Major Depressive Disorder (MDD)

• Major depressive disorder (MDD) is marked by one or more major depressive episodes, without a history of mania or hypomania.

Pathophysiology

• The monoamine hypothesis states that decreased brain levels of norepinephrine (NE), serotonin (5HT), and dopamine (DA) may cause depression.
• Postsynaptic changes affecting NE or 5HT1A receptor desensitization or down-regulation may relate to antidepressant effects.
• The dysregulation hypothesis suggests that failure of homeostatic neurotransmitter regulation can affect brain function.
• Chronic stress and inflammation may alter glutamatergic and GABA transmission and reduce brain-derived neurotrophic factor (BDNF) expression.
• Neuroactive steroids are an area of growing depression research.

Clinical Presentation

• Emotional symptoms include diminished pleasure, loss of interest, sadness, pessimism, crying, hopelessness, anxiety, worthlessness, guilt, psychotic features (hallucinations, delusions), and recurrent thoughts of death or suicide.
• Physical symptoms include changes in weight, fatigue, pain (especially headache), sleep disturbance, changes in appetite, loss of sexual interest, gastrointestinal (GI) issues, and cardiovascular complaints.
• Cognitive symptoms include inability to concentrate, poor memory, confusion, and indecisiveness.
• Psychomotor disturbances involve psychomotor retardation (slowed movements, thought, speech) or agitation.

Diagnosis

• MDD is characterized by one or more major depressive episodes as defined in the DSM-5.
• Diagnosis necessitates having 5+ symptoms nearly every day for 2 weeks causing significant distress or impairment.
• Depressed mood or loss of interest/pleasure has to be present in adults, where as in children/adolescents, irritable mood occurs.
• Depressive episodes should not be due to substance or medical conditions, or a history of manic/hypomanic episodes (unless substance-induced).
• Diagnosis involves medication review, physical and mental status exams, complete blood count, thyroid function and electrolyte tests.
• Chronic illnesses (stroke, Parkinson's, TBI, hypothyroidism) and substance use disorders relate to depression.
• Medications with depressive symptoms include antihypertensives, oral contraceptives, isotretinoin, and interferon.
• Standardized rating scales aid in diagnosing depression and assessing treatment.

Treatment Goals

• Treatment aims to resolve current symptoms (remission), prevent future depressive episodes (relapse/recurrence), and prevent suicide.

Nonpharmacologic Therapy

• Psychotherapy (cognitive, dialectical behavior, interpersonal) is a primary treatment for mild to moderately severe MDD, in severe cases it's used with meds, it isn't recommended for severe/psychotic MDD.
• Electroconvulsive therapy (ECT) is considered when quick response is needed, risks of other treatments are greater, with history of poor medication response/patient preference and has therapeutic response in 10-14 days.
• Repetitive transcranial magnetic stimulation has demonstrated effectiveness and does not needs anesthesia, unlike ECT.
• Physical activity benefits those with MDD, the American Psychiatric Association endorses exercise in MDD treatment plans.

Pharmacologic Therapy: General Approach

• Antidepressants are first-line treatments with equal efficacy at comparable doses and classified by chemical structure/mechanism.
• Initial antidepressant selection considers patient/family history, coexisting conditions, interacting medications, presenting symptoms, adverse effect profiles, patient preference, and cost.
• Pharmacogenomics may predict therapy adverse effects/response, dosing is available through Clinical Pharmacogenomics Implementation Consortium (CPIC) and FDA-approved inserts.
• About 50%-60% of depression patients improve with drug treatment, an antidepressant is considered adequate after a 6-week trial at maximum dosage.
• Acute treatment of the phase lasts 6-12 weeks (goal remission), continuation lasts 4–9 months after remission (eliminate residual symptoms/prevent relapse), and maintenance lasts 12–36+ months (prevent recurrence).
• Guidelines advise lifelong maintenance therapy for high-risk patients (younger than 40 with 2+ prior episodes, or any age with 3+ episodes).
• Older patients need half the initial dose, increased slowly, and may require 6-12 weeks to achieve response.
• All antidepressants can increase suicidal thoughts/behavior early on in those aged <25 with elevated risk 30 days post discontinuation.
• Patients and those around them have to be educated on the 2-4 week antidepressant response delay, and adherence importance during treatment.
• Withdrawal syndrome with specific antidepressants can be reduced with a slow taper (weeks/months).
• Antidepressant CYP450 enzyme inhibition/induction impacts pharmacokinetic interactions.

