Overview of drugs used for the treatment of depression and mania associated with bipolar disorder.

While most patients respond favorly to antidepressants, so requires dual therapy which second gen antipsychotics (SGAs like aripipazole, brexpiprazole, quetiapine) which complete block serotonin and dopamine receptors.

Mechanism of Action

Most antidepressants potentiate the action of norepi or serotonin (directly or indirectly). This is based on the theory that depression is due to a deficiency of monoamines (opposite for mania). Treatment takes weeks-months for a therapeutic response

Selective serotonin reuptake inhibitors (SSRIs)

Examples of these include: citalopram, escitalopram, flouxetine, fluvoxamine, paroxetine, sertaline.

These inhibit the reuptake of serotonin are and selective for the serotonin transporter (not norepi). Very little blockage of muscarininc, alpha adrenergic, and H1 receptors. Drugs of choice for depression treatment due to safety profile.

Okay so if we inhibit the reuptake, we increase the levels of serotonin in the synaptic cleft. Typically takes 2 weeks to start working. Given orally and peak drug levels happen at around 2-8 hours. Plasma half live is 16-36 hours. Metabolized by CYP450s and round 2. Flouxetine has a much longer half live at 50 hours and its active metabolite last for 10 days because it (and paroxetine, fluvoxamine) are potent inhibitors of some CYP450s

Indications: depression (in peds use fluoxetine, escitalopram), OCD (use flouxetine, seraline, fluvoxamine in peds), panic disorder, GAD, PTSD, social anxiety disorder, premenstrual dysphoric disorder, bulima nervosa (just flouxetine), premature ejaculation, difficulty sleeping (paroxetine and fluvoxamine are more sedating), Fatigue (activating SSRIs like fluoxetine/sertaline)

ADRs: HA, sweating, anxiety/agitation, hyponatrenia, N/V/D, weakness, fatigue, sexual dysfunction, weight changes, insomnia, somnlence, QT prolongation (more likely with Citalopram). Increased risk of SI with pediatric patients.

In the case of TI/OD citalopram may cause QT prolongation. Seizures are possible since antidepressants lower the seizure threshold. Serotonin syndrome includes hyperthermia, muscle rigidity, sweating, clonic muscle twitching, mental status and vital sign changes especially when used in combinatation with a MAOI.

Discontinuing the drug → fluoxetine has the lowest risk of withdrawl symptoms (longer halflife and active metabolite). Discontinuation syndrome looks like HA, malaise, flu-like symptoms, agitation/irritability, nervousness, changes in sleep. Taper your patients meds.

Serotonin-Norepinephrine reuptake inhibtors (SNRIs)

Includes venlafaxine, desvenlafexine, levomilnacipran, and duloxetine. These work by inhibiting the reuptake of serotonin and norepi. These are more efficacious in treating depression accompanied with chronic pain. Little activity at muscarinic, H1, or alpha adrenergic receptors.

ADRs: nausea, sexual dysfunction, dizziness, diaphoresis, if stopped abruptly you may see discontinuation syndrome

Venlafaxine, Desvenlafexine

Venlafaxine inhibits serotonin reuptake at low doses and blocks norepi at higher doses. Minimal inhibtion of some CYP450s. Desvenlafexine is the active metabolite of venlafaxine.

ADRs: nausea, HA, sexual dysfunction, dizziness, insomnia, sedation, constipation, HTN and tachycardia at higher doses

Duloxetine

Inhibits both serotonin and norepi at any dose. Exclusively metabolized in the liver so don’t use it in liver peeps. Inhibits CYP2D6 so watch it with drugs that are metabolized by this (antipsychotics).

ADRs: nausea, constipation, dry mouth, insomnia, somnolence, sweating, sexual dysfunction

Levomilacipran

A enantiomer of an older SNRI. Primarily metabolized by CTP3A4

ADRs: nausea, HA, dry mouth

Atypical Antidepressants

Mixed group with actions at several sites

Brexanaolone

Allosteric modulator of GABAa receptors and is used for postpartum depression because it replaces allopregnanolone which declines after delivery. Given IV 60 hours post delivery.

ADRs: excessive sedation, sudden LOC, hypoxia → monitor your peeps

Bupropion

Weak dopamine and norepi reuptake inhibitor that is used to alleviate the symptoms of depression. Useful decreasing cravings and attenuating withdrawl symptoms of nicotine. Metabolized by the CYP2B6 pathways and has relatively low risk for drug to drug interactions. Avoid in patients with risk for seizures (including concurrent electrolyte abnormalities, hx of anorexia/bulimia)

ADRs: dry mouth, sweating, nervousness, tremor, dose-dependent seizure risk, low risk of sexual dysfunction

Esketamine - not on exam

S-enantiomer of ketamine → nonselective, noncompetitive antagonist of N-methyl-D-aspartate glutamate receptor. Faster acting than standard antidepressants. Used in treating treatment-resistant depression or major depressive disorder with SI/suicidal behavior. Must be administered in controlled environment. Controlled substance with abuse and misuse.

