Current Psychiatric Pharmacology: Antidepressants, Anxiolytics, and Mood Stabilizers

Educational Objectives

The goal of this program is to improve the management of various psychiatric disorders using antidepressants, anxiolytics, and mood stabilizers. After hearing and assimilating this program, the clinician will be better able to:

1. Describe the neurobiological basis for neurotransmitter release that contributes to psychiatric disease.
2. Optimize the use of antidepressants in specific patient populations.
3. Outline the mechanism of action of bupropion in the treatment of depression.
4. List the adverse effects associated with the psychotropic drug classes used for the management of various mental disorders.
5. Choose appropriate psychotropic drugs for the treatment of various psychiatric syndromes.

Summary

Psychiatric disease: 3 main chemicals manipulated in psychiatry are norepinephrine (NE), dopamine, and serotonin (5-HT); NE contributes to concentration and energy; dopamine contributes to alertness, energy, and pleasure; 5-HT contributes to anxiety and the general sense of happiness; the goal of psychiatric evaluation is to arrive at a unifying diagnosis or set of diagnoses and narrow down drug choices based on the patient’s symptoms; the brain biogenic amine hypothesis — suggested too little catecholamine neurotransmitters; all psychiatric symptoms are caused by a lack of flow or speeding up of chemicals; drugs that decrease 5-HT and NE can cause depression (eg, reserpine) and drugs that increase it treat depression (eg, tricyclics, selective serotonin reuptake inhibitors [SSRIs]); delay in the action of certain drugs (eg, sertraline [Zoloft]) may be explained by second messengers

Mechanism of action: drugs that block dopamine 2 receptors can help stop hallucinations and delusions; drugs that block 5-HT2A receptors help improve thinking and reduce confusion and the likelihood of doing funny things; 5-HT1D antagonists act as antidepressants; α-adrenergic antagonists, 5-HT antagonists, and muscarinic receptor agonists can cause sedation and weight gain; 5-HT and NE reuptake inhibitors (SNRIs) can be used as antidepressants, anxiolytics, and for chronic pain, eg, duloxetine (Cymbalta, Drizalma Sprinkle, Irenka)

Antidepressants

Introduction: all drug classes are equally effective overall; antidepressants are chosen based on cost, adverse effects (AEs), and the patient’s medical history; educate patients that antidepressants have no immediate effects; inadequate dose and time are the main reasons for drug failure

Selective serotonin reuptake inhibitors: the third most prescribed drug group in the United States (after antibiotics and pain medications); blocks reuptake of 5-HT at synaptic clefts; effective for mood and anxiety disorders; it mediates gut peristalsis, sweat glands, platelet activity, and sexual functioning; it promotes 5-HT flow through the inguinal nerves and inhibits sexual processes; more potent drugs cause more sexual AEs; drugs that promote NE and dopamine through the inguinal nerves activate sexual functioning; safe in overdose; withdrawal can be an issue, with no addictive potential; the shorter the half-life, the higher the risk for withdrawal; withdrawal symptoms include diarrhea, flu, goosebumps, headaches, and sweating; important to regimen the drug; medications — include paroxetine (eg, Brisdelle, Paxil, Pexeva), fluoxetine (Prozac), citalopram (Celexa), sertraline, and venlafaxine (Effexor); safe and effective, mostly focused on 5-HT (less histamine 1 [H1], α, and muscarinic acetylcholine receptor [M1] activity); sertraline and fluoxetine have the longest half-lives, with fluoxetine having a week-long half-life (taper itself; not the case with fluvoxamine [Luvox] or paroxetine); all are metabolized by cytochrome P450 2D6; potential 2D6 blockers; typically, fluoxetine is dose activating, while paroxetine is sedating; fluoxetine and sertraline are used for those with anxiety and no energy, while fluvoxamine and paroxetine are used for those with anxiety and too much energy; sexual dysfunction occurs with all (worst with paroxetine; bupropion [eg, Aplenzin, Wellbutrin, Zyban] can help manage this); restart at half the dose and return to the previous dose within 24 to 48 hr to manage discontinuation syndrome

Tricyclic antidepressants (TCAs): work on various receptors in the brain and spinal cord, including NE, dopamine, 5-HT, H1, α-receptors, and acetylcholine; can treat migraine headaches, diabetic neuropathic pain, postherpetic neuralgia pain, and bulimia, and help with somatic symptom disorder (nonspecific multiple somatic complaints); overdose can be fatal; AEs include dry eyes, dry mouth, sedation, orthostasis, constipation, urinary retention, and arrhythmias; patient selection is important (not recommended for patients with narrow-angle glaucoma and prostatic hypertrophy); can be added to SSRI (safe at low dose); tertiary amine TCAs (amitriptyline, clomipramine, doxepin) activate 5-HT more than NE; secondary amine TCAs activate NE more than 5-HT (less anticholinergic than tertiary amine TCAs; include nortriptyline [Aventyl, Pamelor]); tertiary amine TCAs are preferred for patients with obsessive-compulsive disorder (OCD), gastroesophageal reflux disease, and itching and are extremely sedating; secondary amine TCAs are preferred for patients with cardiac issues and weight gain

