Major Depressive Disorder (MDD) Fall 2024 - 2025 PDF

1 Major Depressive Disorder (MDD) Fall 2024 – 2025 Beirut: Dr. Jihan Safwan – Dr. Maryline Mansour – Dr. Riwa Kfoury Bekaa: Dr. Samar Younes – Dr. Shahnaz Al Masri School of Pharmacy Lebanese International Uni...

1 Major Depressive Disorder (MDD) Fall 2024 – 2025 Beirut: Dr. Jihan Safwan – Dr. Maryline Mansour – Dr. Riwa Kfoury Bekaa: Dr. Samar Younes – Dr. Shahnaz Al Masri School of Pharmacy Lebanese International University  2 Learning Objectives Learn about the prevalence of depression in various populations Explain the pathophysiologic mechanisms underlying Depression Be able to recognize the signs and symptoms of MDD Recommend an appropriate antidepressant therapy based on the patient’s treatment phase and history Apply pharmacokinetic principles and patient specific data when choosing the most appropriate pharmacologic therapy Learn how to monitor treatment efficacy and adjust medications based on the patient’s response and tolerability.  3 Definition Depression is a mood state, as indicated by feelings of sadness, despair, anxiety, emptiness, discouragement, or hopelessness; having no feelings; or appearing tearful Syndrome, which is a combination of signs and symptoms Mental disorder that identifies a distinct clinical condition (eg, unipolar major depression)  4 Assessment History of present illness Depressive symptoms and their context Suicide risk General medical illness Family history Social history Mental status examination Physical examination Laboratory evaluation Screening for depression Diagnostic instruments  5 Epidemiology Estimated lifetime prevalence 12 % Sex Developed countries like USA & Europe → 18% Two times greater in females Developing countries like Peoples’ Republic of China, Mexico, & Brazil → 9% Race Whites → 18 % World Health Organization Caribbean blacks → 13 % Unipolar major depression is the 11th greatest African Americans → 10 % cause of disability and mortality in the world Age United States Less common in older than Major depression ranks 2nd among all diseases younger adults living in the and injuries as a cause of disability, and community persistent depressive disorder (dysthymia) as the 20th  6 Pathogenesis Genetics Pharmacogenetics may influence response to antidepressants Early life adversity Childhood trauma Social factors Isolation, poor social relationships, criticism from family members, and depression in one's friends and neighbors Psychologic factors Negative patterns of thinking, early life losses, self-esteem, and difficulties in managing acute losses and interpersonal relationships Secondary depression General medical disorders: Epilepsy, Parkinson, Heart Failure, HIV/AIDS, Cancer… Medications: Glucocorticoids, interferons…  7 Neurobiology Neurotransmitters Monoamines Serotonin Norepinephrine Dopamine Gamma-aminobutyric acid (GABA) → BDZ Glutamate → primary excitatory NT in the brain Excitatory Inhibitory  8 Cont’d Neurobiology  9 Diagnostic criteria & classification Criteria in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)  10 Cont’d Diagnostic criteria & classification  11 Cont’d Diagnostic criteria & classification  12 Cont’d Diagnostic criteria & classification  13 Cont’d Diagnostic criteria & classification  14 Treatment goals The main goals of initial treatment for depression are: Symptom remission Restoring baseline functioning  15 Classification MILD TO MODERATE MAJOR DEPRESSION SEVERE MAJOR DEPRESSION  16 Mild to moderate major depression Manifestations: Either no suicidal or homicidal ideation or behavior, or the presence of ideation that does not pose an imminent risk (eg, thoughts