ADRs: sedation risk, feelings of dissociation. Acute symptoms include sedation, N/V, hallucinations/dissociation, increased bp

Mirtazapine - not on exam

Enhances serotonin and norepi neurotransmission because it is an agonist central presynaptic alpha-2 receptors. Some antagonism at 5-HT2 receptors (hits antihistamine receptors so its sedating). No antimuscarinic or sexual functions side effects.

ADRs: sedation, dry mouth, increased appetite, weight gain

Nefazodone and Trazodone

Weak inhibitors of serotonin/norepi reuptake and block the postsynaptic 5HT2a receptor. Trazodone can be used to manage insomnia. These are metabolized by CYP3A4 however, nefazodone inhibits this enzyme.

ADRs: sedation (block histamine H1), hepatoxicity (nefrazodone), priapism (trazodone), orthostasis/dizziness (block alpha 1), nausea, dry mouth

Vilazodone - not on exam

Sertonin reuptake inhibitor and 5-HT1a receptor partial agonist. Metabolized by CYP3A4.

ADRs are similar to SSRIs → nausea, diarrhea, sexual dysfunction, dizziness, discontinuation syndrome

Vortioxetine - not on exam

Sertonin reuptake inhibitor, 5-HT1a receptor partial agonist, and 5HT3/5HT7 blockers. Metabolized by CYP2D6.

ADRs: sexual dysfunction, nausea, constipation

Tricyclic Antidepressants (TCAs)

Inhibit norepi and serotinin reuptake into the presynaptic neuron. TCA also affects other receptors types. Includes tertiary amines imipramine, amitriptyline, clomipramine, doxepin, and trimipramine as well as secondary amines like desipramine, nortiptyline, protriptyline. Maprotiline, and amoxaprine, are tetracylic but included in this category

Improve mood in 50-70% of peeps with major depression, slow onset though (like 2 weeks+). Patient response is used to adjust dosage. Narrow TI so watch your patients

Given orally and have a pretty high 1st pass effect. Metabolized by CYP450s and round 2 enzymes. Excreted as inactive metabolites by the kidneys

Mechanism of action

Inhibits nuerotransmitter reuptake: TCAs and amoxapine are extremely potent. Maprotiline and desipramine are basically selective to norepi.

Receptor blocking: TCAs block serotonergic, alpha adrenergic, muscarinicm and histamine H1 receptors. Amoxapine also blocks dopamine D2s and 5HT2s.

Therapeutic Uses

Treating moderate to severe depression sometimes panic disorder. Imipramine is an alternative to desmopressin and can be used in treating bed-wetting in children. Ampitriptyline can be used to prevent migraines and treat chronic pain syndromes. Doxepin and some other TCAs can help with insomnia.

ADRs

Blocking muscarinic: blurred vision, xerostomia, urinary retention, constipation, sinus tachycardia, aggravation of angle closure gluacoma, rhythm changes can occur with OD

Block alpha adrenergics: orthostatic HTN, dizziness, reflex tachycardia

Histamine H1 blockage: sedation

Weight gain, sexual dysfunction (minority)

Watch in peeps with bipolar. Monitor depressed patients with SI. May exacerbate BPH, epilepsy, pre-existing arrhythmias

Monoamine Oxidase Inhibitors (MAOIs)

In the neuron MAO functions to irreversibly inactivate any neurotransmitters brought back into the cell or those that leak out of synaptic vesicles. Include phenelzine, tranylcypromina, isocarboxazid, and selegiline. All are nonselective for MAO-A and B (except for selegine which likes B at low doses). Lots of interactions except for selegine which is available as a transdermal patch.

Well absorbed after oral since MAO is irreversible inhibited the only way to over come it is to make more enzymes which takes time (usually several weeks after termination). Once you stop, you must wait 2 weeks before restarting or starting a new medication. Metabolized by liver and excreted by kidney.

Mechanism of Action

Most form stable complexes with the enzyme and irreversibly inactivate it - not just in the brain but in the liver and gut. This leads to increased stores of neurotransmitters.

Therapeutic Uses

Depressive patients who are intolerant/unresponsive to other antidepressants (LAST RESORT)

ADRs

Selegiline and tranylcypromine may produce agitation and insomnia.

Toxins in the gut like tyramine cannot be inactivated by MAO-A because we inhibited it → HTN crisis, occipital headaches, stiff neck, tachycardia, seizures, stroke maybe.

Drowsiness, orthostatic HTN, blurred vision, dry mouth, constipation

Do not coadminister with SSRIs → serotonin syndrome, wait the 2 weeks (unless its fluxetine then wait 6 weeks)

Do not take pseudoephedrine → significant HTN

Treating Mania and Bipolar

Lithium - NOT ON EXAM

Used acutely and prophylactically. Low TI and patients must be monitored. ADRS include dry mouth, polydipsia, polyuria, polyphagia, GI distress, fine hand tremor, dizziness, fatigue, dermatologic reactions, and sedation. Lithium toxicity may show up as ataxia, slurred speech, coarse tremors, confusion, and convulsions. Eliminated by the kidneys → watch your renal patients but a great choice for liver patients. Associated with development of DI and decreased thyroid function

Other - NOT ON EXAM

Stuff like carbamazepine, divalproex, and lamotrigine which are antiepileptics can be used as a mood stabilizer.

Some other antipsychotics like chlopromazine and haloperidol and SGAs can also reduce manic symptoms.