Serotonin-norepinephrine reuptake inhibitors: include venlafaxine and duloxetine; venlafaxine inhibits reuptake of 5-HT more than NE and does not have a pure noradrenergic effect until a dose of 150 mg/day; duloxetine has equal affinity for 5-HT and NE; AEs include gastrointestinal (GI) distress, insomnia, and dizziness; duloxetine is better for chronic pain; venlafaxine is better for energy and anxiety; duloxetine provides less anxiety benefit until 60 to 90 mg/day, while venlafaxine offers less chronic pain benefit until 150 mg/day

Monoamine oxidase inhibitors (MAOIs): treatment-refractory depression has increased over time; these drugs have been used to treat atypical refractory depression since the 1970s; selegiline skin patches are used more because of their low doses and lack of dietary restrictions; initially developed as tuberculosis drugs; it blocks the enzyme that degrades the neurotransmitters; these drugs require diet and medication restrictions and are primarily used as monotherapy (requires ≥2 wk of washout period before use); can be mixed with trazodone, lithium, and benzodiazepines; can suppress anginal pain and augment hypoglycemic reactions; avoid drinking tap or nonpasteurized beer with it, as well as excessive caffeine and chocolate consumption; ensure there are no significant serotonergic drugs; avoid pseudoephedrine (eg, cough suppressants); be cautious about drug-drug interactions

Bupropion: increases the levels of dopamine and NE in the central nervous system; not effective for anxiety; the second most stimulating antidepressant in the market; used for major depressive disorder (MDD) with vegetative symptoms; can help treat sexual dysfunction, especially when combined with an SSRI; high doses can cause seizures in nonepileptic individuals (keep the dose <450 mg); be careful in patients with traumatic brain injury, stroke, renal disease, and bulimia; safe in patients with cardiac disease

Mirtazapine (Remeron): the atypical antidepressant works by blocking 5-HT2, 5-HT3 receptors and α-receptors; effective in treating MDD and anxiety, especially in the elderly, as it helps with sleep and appetite; useful in oncology because of its antinausea component; mirtazapine provides a convenient option for those who cannot swallow for any issues; has modest antinausea effects and is not affected by food; lower doses (7.5 mg) increase appetite and sleep, and higher dose (45 mg) has an antidepressant effect; preferred dose is 30 mg and can be combined with an SSRI

Vilazodone (Viibryd): a potent SSRI that has increased activity of the 5-HT1A receptor; an energizing antidepressant; often causes GI distress (recommended with food); does not cause weight gain and has minimal sexual AEs; ketoconazole and erythromycin can cause toxicity; gradual increase in dose can avoid headaches and tremors

Vortioxetine (Trintellix): affects several 5HT receptors, including 5-HT1A/1B; no effects on weight and libido; can cause GI effects (probably more than vilazodone); can displace protein-bound drugs, eg, thyroid medicines, coumadin; primarily used for MDD; showed to improve anxiety but has not received US Food and Drug Administration (FDA) approval

Levomilnacipran (Fetzima): the most energizing antidepressant on the market; a pure NE reuptake inhibitor (less affinity for 5-HT); used more in neurology patients with profound fatigue, poststroke, and multiple sclerosis; mild 3A4 inhibition; do not use >40 mg in patients with stage 3 chronic kidney disease; can affect hypertension; hyponatremia can occur; agitation, insomnia, and tachycardia are common AEs

Trazodone (eg, Desyrel, Oleptro, Raldesy): the antidepressant doses (ie, 150-300 mg) can cause sedation; the maximum dose is 600 mg/day; an exquisitely weak agent and can be mixed with other drugs (even with MAOIs); very safe drug; the speaker recommends 25 mg at night and increasing by 25 mg daily (≤150 mg) until 8 hr of sleep is achieved without a hangover; priapism occurs in 1 in 6000 men (idiosyncratic); high doses can cause arrhythmias

Regimen: start with a lower dose and gradually increase the dosage, eg, take 10 mg of fluoxetine for 1 or 2 wk, then assess the patient after 14 days; can start 20 mg paroxetine; starting at lower doses and blending them in can help patients acclimate better and stay on the drug; an adequate dose and adequate trial is the key to efficacy for all antidepressants; titrate up the dose; before switching to another drug, ensure the current drug is not effective over 6 to 8 wk; if the condition does not improve after 3 drugs, then refer to psychiatry