that family members would be better off if the patient was dead; or fleeting thoughts of killing oneself, with nonexistent or vague plans to commit suicide and no intent) No psychotic features (eg, delusions or hallucinations) Little to no aggressiveness Intact judgment such that the patient or others are not at imminent risk of being harmed Mild to moderate depression can generally be treated in an outpatient setting or partial (day) hospital program  17 Cont’d Mild to moderate major depression Treatment Antidepressants plus psychotherapy Antidepressants Classes of AD Selecting an AD Side effects Dose Response Adequate trial Psychotherapy  18 Antidepressants plus psychotherapy Randomized trials indicate that the combination of pharmacotherapy and psychotherapy (eg, cognitive- behavioral therapy (CBT) or interpersonal psychotherapy (IPT)) is more efficacious than either pharmacotherapy alone or psychotherapy alone However, psychotherapy is often not available or is declined  19 Antidepressants Second-generation antidepressants Selective serotonin reuptake inhibitors (SSRIs) Serotonin-norepinephrine reuptake inhibitors (SNRIs) Atypical antidepressants Serotonin modulators Older, first-generation antidepressants Tricyclic antidepressants (TCAs) Monoamine oxidase inhibitors (MAOIs)  20 Selective serotonin reuptake inhibitors (SSRIs) Dose Metabolism & SSRIs Administration DDI (mg/day) elimination Citalopram 20 – 40 QD None Liver (Cipram®) Escitalopram 10 – 20 QD None Liver (Cipralex®) 2D6 (potent at doses Sertraline > 200 mg per day), 50 – 200 QD Liver (Zoloft®) 2B6, 2C9, 2C19, and 3A4 20 – 40 Paroxetine 2D6 (potent) and (CR: 25- QD Liver (Seroxat®) 2B6 (potent) 50) QD Fluoxetine 2D6 (potent), 2C9, 20 – 60 Active mtb: norfluoxetine Liver (Prozac®) 2C19, 2B6, and 3A4 (4 - 16 days) → withdrawal? 1A2 (potent), 2C19 Fluvoxamine 50 – 200 QD (potent), 2B6, 2C9, Liver (Faverin®) and 3A4  21 Cont’d Selective serotonin reuptake inhibitors (SSRIs) Use Frequently used as first-line antidepressants because of their efficacy, tolerability, and general safety in overdose Pharmacology SSRIs inhibit the serotonin reuptake pump and increase postsynaptic serotonin receptor occupancy SSRIs are selective in that they have relatively little affinity for other types of receptors Efficacy There is no compelling evidence that one SSRI is more efficacious than another Choice is based upon cost, individual patient tolerance, and clinician experience  Cont’d Selective serotonin reuptake inhibitors (SSRIs) Serotonergic nerve ending Serotonin reuptake Serotonin- channel (reduces containing vesicle Increased synaptic 5HT levels) serotonin levels in 5HT SSRI synapse Synapse Blocking 5HT reuptake Increased 5HT Serotonin binding → receptor enhanced Postsynaptic neuron neurotransmission  23 Cont’d Selective serotonin reuptake inhibitors (SSRIs) Side Effects (SE) Drug Agent specific SE Common SE to all SSRIs Citalopram QT Prolongation Insomnia/agitation Escitalopram QT Prolongation Orthostatic hypotension (OH) Sertraline QT Prolongation, Diarrhea Transient nausea and GI discomfort upon initiation or Paroxetine Anticholinergic, Drowsiness dose increase Fluoxetine QT Prolongation Weight gain Sexual dysfunction Fluvoxamine Drowsiness Sexual dysfunction ➔ anorgasmia in women and erectile dysfunction in men, and increase ejaculation latency in men Weight gain ➔ improved appetite, increased carbohydrate craving, and changes in serotonin 2C receptor activity  24 Cont’d Selective serotonin reuptake inhibitors (SSRIs) Switching between antidepressants Cross-tapering is the best technique Dose of the current antidepressant is gradually reduced over a 1-2 week