NU553 Unit 3 Seminar: Mental Health

Pathophysiology of Mental Health Disorders

• General Pathophysiology: Mental health disorders are often characterized by abnormal neurotransmitter release or decreased postsynaptic receptor sensitivity. This results in a functional or absolute deficiency in neurotransmitters, impacting brain functions.

Key Neurotransmitters and Physiological Roles

• Serotonin ($5-HT$): Known as the "feel-good" neurotransmitter. It influences mood, sleep, appetite, and learning. Deficiencies are linked to depression and anxiety.

• Dopamine (DA): Involved in motivation, movement, reward, and learning. Deficiencies are associated with Parkinson's disease.

• Norepinephrine (NE): Acts as an energizing agent responsible for alertness, attention, mood, and memory. Deficiencies are linked to depression and anxiety.

• GABA ($\gamma$-aminobutyric acid): An inhibitory neurotransmitter that calms firing nerves. Low levels are associated with anxiety.

• Acetylcholine (ACh): Essential for thought, learning, and memory. Deficiencies are linked to dementia and Alzheimer’s disease.

Generalized Anxiety Disorder (GAD)

• Prevalence and Nature:

  • Anxiety is the most commonly occurring class of mental disorders.

  • Normal anxiety is healthy when it motivates action or warns of harm.

  • Anxiety is considered a disorder when stress levels become persistent, excessive, overwhelming, and disabling.

  • Usually presents in later adolescence, though cases can occur in children aged $12$ years and younger.

• Diagnostic Markers (GAD Questionnaire):

  • Excessive anxiety and worry regarding multiple events or activities.

  • Restlessness or feeling on edge.

  • Easy fatigability.

  • Difficulty concentrating.

  • Irritability.

  • Muscle tension.

  • Sleep disturbance.

• Neurochemical Links: Dopamine, serotonin, norepinephrine, and GABA are all linked to anxiety states and their subsequent treatment.

Anxiolytic Pharmacotherapy

• Benzodiazepines:

  • Clinical Use: Used for short-term treatment of anxiety and as abortive treatment. They are extensively used as muscle relaxants, for pre-anesthesia sedation, prevention/treatment of panic attacks, acute agitation, dystonia, emergency treatment of uncontrollable seizures, and restless legs syndrome.

  • DEA Status: Schedule IV Controlled Substances due to the potential for tolerance and dependence.

  • Specific Agents:

    • Clonazepam (Klonopin)

    • Clorazepate (Tranxene)

    • Diazepam (Valium)

    • Lorazepam (Ativan)

    • Oxazepam (Serax)

    • Midazolam (Versed)

    • Temazepam (Restoril)

• Serotonergic Anxiolytics (Buspirone):

  • Classification: Belongs to the azapirones class.

  • Mechanism: Exerts effects without the CNS depression, sedation, anticonvulsant, or muscle-relaxant qualities found in barbiturates or benzodiazepines.

  • Safety Profile: Little risk of dependence and few drug interactions; considered safe even in high doses.

  • Pharmacokinetics:

    • No effect on GABA receptors.

    • Rapidly absorbed but undergoes extensive first-pass metabolism.

    • Administration with food reduces the first-pass effect, increasing circulation of the active drug.

    • Short half-life ($1$ to $10$ hours) but slow onset of action (up to $6$ weeks).

    • Requires multiple daily doses.

    • Highly protein-bound and lipid-soluble, allowing broad distribution in adipose tissue and the brain.

Non-Pharmacologic Therapy for Anxiety

• First-line Treatment: Cognitive-behavioral therapies (CBT) should be considered first-line either as monotherapy or with medication. Must be administered by trained psychotherapists.

• Specific Trauma/Disorders:

  • PTSD: Trauma-focused therapy is effective.

  • OCD: Exposure, systematic desensitization, and CBT are effective in extinguishing symptoms.

• Exercise: Meta-analysis indicates higher-intensity aerobic exercise is more beneficial for reducing overall anxiety in general practice settings.

Insomnia and Sleep Regulation

• Definition: Dissatisfaction with sleep quality occurring at least $3$ nights per week for at least $3$ months. Associated with difficulty falling asleep, staying asleep, or early morning awakenings.

• Causes:

  • Situational: Work, financial stress, jet lag.

  • Medical: Arrhythmia, chronic pain, Diabetes Mellitus.

  • Psychiatric: Mood disorders, anxiety, Substance Use Disorder (SUD).

