Module 7 - Lecture note - Serotonin Receptors and SSRIs

• Serotonin (5-HT) is highly involved in emotions and mood, with diverse receptor actions across tissues.
• 5-HT1A receptors are inhibitory and regulate neuronal activity, contributing to antidepressant mechanisms.
• 5-HT2A receptors are excitatory, influencing cognition, psychosis, and potentially causing serotonin syndrome; they're antagonized by certain antipsychotics but agonized by hallucinogens.
• 5-HT3 receptors, ligand-gated ion channels, regulate nausea/vomiting and can interact with some psychotropic drugs and anesthetics.
• SSRIs like fluoxetine, sertraline, citalopram, and escitalopram increase serotonin availability by blocking its reuptake transporter.
• SSRIs are used for mild to moderate depression, panic disorder, OCD, phobias, and PTSD.
• SSRIs clinical effects take weeks to appear, related to changes in receptor number/sensitivity.
• SSRI side effects include insomnia, agitation, decreased serum sodium (risk of SIADH, especially in elderly women with cardiovascular disease), increased suicidal thoughts/behaviors in children/adolescents (black box warning), CYP450 inhibition, increased antiplatelet activity, and QT prolongation.
• SSRI discontinuation syndrome involves major depressive episode, dizziness, and paresthesias upon abrupt cessation.
• Continue SSRIs perioperatively due to risk of discontinuation syndrome and consider lower doses of opioids and antiemetics in patients on SSRIs.
• Serotonin Syndrome: risk of excess serotonin in the synapse with other serotonergic drugs.
• Serotonin Syndrome anesthesia-related risks: Phenylpiperidine opioids (fentanyl, meperidine), methadone, tramadol, ondansetron, and drugs inhibiting CYP450 enzymes.
• Serotonin Syndrome symptoms: Autonomic instability (tachycardia, hypertension, hyperthermia, tachypnea, diaphoresis, neuromuscular abnormalities (hyperreflexia, tremors, rigidity), mental status changes (restlessness, agitation, hallucinations, confusion, seizures). Can be fatal and mimic normal post-anesthesia effects.
• SNRIs like venlafaxine and duloxetine block reuptake of serotonin and norepinephrine and are used for depressive, anxiety disorders, and chronic pain.
• SNRI side effects are similar to SSRIs, plus norepinephrine-related effects (tachycardia, hypertension, potential arrhythmias), and CYP2D6 inhibition.
• TCAs like amitriptyline and imipramine block serotonin and norepinephrine reuptake and also block muscarinic acetylcholine and histamine receptors, antagonize alpha-1 receptors and NMDA, and deplete catecholamine stores.
• TCA side effects: Anticholinergic effects (dry mouth, blurry vision, sedation, delirium risk in elderly), lower seizure threshold in pediatrics, extrapyramidal symptoms, tremors, increased toxicity with MAOIs, cardiovascular effects, and are fatal in overdose.
• TCAs impact on anesthesia: Increased anesthetic requirements (due to increased catecholamines), exaggerated response to anticholinergics and indirect-acting vasopressors, ventilatory depressant effects, avoid tachycardic-inducing drugs.
• MAOIs like phenelzine, tranylcypromine, and isocarboxazid inhibit monoamine oxidase, reducing breakdown of norepinephrine, dopamine, and serotonin.
• MAOI side effects: Hypotension, anticholinergic effects, hepatitis, weight gain, tyramine interaction.
• MAOI adverse reactions: Type 1 (Excitatory) resembles serotonin syndrome, avoid opioids affecting serotonin (fentanyl, meperidine), use morphine or hydromorphone cautiously. Type 2 (Depressive): MAO inhibition of hepatic enzymes can prolong opioid metabolism (hypotension, respiratory depression). Treat with naloxone.
• MAOI anesthesia impact: Contraindicated with indirect-acting sympathomimetics (avoid ephedrine - risk of fatal hypertensive crisis), Propofol, etomidate, benzodiazepines, inhaled agents, anticholinergics in smaller doses, and IV fluids generally safe. Treat hypotension with low-dose phenylephrine and avoid tachycardic drugs.
• Miscellaneous antidepressants like trazodone (can cause hypotension and dry mouth), buspirone (anxiolytic, can elevate norepinephrine and dopamine), mirtazapine (tetracyclic), and bupropion (inhibits dopamine and norepinephrine reuptake, used for depression, ADHD, smoking cessation).