Anxiolytic Options

Benzodiazepines: previously replaced barbiturates (were intended to be cleaner, safer, and nonaddictive); they activate the γ-aminobutyric acid (GABA) receptor; effective for anxiety disorder but do not work as well for thought-provoking anxiety like OCD or posttraumatic stress disorder (PTSD); provides symptom relief; can be used as initial treatment but must be accompanied by chronic treatment; AEs include sedation, drowsiness, and mental slowing; long-term use leads to depression and persistent cognitive impairment; tolerance, withdrawal, and addiction are possible (especially with drugs with shorter half-lives)

Use in pregnancy: increased risk for cleft lip and cleft palate; may cause floppy infant syndrome as the baby may become addicted and experience muscle atonia or withdrawal seizures; an addictive drug needs potency, rapid onset, and quick wear-off to be effective; 0.5 mg alprazolam (Niravam, Xanax) is equivalent to 5 mg diazepam (eg, Diastat, Diastat AcuDia, Valium) and 25 mg chlordiazepoxide (eg, Librium, Mitran, Poxi); the peak plasma level time of alprazolam is relatively fast, and its half-life is variable (2 different metabolism routes); alprazolam provides euphoria and can be used as an antidepressant; treatment should not be started with alprazolam (or clonazepam [Klonopin]); lorazepam (Ativan, Lorazepam Intensol, Loreev) has a longer half-life and time to peak plasma level

Buspirone (Buspar, Vanspar): a 5-HT1A agonist and 5-HT partial agonist; stops the paralyzed feelings from anxiety; FDA-approved for generalized anxiety disorder (GAD) and can be used as an augmenter of other drugs; can cause serotonin syndrome if added too aggressively to an SSRI; there is no abuse potential, psychomotor retardation, or respiratory depression (safe for elderly people); can be considered for patients with stroke and heart failure; can cause dizziness, light headache, and lightheadedness; sedation can be an issue; does not cause euphoria or have rapid onset; not recommended on an as-needed basis and takes 8 to 12 wk to have an effect; keep the dose low when added with SSRI; longer use improves effect

Alternatives: propranolol — most centrally acting β-blocker; most fat-soluble; effective for panic disorder, GAD, especially performance phobia; helps with sweating, palm sweating, rapid heart rate, and tremor; nonselective β-blocker (not suitable for patients with chronic obstructive pulmonary disease [metoprolol can be used]); hydroxyzine — not anticholinergic; traditionally used for itching and allergies; studies show efficacy in GAD and panic disorder (equivalent to clonazepam); risk for fall is similar and may cause sedation, dry mouth, and mental slowing (not as addictive); dosing tips — higher dose and longer treatment durations are required for anxiety disorders; acclimating slowly is necessary to tolerate higher doses

Mood Stabilizers

Lithium: FDA-approved for bipolar disorder in 1970; the gold standard for treatment of mania; blocks glycogen synthase 3; normalizes glutamate activity; very serotonergic; a mainstay for major bipolar disorder (especially for bipolar I disorder); reduces aggression, with a 70% response rate; reduces suicidal ideation (electroconvulsive therapy, clozapine [eg, Clozaril, FazaClo, Versacloz], and ketamine are also effective); antidepressants do not help a patient with a personality disorder who has repeated suicidal attempts (lithium helps); nuisance effects are most common; can affect thyroid function (hypothyroidism) and can damage the tubules in the kidney; can cause severe and often irreversible neurologic damage; lithium toxicity can lead to overdose or dehydration; maintaining hydration is important; monitor blood levels every 3 mo, or every 6 mo if no acute changes occur; adjustments are needed with use of nonsteroidal anti-inflammatory drugs, angiotensin-converting inhibitors, and diuretics (affect kidney function and fluid balance); weight gain — lithium tends to cause fluid retention; people often become thirsty and drink empty calories; maintain a low dose to avoid tremors, acne, and diarrhea; can be managed with adequate fluid intake

Valproate (eg, Depacon, Depakote, Stavzor): has a unique structure among antiepileptic drugs; blocks glycogen synthase 3 and histone deacetylase; activates extracellular signal-regulated kinase; effective for agitation and irritability; beneficial for intellectually disabled and autistic populations; has 2 pathways; the glucuronidation pathway is safe, but when mixed with other antiepileptic drugs (lamotrigine or carbamazepine), it takes the oxidative pathway (mitochondria or microsome) and can produce toxic metabolites; avoid mixing with other antiepileptic drugs; AEs — GI issues are dose-dependent; increased risk is relative to immediate- vs extended-release form; weight gain is more likely with blood levels >125 μg/mL (reduce dosage); can cause mild thrombocytopenia; there is a risk for serious bleeding at <75 μg/mL; hair loss can occur (reduce the dose; a multivitamin supplemented with biotin and zinc can be added for hair growth promotion); toxicity — hyperammonemia (microsomal pathway) and hyperosmolality (mitochondrial pathway); monitor blood levels (complete blood cell count, liver function tests, and valproic acid); rash — can be caused by mixing valproate with antiepileptics, especially lamotrigine; presents as fixed drug eruption, thrombocytopenic purpura, Stevens Johnson syndrome, or toxic epidermal necrolysis

