psychotropic drugs (which affect the CNS) are prescribed in ambulatory care settings, including primary care offices, surgical/medical specialty offices, hospital outpatient departments, and emergency departments.     * Prescribing Patterns: Most often provided and continued in primary care offices followed by medical specialty offices (psychiatrists and neurologists).     * Exceptions: Antipsychotic and antimanic drugs are most often prescribed by medical specialty offices rather than primary care.

Antipsychotic Drugs: Traditional (Neuroleptics)

• Synonyms: Also known as major tranquilizers or neuroleptics.
• Classification by Type:     * Phenothiazine: Examples include Chlorpromazine and Fluphenazine.     * Thioxanthene: Example includes Thiothixene.     * Butyrophenone: Example includes Haloperidol.
• Therapeutic Use:     * Treatment of positive symptoms of schizophrenia, such as hallucinations, delusions, and agitation.     * These are not effective for negative symptoms.     * Used for acute mania, and hallucinations/delusions associated with Major Depressive Disorder and organic psychosis.
• Mode of Action:     * These drugs work by blocking dopamine receptors, specifically $D_2$.     * Dopamine Hypothesis of Schizophrenia: Suggests that dopamine receptors are oversensitive or there is an excess of dopamine. This is supported by the fact that amphetamines (which elevate dopamine) cause psychotic symptoms in non-schizophrenics, and low doses of these drugs exacerbate symptoms in schizophrenics.
• Side Effects - Anticholinergic Effects: These result from blocking the action of acetylcholine.     * Symptoms include: Dry mouth, blurred vision, urinary retention, constipation, tachycardia, and delayed ejaculation.
• Side Effects - Extrapyramidal Effects: Result from effects on dopamine receptors in the caudate nucleus.     * Parkinsonism: Symptoms resembling Parkinson's disease.     * Akathisia: Extreme motor restlessness.     * Acute Dystonia: Muscle spasms occurring in the mouth, face, and neck.     * Tardive Dyskinesia: The latest and most serious extrapyramidal effect. It involves involuntary rhythmic movements of the jaw, lips, tongue, and extremities. It is more common in females. Haloperidol, one of the strongest antipsychotics, has the most associated extrapyramidal side effects. While traditionally thought to be irreversible, new research shows symptoms can sometimes improve later. It can be alleviated by benzodiazepines or other GABA agonists.
• Neuroleptic Malignant Syndrome (NMS):     * A rapid onset syndrome involving motor, mental, and autonomic symptoms.     * Symptoms: Muscle rigidity, tachycardia, hyperthermia (fever), and altered consciousness.     * Clinical Warning: This can be fatal; the drug must be stopped immediately.

Antipsychotic Drugs: Atypical (Novel)

• Classification by Type:     * Dibenzodiazepine: Clozapine.     * Benzisoxazole: Risperidone.     * Thienobenzodiazepine: Olanzapine.     * Dibenzothiazepine: Quetiapine.
• Therapeutic Use:     * Schizophrenia (addresses both positive and negative symptoms).     * Clozapine: Used for Bipolar disorder that did not respond to mood stabilizers.     * Other uses: Depression, suicidality, alcohol/drug addiction, hostility, and motor symptoms of Huntington’s and Parkinson’s.
• Mode of Action: These drugs target $D_4$ and other dopamine receptors, as well as receptors for serotonin and glutamate.
• Clinical Comparison:     * Advantage: Effective when traditional antipsychotics are not.     * Disadvantage: Slower onset of effects compared to traditional options.
• Side Effects:     * Anticholinergic effects (dry mouth, blurred vision, etc.).     * Lowered seizure threshold and sedation.     * Extrapyramidal symptoms and Tardive Dyskinesia are much less common (except for akathisia).     * Agranulocytosis: A dangerous decrease in a specific type of white blood cells (notable with Clozapine).     * Neuroleptic Malignant Syndrome is rare with atypical antipsychotics.

Antidepressant Medications: Tricyclics (TCAs)

• Drug Examples: Amitriptyline, Nortriptyline, Doxepin, Imipramine, and Clomipramine.
• Mode of Action: Block the reuptake of norepinephrine, serotonin, and dopamine.     * Catecholamine Hypothesis: The focus on norepinephrine supports the theory that depression is related to a norepinephrine deficiency.
• Therapeutic Use:     * Depression involving decreased appetite, early awakening, sleep problems, psychomotor retardation, and anhedonia.     * Effective at alleviating vegetative and somatic symptoms.     * Onset of Effect: $2-4$ weeks.     * Specific uses: Panic disorder, agoraphobia, bulimia, and OCD (especially Clomipramine). Imipramine is used for Enuresis; Amitriptyline and Nortriptyline are used for neuropathic pain.
• Side Effects and Overdose:     * Cardiotoxic: Can cause tachycardia, palpitations, hypertension, hypotension, and arrhythmia. More common in older patients.     * Overdose Symptoms: Ataxia, impaired concentration, agitation, severe hypotension, fever, cardiac arrhythmia, delirium, seizure, coma.     * Clinical Warning: Overdose can be lethal; drugs should be prescribed in small dosages.