Bipolar Disorder

• Bipolar disorder treatment includes mood stabilizers, antidepressants, antipsychotics, benzodiazepines, and psychotherapy.
• Lithium is a treatment of choice for bipolar disorder, treatment-resistant major depression, and suicide risk.
• Lithium may lead to decreased anesthetic requirements because it has similar GABAergic mechanisms.
• Lithium side effects: Decreased ability to concentrate urine (polydipsia, polyuria, nephrogenic DI, chronic kidney issues due to aquaporin downregulation), hypothyroidism, cardiac effects (T-wave flattening/inversion, SA nodal block, bradycardia).
• Lithium drug interactions: Increased Lithium Levels with Thiazide and loop diuretics, NSAIDs, ACE inhibitors. Increased neurotoxicity with neuroleptics and anticonvulsants, beta-blockers can decrease lithium-induced tremor, prolonged muscle blockade with muscle relaxants, delayed recovery with barbiturates.
• Lithium perioperative management recommends stopping 1-3 days before surgery (abrupt cessation not associated with withdrawal). Avoid sodium depletion, diuretics, and NSAIDs perioperatively. Use IV fluids containing sodium (LR common).
• Lithium therapeutic index: Narrow (1-1.2 mEq/L).
• Lithium toxicity (>1.5 mEq/L): Dysrhythmias, ECG changes, hypotension, weakness, ataxia, seizures, confusion. Treatment includes dialysis and sodium bicarbonate.

Schizophrenia and Psychosis

• Psychosis: Loss of contact with reality, hallucinations, delusions, disorganized speech/behavior, flattened affect, cognitive deficits
• Typical (First Generation) Antipsychotics (FGAs) / Neuroleptics like haloperidol, chlorpromazine, and prochlorperazine are primarily dopamine D2 receptor antagonists and are used for acute psychosis, emergence and ICU delirium, acute agitation/aggression, antiemetic
• Atypical (Second Generation) Antipsychotics (SGAs) like clozapine, olanzapine, risperidone, quetiapine, and aripiprazole are D2 antagonists with significant activity at other receptors, and are less prone to cause extrapyramidal side effects.
• Emergence delirium risk factors: Extremes of age, male gender, history of mental health/cognitive dysfunction, substance use, longer surgery, residual neuromuscular blockade, pain, endotracheal tube presence, vital sign changes.
• Emergence delirium management includes pain and agitation control and identifying/treating underlying cause (haloperidol is often first-line).
• Droperidol is a butyrophenone antipsychotic with antiemetic and sedative effect, and limited use despite efficacy at low antiemetic doses.
• Extrapyramidal Side Effects (EPS) (Primarily FGAs): Tardive dyskinesia, akathisia, dystonia .
• Other FGA Side Effects: Hypotension, anti-dysrhythmic effects, QT prolongation , endocrine, CNS, liver, Neuroleptic Malignant Syndrome (NMS).
• Neuroleptic Malignant Syndrome (NMS) symptoms: Fever, skeletal muscle rigidity, autonomic instability, altered consciousness.
• NMS differentiation from Malignant Hyperthermia (MH): Non-depolarizing muscle relaxants produce paralysis in NMS but not in acute MH.
• NMS treatment: Dantrolene, dopamine agonists, benzodiazepines for agitation, IV fluids, cooling, supportive measures.
• Anesthesia considerations for patients on antipsychotics include proneness to tachycardia, hypotension, and arrhythmias, higher incidence of diabetes and glucose intolerance, weight gain, impaired temperature regulation, altered HPA function, skeletal muscle relaxation, risk for oversedation.
• Atypical Antipsychotics (SGAs) Specifics: Clozapine is most effective second generation, Olanzapine caution with benzodiazepines , Risperidone studied for delirium prophylaxis post-cardiac surgery, Aripiprazole is Dopamine receptor partial agonist/antagonist.
• Side effects for Second Generation side effects are similar risk for EPS and NMS, significant metabolic effects and related cardiovascular side effects.

Neurodevelopmental Disorders

• Attention Deficit Hyperactivity Disorder (ADHD) treatment includes stimulants, behavioral therapy, educational interventions. Methylphenidate (Ritalin) is a indirect sympathomimetic, and may reverse anesthesia related to inhaled agents and propofol.
• Mixed Amphetamine Salts (Adderall) blocks reuptake of norepinephrine and dopamine, increases dopamine release
• Clonidine is Alpha-2 agonist, approved for ADHD. Also used for regional anesthesia adjunct, anxiety, opioid withdrawal, impulsivity/aggression.
• Cannabis and Cannabinoids: THC is the most potent psychoactive cannabinoid, Anesthetic Implications: Increased anesthetic requirements are common in acutely intoxicated patients and Chronic use can also increase requirements.