• Waking Promotion (Antagonism of Sleep):

  • Catecholamines: Dopamine, Norepinephrine, Adrenaline.

  • Orexin (Hypocretins): Produced in the lateral and posterior hypothalamus; promotes arousal by binding to receptors and releasing glutamate (excitatory). Mutated orexin receptors are linked to narcolepsy.

  • Histamine: Activates neurons in the hypothalamus to maintain alertness.

Pharmacotherapy for Sleep Disorders

• Nonbenzodiazepine Hypnotics (Z-Drugs):

  • Act on GABA receptors but not at the benzodiazepine site. Lower risk of dependence/abuse compared to BZDs.

  • May cause complex sleep behaviors (e.g., sleep-driving) and next-day somnolence.

  • Eszopiclone (Lunesta): Half-life of $6$ hours; dosages $1$, $2$, or $3\,mg$. Safe for up to $6$ months.

  • Zaleplon (Sonata): Dosages $5$ and $10\,mg$. Ideal for sleep initiation.

  • Zolpidem (Ambien): Dosages $5$, $10\,mg$, or $8.2\,mg$ spray. Ideal for sleep initiation.

• Melatonin Receptor Agonists:

  • Ramelteon (Rozerem): High affinity for MT1 and MT2 receptors; similar to exogenous melatonin.

• Orexin Receptor Antagonists:

  • Suvorexant (Belsomra): Blocks Orexin A and B receptors to promote sleep. Improves sleep on the first day. Risks include next-day somnolence, sleep paralysis, and hallucinations.

  • Lemborexant (Dayvigo) and Daridorexant (Quviviq): Dual orexin receptor antagonists approved by the FDA.

Major Depressive Disorder (MDD)

• Statistics:

  • $12$-month prevalence in the U.S.: approximately $10\%$.

  • Lifetime prevalence: approximately $21\%$.

  • Annual cost (direct and indirect): estimated at $\$210.5$ billion.

  • Leading cause of disability worldwide; associated with low earnings and marital difficulties.

• Comorbidities: MDD is linked to cardiovascular disease, stroke, chronic fatigue syndrome, fibromyalgia, and IBS.

• Treatment Hierarchy: SSRIs are typically first, followed by atypical antidepressants, then Tricyclic Antidepressants (TCAs).

Antidepressant Classifications and Profiles

• Potency Table (Neurotransmitters Affected):

  • SSRIs (e.g., Citalopram, Fluoxetine, Sertraline, Escitalopram): Highly potent ($++++$) on $5-HT$, no effect ($0$) on NE or D.

  • SNRIs (e.g., Venlafaxine, Desvenlafaxine, Duloxetine): Highly potent ($++++$) on NE and highly potent ($+++/++++$) on $5-HT$.

  • TCAs (e.g., Amitriptyline): Highly potent on both NE and $5-HT$.

  • Atypicals:

    • Bupropion (Wellbutrin): Weak inhibitor of NE and D reuptake. Metabolites also inhibit NE reuptake. Virtually no sexual side effects; aids smoking cessation; weight neutral (decreases appetite); energizing.

    • Mirtazapine (Remeron): Selective $\alpha_2$-adrenergic antagonist. Increases appetite (weight gain), promotes sleep (somnolence). Dosed at bedtime.

    • Trazodone: Weak serotonin antagonist/reuptake inhibitor. Highly sedating due to antihistamine properties; used for insomnia.

Clinical Considerations and Safety for Antidepressants

• Timing: Requires $4$ to $6$ weeks (up to $12$ weeks) for full effect.

• Black Box Warning: Risk of suicidal ideation.

• Serotonin Syndrome: Caused by interactions with Tramadol, Meperidine, St. John's wort, dextromethorphan, and decongestants.

• Citalopram Warning: Doses should not exceed $40\,mg/day$ due to risks of QT prolongation (cardiac electrical activity abnormalities).

• Fluoxetine: Lowest risk of discontinuation syndrome due to long half-life.

• Paroxetine: Higher risk of discontinuation symptoms.

• Discontinuation Syndrome: Symptoms include nausea, headache, brain zaps, chills, body aches, and insomnia. Occurs $1$ to $2$ days after stopping; typically lasts $1$ to $2$ weeks. Tapering is required.

Bipolar Disorder

• Characteristics: Variation in mood between extreme highs (mania) and lows (depression). Linked to genetic polymorphisms in dopamine transmission and imbalances in NE/$5-HT$.