Antidepressant Medications: SSRIs and MAOIs

• Selective Serotonin Reuptake Inhibitors (SSRIs):     * Drug Examples: Fluoxetine (Prozac), Fluvoxamine (Luvox), Paroxetine (Paxil, Pexeva), and Sertraline (Zoloft).     * Mode of Action: Selectively block serotonin reuptake.     * Use: Melancholic depression, OCD, Bulimia, Panic disorder, and PTSD.     * Side Effects: Less cardiotoxic than TCAs, safer in overdose, and less likely to cause cognitive impairment. Rapid onset usually within $2-4$ weeks (sometimes $6-8$ weeks).     * Prozac (1987): Most widely prescribed but controversial due to linked reports of violence and suicide.     * Serotonin Syndrome: Occurs when SSRIs are taken with MAOIs. Symptoms include headache, nystagmus, tremor, dizziness, unsteady gait, irritability, confusion, delirium, cardiac arrhythmia, coma, and death.
• Monoamine Oxidase Inhibitors (MAOIs):     * Drug Examples: Isocarboxazid (Marplan), Phenelzine (Nardil), and Tranylcypromine (Parnate).     * Mode of Action: Inhibits monoamine oxidase, the enzyme that deactivates dopamine, serotonin, and norepinephrine.     * Use: Non-endogenous and atypical depression specifically involving anxiety, reversed vegetative symptoms (hypersomnia, hyperphagia), and interpersonal sensitivity.     * Side Effects - Hypertensive Crisis: A severe increase in blood pressure occurs if MAOIs are taken with barbiturates, amphetamines, antihistamines, or foods containing tyramine.     * Tyramine-Rich Foods: Aged cheeses, sauerkraut, cured meats, chicken liver, red wine, draft beer, fermented soy products, avocados, bananas, and fava beans.     * Crisis Symptoms: Headache, stiff neck, rapid heart rate, nausea, vomiting, sweating, and light sensitivity.

New Antidepressant Drugs: DRIs and SNRIs

• Norepinephrine and Dopamine Reuptake Inhibitors (DRIs):     * Example: Bupropion (Wellbutrin, Zyban).     * Use: Major Depressive Disorder (MDD), the depressive phase of bipolar, and smoking cessation ($Zyban$). Used for people who failed other antidepressants.     * Side Effects: Fewer anticholinergic and cardiotoxic effects than TCAs, but may aggravate psychosis and seizures.
• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs):     * Examples: Venlafaxine (Effexor) and Duloxetine (Cymbalta).     * Venlafaxine Use: MDD, Generalized Anxiety Disorder (GAD), Social Anxiety Disorder, OCD, and pain syndromes (fibromyalgia, back pain, neuropathic pain).     * Duloxetine Use: MDD and GAD.     * Characteristics: Faster onset of effect and less dangerous in overdose than TCAs. Side effects include increased blood pressure, necessitated frequent monitoring.

Mood Stabilizers: Lithium and Carbamazepine

• Lithium:     * Use: Traditionally for gout, diabetes, and epilepsy. Primary modern use is for Classic Bipolar Disorder (manic episodes without rapid cycling). It eliminates manic symptoms and suppresses mood swings.     * Mode of Action: Not fully understood; related to serotonin and norepinephrine reuptake.     * Side Effects: Usually subside within a few weeks; include nausea, vomiting, metallic taste, weight gain, hand tremor, fatigue, polyuria (excessive urination), and polydipsia (excessive thirst).     * Lithium Toxicity: Occurs when serum levels are too high. Initial signs are diarrhea, ataxia, drowsiness, slurred speech, and confusion. Severe toxicity leads to seizures, coma, and death.     * Specific Management: Serum levels must be monitored. Retention depends on body salt levels; patients must avoid fluctuations in salt intake and avoid diuretics (caffeine, alcohol).
• Carbamazepine (Tegretol):     * Initial Use: Anticonvulsant.     * Psychiatric Use: Bipolar Disorder for lithium non-responders and rapid cycling.     * Related Anticonvulsants for Mania: Valproic acid (Depakote) and Clonazepam (Klonopin).     * Side Effects: Tolerance develops quickly. Symptoms include dizziness, ataxia, visual disturbance, nausea, and rash. It is contraindicated for those with cardiac conduction problems.