Selective Serotonin Reuptake Inhibitors

• SSRIs inhibit 5HT reuptake into presynaptic neurons and are first-line antidepressants for safety/tolerability.
• Nonresponse to one SSRI doesn't predict nonresponse to another.
• SSRIs can have nonlinear accumulation with chronic dosing, liver/kidney impairment and age can influence pharmacokinetics.
• Antidepressants that enhance serotonergic activity may cause serotonin syndrome characterized by mental status changes, autonomic instability, and neuromuscular abnormalities, it's risky to combine with another 5HT augmenting agent.
• SSRI adverse effects include nausea, emesis, diarrhea, headache, insomnia, fatigue, sexual dysfunction, reduced sedative, anticholinergic, and cardiovascular effects.
• Few patients have early anxiety symptoms that can be reduced by lower doses/slow titration.
• Citalopram/escitalopram can cause QT interval increase >40 mg/day.
• Fatal reactions can occur when SSRIs/MAOIs are coadministered, a 5 week washout post fluoxetine cessation is important with MAOIs.
• Low SSRI starting doses/slow titration should be used when adding to interacting medications.
• CYP2D6 and 3A4 metabolize 80%+ of current medications.

Serotonin-Norepinephrine Reuptake Inhibitors

• Venlafaxine may have a minor efficacy advantage with dose-related effects like nausea, sexual dysfunction, activation, and hyperhidrosis.
• Venlafaxine may increase diastolic BP (reduce dose/discontinue if persistent hypertension occurs), and is worse for nausea/vomiting and has more adverse effect-related discontinuation rates than SSRIs.
• Duloxetine adverse effects: nausea, xerostomia, constipation, appetite reduction, insomnia, and diaphoresis.

Antidepressants with Mixed Serotonin Effects

• Mirtazapine enhances central noradrenergic/serotonergic activity by antagonizing α2adrenergic auto/hetero-receptors, antagonizes 5HT2/5HT3 and blocks histamine receptors and can be used for those with sexual side effects associated with other antidepressants (somnolence/weight gain).
• Levomilnacipran is a single isomer of milnacipran (treat fibromyalgia), inhibits NE reuptake more than 5HT reuptake and increases BP/HR (place in therapy for MDD is not known).
• Trazodone/nefazodone antagonize the 5HT2 receptor/inhibit 5HT reuptake, enhance 5HT1A neurotransmission, block α1adrenergic/histaminergic receptors (increasing dizziness, sedation).
• Sedation, dizziness, and cognitive slowing are the most frequent dose limiting adverse effects with trazodone and dizziness, orthostatic hypotension, and somnolence are common with nefazodone.
• Priapism rarely occurs with trazodone (surgical intervention/impotence) along with black box warning (life-threatening liver failure with no initiation in active liver disease/increased serum transaminases) with nefazodone.
• Vilazodone/vortioxetine are antidepressants with mixed serotonin that combine SSRI/5HT1A presynaptic receptor partial agonists (vilazodone: for anxiety/vortioxetine: for cognitive difficulties).
• Vilazodone associates with nausea, diarrhea, dizziness, insomnia, and decreased libido (males) and vortioxetine causes nausea, constipation, and sexual dysfunction (males at highest dose 20 mg/day).

Bupropion

• Bupropion inhibits NE/DA reuptake, making it an activating antidepressant where seizures correlate with dose and increase by predisposing factors (head trauma/CNS tumor) that occur at the ceiling dose (450 mg/day), with an incidence of 0.4%.
• Adverse effects include nausea, emesis, tremor, insomnia, dry mouth/skin reactions and are contraindicated with bulimia/anorexia (seizure risk causing less sexual dysfunction than SSRIs).

Tricyclic Antidepressants

• TCAs are equally effective but have diminished usage due to safer and more tolerable alternatives that inhibit NE/5HT reuptake and have affinity for adrenergic, cholinergic, and histaminergic receptors.
• TCAs cause anticholinergic effects (xerostomia, blurry vision, constipation, urinary retention, tachycardia, amnesia, delirium) and sedation, additional adverse effects comprise weight gain, orthostatic hypotension, cardiac conduction delay, and sexual dysfunction.
• Desipramine may increase risk of death in those with sudden death and with cardiac dysrhythmias/conduction disturbances.
• Abrupt TCA withdrawal (especially high doses) may trigger cholinergic rebound (dizziness, nausea, diarrhea, insomnia, restlessness)
• TCA metabolism is within the linear usual dosage range although dose-related kinetics cannot be ruled out in older patients.
• Factors impacting TCA plasma concentrations include renal/hepatic dysfunction, genetics, age, smoking, and concurrent medications where antidepressant effect and plasma concentrations correlate in depressed patients for some TCAs (nortriptyline is the best established (therapeutic window)).
• TCA plasma level monitoring indications include inadequate response/relapse, adverse effects, higher than standard doses, suspected nonadherence, pharmacokinetic interactions, older, pediatric, adolescent patients; pregnant patients; pharmacogenomic indications; and cardiac disease, obtain steady state plasma concentrations commonly after 1+ week at constant dosage, during elimination 12 hours post last dose.
• TCAs may interact with medications that change hepatic cytochrome P450 (CYP450) enzyme activity/hepatic blood flow, also involved in interactions through displacement from protein binding sites.
• CYP2D6 inhibitors increase plasma concentrations of TCAs and symptoms of toxicity.