• Symptoms of Mania (DIGFAST):

  • D: Distractibility

  • I: Irresponsible/uninhibited behavior

  • G: Grandiosity

  • F: Flight of ideas

  • A: Activity increase

  • S: Sleep decrease

  • T: Talkativeness

• Treatment: Mood stabilizers (Lithium, Lamotrigine, Divalproex, Carbamazepine), anticonvulsants, and antipsychotics.

• Caution: SNRIs may trigger manic episodes or rapid cycling.

Attention Deficit Hyperactivity Disorder (ADHD)

• Pathophysiology: Dopamine (DA) deficiency causing inhibition deficits. Methylphenidate affects DA in the caudate.

• Symptom Manifestations by Age:

  • Child: Squirms, fidgets, runs, climbs, interrupts, cannot stay seated.

  • Adolescent: Internal restlessness, impulsive/risk-taking activities, interruptions, easily frustrated.

  • Adult: Difficulties in meetings, impulsive job changes, inefficient work, poor time/money management.

• First-line Treatment: Stimulants (Methylphenidate, Amphetamines).

  • Side Effects: Appetite suppression (monitor weight), nervousness, insomnia.

  • Contraindications: Cardiovascular disease, hypertension, glaucoma, drug abuse history.

• Non-Stimulant Options (Second-line): Atomoxetine, ER Guanfacine, ER Clonidine.

  • Atomoxetine: Good for patients with tics. Not a stimulant.

  • Clonidine/Guanfacine: Affect agonist receptors in the prefrontal cortex to improve attention and memory.

Neurocognitive Disorders: Dementia and Alzheimer’s Disease

• Alzheimer’s Disease (AD): Accounts for $60\%-80\%$ of dementia cases. Characterized by $\beta$-amyloid plaques and neurofibrillary tangles.

• Pharmacotherapy:

  • Cholinesterase Inhibitors (First-line): Donepezil (Aricept), Galantamine, Rivastigmine. They block AChE, prolonging ACh effects.

    • Donepezil: Dosed $5$ or $10\,mg$ once daily in the evening. Half-life is $70$ hours.

    • Cautions: Bradycardia, nausea, vomiting, weight loss.

  • NMDA Antagonists: Memantine. Noncompetitive antagonist; neuroprotective. Does not affect AChE inhibition by donepezil.

• Futility: If no effect is seen in $3$ to $6$ months, switch agents. Discontinue in severe AD if there is no benefit.

Parkinson’s Disease (PD)

• Pathophysiology: Loss of at least $50\%$ of dopaminergic neurons in the substantia nigra pars compacta (SNpc) at diagnosis.

• Cardinal Motor Symptoms:

  • Bradykinesia (slowing movement)

  • Resting or postural tremor

  • Cogwheel rigidity

  • Postural instability (balance difficulty)

• Levodopa/Carbidopa Therapy:

  • Levodopa crosses the blood-brain barrier (dopamine cannot).

  • Carbidopa prevents peripheral breakdown of levodopa.

  • Half-life: $60$ to $90$ minutes (requires $3$ to $6$ daily doses).

  • "Wearing-off" phenomenon: symptoms return before the next dose.

  • Dietary interaction: Avoid high-protein meals as they reduce intestinal absorption.

• Other Agents:

  • Dopamine Agonists: Pramipexole, Ropinirole.

  • Antivirals: Amantadine (used for dyskinesia).

  • Anticholinergics: Benztropine (for extrapyramidal symptoms).

Anticonvulsant Therapy

• Hydantoins (Phenytoin/Dilantin):

  • Stabilize electrical discharge by affecting sodium ion influx.

  • Therapeutic Range: $10$ to $20\,\mu g/mL$.

  • IV Boxed Warning: Do not exceed $50\,mg/min$ in adults ($1$ to $3\,mg/kg/min$ in peds) to avoid cardiovascular reactions.

  • Side Effects: Gingival hyperplasia, SJS, CNS effects, nystagmus.

• Carbamazepine:

  • Affects sodium channels; long half-life ($65$ hours initially, reduces to $12$ to $17$ hours with use).

  • Interactions: Grapefruit juice increases levels. Estrogen contraceptives decrease Lamotrigine levels by $50\%$.

• Levetiracetam (Keppra):

  • Unique class; mechanism unknown. Not metabolized by CYP450 enzymes.

  • Adverse Reactions: Somnolence ($12\%$), dizziness ($9\%$), and increased risk of suicidal thoughts.