Sedative-Hypnotics: Barbiturates and Benzodiazepines

• General Characteristics: Includes barbiturates, anxiolytics, and alcohol. These are CNS depressants.
• Dose-Dependent Effects:     * Low dose: Reduces arousal and motor activity.     * Moderate dose: Induces sedation and sleep.     * High dose: Anesthesia, coma, and death.     * Initial effect is often elation due to suppression of inhibitory mechanisms.
• Risks of Chronic Use: Tolerance, physical/psychological dependence, and withdrawal syndrome (tremors, hallucinations, life-threatening seizures).
• Synergistic Effects: Combining these substances is often lethal due to a super-additive action on respiration. Cross-tolerance exists between them.
• Barbiturates:     * Examples: Amobarbital, Pentobarbital, Secobarbital, Phenobarbital.     * Mode of Action: Interrupts signals to the reticular activation system.     * Effects on Sleep: Decreases REM sleep. Abrupt cessation leads to REM rebound and nightmares. Sleep-inducing effectiveness lasts only a few weeks.     * Clinical Warning: Tolerance to sleep induction develops, but tolerance to the respiratory center suppression does not, making dose increases lethal.
• Benzodiazepines (Anxiolytics):     * Examples: Diazepam (Valium), Alprazolam (Xanax), Clonazepam (Rivotril), Lorazepam (Ativan), etc.     * Mode of Action: Stimulate GABA (inhibitory neurotransmitter).     * Uses: Anxiety, sleep disturbances, seizures, cerebral palsy/muscle spasms, and alcohol withdrawal.     * Side Effects: Drowsiness, ataxia, impaired psychomotor ability, paradoxical excitation (hostility), anterograde amnesia, and sleep disturbance (no REM).     * Withdrawal: Abrupt cessation causes rebound hyperexcitability, seizures, panic, or stroke.
• Azapirone: An anxiolytic that provides effect without sedation. It is non-addictive, non-habit forming, and not subject to abuse, though it takes several weeks to become effective.

Beta-Blockers, Narcotic-Analgesics, and Psychostimulants

• Beta-Blockers (Propranolol):     * Mechanisms: Block beta-adrenergic receptors that respond to epinephrine and norepinephrine.     * Use: High blood pressure, cardiovascular disorders, tremors, migraines, glaucoma, and physical symptoms of anxiety (palpitations, sweating).     * Side Effects: Bradycardia, shortness of breath, sexual dysfunction. Should not be prescribed for obstructive pulmonary disease. Abrupt discontinuation causes sweating and arrhythmia.
• Narcotic-Analgesics (Opioids):     * Classes: Natural (Opium, Morphine, Codeine), Semi-synthetic (Heroin, Dilaudid), and Pure synthetic (Demerol, Methadone).     * Mode of Action: Opioid receptors in the brain (amygdala, thalamus, hypothalamus) and spinal cord. Endorphins/enkephalins reduce emotional receptivity to pain.     * Side Effects: Constricted pupils, respiratory depression, constipation. Overdose involves clammy skin, catalepsy (muscular rigidity), and coma.     * Methadone: Used in heroin detox because it satisfies physical dependence without euphoria. Milder withdrawal than heroin but nearly as addictive.
• Psychostimulants:     * Amphetamine (e.g., Dexamphetamine sulfate): Used for narcolepsy and ADHD.     * Methylphenidate (e.g., Ritalin, Concerta): Used for ADHD.     * Mechanism: Increase release and block reuptake of norepinephrine and dopamine.     * Side Effects: Restlessness, cardiac arrhythmia, sensitization, and growth suppression in children (temporary). Prolonged use can cause a psychotic state similar to paranoid schizophrenia.     * Drug Holidays: Used to stop growth suppression and assess ongoing need for the drug.

Anti-Alcohol Drugs and Clinical Testing

• Anti-Alcohol Medications:     * Disulfiram (Antabuse): Inhibits alcohol metabolism leading to acetaldehyde collection. Causes nausea, vomiting, and hypotension if alcohol is consumed.     * Naltrexone (Vivitrol): An opioid receptor antagonist that blocks the craving and reinforcing effects of alcohol.
• Efficacy Clinical Trials: Evaluate interventions under experimental conditions with careful sample selection and placebo control. Phase III trials demonstrate intrinsic pharmacological effects for authorization.
• Practical/Pragmatic Clinical Trials (PCTs): These are large, simple randomized trials conducted in practice settings to study effects under typical community conditions. They address clinical dilemmas with broad entry criteria and minimal burden on clinicians/patients.
• Therapeutic Drug Monitoring (TDM): The practice of measuring drug concentrations at designated intervals to maintain a constant level in the bloodstream. Used for drugs with limited therapeutic ranges and high pharmacokinetic variability.
• Genetic Screening Methods: Includes Cytogenetics (examination of chromosomes), Biochemical tests (protein function), and Direct DNA analysis (used when gene sequence is known).     * Example: Cystic Fibrosis: Involves $800$ mutations on one gene ($30$ are most prevalent). Screening usually targets the top $30$ before whole gene sequencing.