Monoamine Oxidase Inhibitors

• Isocarboxazide, phenelzine, tranylcypromine increase NE/5HT/DA in the neuronal synapse (MAO inhibition are nonselective inhibitors of MAOA/MAOB).
• Selegiline patch (major depression) inhibits brain MAOA/MAOB but reduces effects on MAOA in the gut.
• Postural hypotension (more likely with phenelzine than tranylcypromine which divides dosing to minimize).
• Phenelzine is mildly-moderately sedating (tranylcypromine is often stimulating with last dose in the early afternoon), sexual dysfunction (both genders), hepatocellular damage and weight gain.
• Hypertensive crisis can occur with MAOI administration with tyramine high foods and with certain medications (headache, stiff neck, emesis, diaphoresis, sharply increase BP(captopril administration), with education on dietary and medication restrictions).
• Selegiline patch doses >6 mg/24 hours requires adherence to dietary restrictions.
• Fatal reactions can occur when administering SSRI/TCAs with an MAOI, use cautiously with experienced clinicians.

Ketamine

• Ketamine alters glutamate activity by glutamate activity via extra synaptic N-methyl-D- aspartate (NMDA) receptor antagonism, thus increasing BDNF activity and synaptogenesis
• Antidepressant effect occurs rapidly for TRD when intravenously administered (0.5mg/kg)
• Esketamine is the single s-isomer of ketamine with greater affinity for the NMDA receptor
• Intranasal esketamine requires supervised, in-clinic self administration (1–3 sprays in each nostril per session), 2 hour post-administration clinic observation is needed, receiving doses twice weekly for 4 weeks (variable dosing thereafter) for FDA-approved administration
• Adverse effect from medications includes psychotomimetic/dissociative effects and blood pressure elevation, a mandatory Risk Evaluation and Mitigation Strategies (REMS).

Brexanolone

• Brexanolone (exogenous allopregnanolone) assists with antidepressant effect through allosteric modulation of GABAA receptors known to increase 5HT/NE transmission (FDA approved for postpartum depression), with administration involving 60 hour stepped-dose IV infusion
• Adverse effects include dizziness, headache, somnolence, REMS program and Elements to Ensure Safe Use (ETASU) because of too much sedation/loss of consciousness.

Alternative Pharmacotherapy

• Beneficial in mild-moderate depression is St. John’s wort (a herb including hypericum)(, interacts with medications, and Omega3 fatty acids, SAMe, folate (conflicting evidence, use with caution).

Special Populations: Older Patients

• Less apparent compared to other symptoms (appetite loss, cognitive impairment, sleeplessness, exhaustion, physical complains, lack in interests are indications of depression.
• SSRIs and Bupropion/venlafaxine/mirtazapine have proven an effective and well tolerated medication; hyponatremia is typically common in the elderly

Pediatric Patients

• Boredom, anxiety, maladjustment, sleep disturbances indicates childhood symptoms
• Limited data exists to demonstrate antidepressant efficacy with fluoxetine/escitalopram receiving FDA approval with for patients 18 years of age.
• Every antidepressant medication has black box warning due to increased suicide/ideation (FDA recommends monitoring).
• Cases of sudden death have documented in desipramine taking children and adolescents (baseline ECG recommended).

Pregnancy and Lactation

• Individual termination of pregnancy carries a a 5 fold risk of relapse who did not continue medication administration. Risks of SSRI medication encompasses LBW/respiratory distress/congenital heart failure. Risk and benefits are weighed because uncertainty of long term infants expose via human consumption has not been determined.

Relative Resistance and Treatment Resistant Depression

• Only a third remised, a subsequent administration of medication may alleviate depression symptoms with bupropion SR or buspirone.
• A fourth achieves remission with new generation antipsychotics with augmentation of venlafaxine XR or bupropion or sertraline.
• Increase of medications, Lithium,T3, new administration agents and new medications with ketamine etc are augmentations with current antidepressant mediation.
• APA guidelines for after 6-8 weeks should be considered with dose changes, augmentation, ECT, or change with medications/psychotherapy
• Evaluate medication /adherence (typically inadequate medication).
• What is the diagnosis? What are potential adverse reactions/dose limits/patient adherence with proper stepwise approaches for treatment? Did the previous treatment methods measure other compounding factors of psychiatric/medical origin which may affect treatment responses when evaluating nonresponses?

Evaluation of Therapeutic Outcomes

• Track plasma concentrations, adverse effects, symptoms alleviation and function for assurance of medication continuation.
• Assess BP with SNRI administration.
• Pretreatment ECG/ administration of children, adolescents and patients 40+ annually
• Track for suicide and ideation during medication intake.
• psychometric instruments measure rapidly measure and correlate severity/ nature of various issues.