Carbamazepine (eg, Epitol, Equetro, Tegretol): toxic epidermal necrolysis can occur in 3% to 4% of cases; effective for bipolar disorder, depression, chronic pain, neuralgias, and migraine headaches; blocks sodium and potassium channels, stabilizes glutamate; induces its own metabolism, affecting blood levels; oxcarbazepine (Oxtellar, Trileptal) is a modified form of carbamazepine that does not require blood monitoring and has low toxicity; counsel patients who are on carbamazepine (especially female patients of reproductive age because it is a category D drug)

Lamotrigine (eg, Lamictal, Lamotrigine, Subvenite): developed as an antiepileptic drug; blocks glutamate release and calcium channels in the hippocampus; the drug of choice for bipolar II disorder and bipolar disorder in pregnancy; rash can occur (especially when starting medication aggressively); titrate the medication, eg, start with 25 mg daily and gradually increase to 100 mg over a few weeks rather than starting at 75 or 100 mg

Topiramate (eg, Eprontia, Topamax, Trokendi): blocks sodium channels, increases GABA levels, and blocks nicotine receptors (especially in the mesolimbic pathway); FDA-approved for migraines only; do not start topiramate for bipolar disorder (can be used as an adjunct or can be considered if the patient is obese); at low doses, it can be mixed with other medications (eg, bupropion, naltrexone and bupropion [Contrave]) for weight loss; studies are underway for cocaine cravings, gambling, PTSD, smoking, and obesity

Readings

Haenen N, Kamperman AM, Prodan A, et al. The efficacy of lamotrigine in bipolar disorder: A systematic review and meta-analysis. Bipolar Disorders. 2024;. doi: 10.1111/bdi.13452; Harvey AT, Rudolph RL, Preskorn SH. Evidence of the dual mechanisms of action of venlafaxine. Archives of General Psychiatry. 2000;57(5):p503–509; Kamp CB, Petersen JJ, Faltermeier P, et al. Beneficial and harmful effects of tricyclic antidepressants for adults with major depressive disorder: a systematic review with meta-analysis and trial sequential analysis. BMJ Mental Health. 2024;27(1):pe300730. doi: 10.1136/bmjment-2023-300730; Kverno K. Lithium: Current clinical guidelines for nurse practitioners. Journal of Psychosocial Nursing & Mental Health Services. 2022;60(1):p6–9. doi: 10.3928/02793695-20211207-02; Mendels J, Frazer A. Brain biogenic amine depletion and mood. Arch Gen Psychiatry. 1974;30(4):447-451. doi:10.1001/archpsyc.1974.01760100019004; Müller CP. Serotonin and consciousness – A reappraisal. Behavioural Brain Research. 2022;432:p113970. doi: 10.1016/j.bbr.2022.113970; Pae CU, Patkar AA. Paroxetine. Expert Review of Neurotherapeutics. 2007;7(2):p107–120. doi: 10.1586/14737175.7.2.107; Poliacoff Z, Belanger HG, Winsberg M. Does bupropion increase anxiety? A naturalistic study over 12 weeks. Journal of Clinical Psychopharmacology. 2023;43(2):p152–156. doi: 10.1097/JCP.0000000000001658; Pucci M, Roussak P, Pang D, et al. Drug-induced priapism. Adverse Drug Reaction Bulletin. 2020;322(1):p1247–1250. doi: 10.1097/FAD.0000000000000048; Stahl S, Van den Eynde V, Godet LB, et al. The pocket guide to classic monoamine oxidase inhibitors for treatment-resistant depression. Psychiatric Annals. 2023;53(8):p347–352. doi: 10.3928/00485713-20230713-01; Wikner BN, Stiller CO, Kallen B, et al. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: maternal characteristics. Pharmacoepidemiology and Drug Safety. 2007;16(9):p988–994. doi: 10.1002/pds.1391.; Zetin M. A clinician’s guide to monoamine oxidase inhibitors. Current Psychiatry Reviews. 2013; 9(4):p353–364

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Lang’s lecture contains information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Lang was recorded at the 36th Annual Recent Developments in Internal Medicine, held October 17-19, 2024, in Atlantic Beach, NC, and presented by the Brody School of Medicine at East Carolina University Eastern Area Health Education Center. For information on upcoming CME activities from this presenter, please visit cme.ecu.edu. Audio Digest thanks Dr. Lang and the Brody School of Medicine at East Carolina University Eastern Area Health Education Center for their cooperation in the production of this program.

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