period or longer, while the dose of the new antidepressant is gradually increased to therapeutic range over the same time period  25 Cont’d Selective serotonin reuptake inhibitors (SSRIs) Discontinuation of antidepressants Antidepressant dose should be reduced by 25% per week so as to minimize the occurrence of discontinuation side effects Taper over 2-4 weeks DO not discontinue abruptly to avoid discontinuation syndrome Discontinuation syndrome Cause ➔ Abrupt cessation of SSRIs Symptoms ➔ dizziness, nausea, fatigue, muscle aches, chills, anxiety, and irritability, electric shock sensations Symptoms are mild with fluoxetine (long half-life) and can be particularly severe with paroxetine and fluvoxamine  26 Cont’d Selective serotonin reuptake inhibitors (SSRIs) Serotonin syndrome Potentially life-threatening condition associated with increased serotonergic activity in the central nervous system (CNS) Caused by overstimulation of central and peripheral 5HT receptors It can occur after initiating or increasing a single serotonergic drug or even when using a combination of meds that increase 5HT Clinical features include: Anxiety, agitation, delirium, diaphoresis, tachycardia, hypertension, hyperthermia, GI distress, tremor, muscle rigidity, myoclonus and hyperreflexia  27 Serotonin Syndrome  28 Cont’d Serotonin Syndrome Hunter Serotonin Toxicity criteria SS is a clinical diagnosis, no single laboratory test can confirm it  29 Cont’d Serotonin Syndrome Symptoms can range from mild tremor to life-threatening hyperthermia & shock Examination findings: hyperthermia, agitation, ocular clonus, tremor, akathisia, deep tendon hyperreflexia, inducible or spontaneous clonus, muscle rigidity, dilated pupils, dry mucus membranes, increased bowel sounds, diaphoresis… Neuromuscular findings are more pronounced in lower extremities  30 Cont’d Serotonin Syndrome Helpful tests: CBC, electrolytes, Cr, BUN CPK, hepatic transaminases, coagulation panel Blood culture, urine analysis and culture Chest radiograph Head CT and LP Differential diagnosis: Neuroleptic malignant syndrome (NMS) Anticholinergic toxicity Malignant hyperthermia Sympathomimetic toxicity Meningitis or encephalitis  31 Cont’d Serotonin Syndrome Treatment: 1. DISCONTINUE SEROTONERGIC MEDICATION 2. Supportive care: Oxygen (maintain SpO2 ≥ 94) IV fluids Continuous cardiac monitoring 3. BDZ for agitation, neuromuscular abnormalities (tremor, clonus…) and mildly elevated BP and HR (eg. Lorazepam 1-2 mg IV) 4. If BDZ fail or patient becomes severely ill → Cyproheptadine 12mg po 5. Temp > 41.1 C → ICU Immediate sedation, paralysis and endotracheal intibation Treat temperature with standard measures Avoid antipyretics such as acetaminophen → ineffective because increased muscular activity is causing hyperthermia in serotonin syndrome  32 Serotonin-norepinephrine reuptake inhibitors (SNRIs) Dose Metabolism & SNRIs Administration DDI (mg/day) elimination Levomilnacipran CYP3A4 (Fetzima®) – 20-120 QD Renal substrate 2013 Milnacipran Renal and (Savella® or 100 - 200 BID None hepatic Ixel®) – 2009 Duloxetine Inhibits Renal and (Cymbalta®) – 60 - 120 QD CYP2D6 hepatic 2004 Desvenlafaxine Renal and 50 - 100 QD None (Pristiq®) – 2007 hepatic Venlafaxine XR: QD Renal and (Effexor XR®) – XR: 75 - 225 Active mtb None hepatic 1994 (desvenlafaxine)  33 Cont’d Serotonin-norepinephrine reuptake inhibitors (SNRIs) Use Initial treatment of major depression, treatment resistant depression, and other disorders Duloxetine → diabetic peripheral neuropathy, GAD and fibromyalgia among other indications as well Milnacipran is approved to be used in patients with fibromyalgia Venafaxine → SAD, GAD, Panic… Pharmacology Initially blocking presynaptic 5HT and NE transporter proteins ➔ Inhibits reuptake of these NT and leads to increased stimulation of post-synaptic receptors Relatively selective → Little or no effect on dopaminergic, cholinergic, histaminergic, or alpha1-adrenergic receptors → relatively lower SE  34 Cont’d Serotonin-norepinephrine reuptake inhibitors (SNRIs) Side Effects SNRIs Agent specific SE Common SE to all SNRIs Urinary hesitancy Levomilnacipran May increase DBP & HR (monitor BP) Transient nausea and GI Milnacipran Drowsiness discomfort upon initiation May increase DBP and HR (monitor BP) or dose increase Duloxetine Insomnia/agitation Sexual dysfunction Insomnia/agitation Desvenlafaxine May increase DBP and HR (monitor BP) Anticholinergic like Drowsiness effects such as dry mouth Insomnia/agitation and constipation – QT prolongation Caution in narrow angle Venlafaxine glaucoma XR formulation because of less nausea May increase DBP and HR (monitor BP)  35 Atypical antidepressants Metabolism Atypical Administration DDI and Antidepressants elimination Bupropion Inhibit CYP Liver and QD kidney (Wellbutrin®) 2D6 None Liver Agomelatine QD (Valdoxan®) (not available in the US) QHS Mirtazapine None Liver and QD kidney (Remeron ®)  36 Cont’d Atypical antidepressants Metabolism Atypical Administration DDI and Antidepressants elimination Induction phase Multiple Liver and Esketamine Week 1-4: twice per week drugs kidney Maintenance phase intranasal Week 5-8): once weekly (Spravato ®) Week 9 and after: Q2weeks or once weekly IV: Initiate 60-hour (in Multiple Liver and hospital admission) drugs kidney Brexanolone continuous infusion early (Zulresso®) enough in the day to allow for recognition of excessive sedation Zuranolone???  37 Cont’d Atypical antidepressants Use Used in patients with inadequate responses or intolerable side effects during first-line treatment with SSRIs First-line treatment if the drug has a desirable characteristic Bupropion ➔ major depression, seasonal affective disorder, ADHD, tobacco dependence, hypoactive sexual disorder (HSDD), and obesity Agomelatine ➔ major depression + insomnia Mirtazapine ➔ major depression, GAD, and tension type headaches Esketamine ➔ treatment-resistant depression in conjunction with an oral antidepressant Brexanolone ➔ treatment of postpartum depression (PPD) in adults  38 Cont’d Atypical antidepressants Atypical Pharmacology Antidepressants Bupropion Dopamine / norepinephrine reuptake inhibitor (DNRI) Agonist at melatonin receptors (MT1 and MT2) ➔ normal circadian rhythms (preferred in insomnia) Agomelatine 5-HT2C receptor antagonist ➔ increase release of DA and NE Presynaptic alpha-2 receptors antagonist ➔ increases release of 5HT and NE Antagonist of postsynaptic serotonin 5-HT2 and 5-HT3 receptors ➔ increases neurotransmission mediated by Mirtazapine serotonin 5-HT1 receptors H1 receptor antagonist ➔ sedation Low affinity for cholinergic, alpha-1 adrenergic, and dopaminergic receptors  39 Cont’d Atypical antidepressants Atypical Pharmacology Antidepressants S-enantiomer of racemic ketamine Nonselective, noncompetitive NMDA receptor antagonist (NMDA is a glutamate receptor) Esketamine The mechanism causing antidepressant effect is unknown GABA-A Receptor Positive Modulator Brexanolone  40 Cont’d Atypical antidepressants Side effects Atypical Agent specific SE Antidepressants Seizures Insomnia/agitation (more with IR and less with SR) Bupropion QT Prolongation GI toxicity NO SEXUAL DYSFUNCTION Drowsiness Agomelatine GI toxicity Drowsiness Anticholinergic SE Mirtazapine QT prolongation Increased appetite and weight gain Sexual dysfunction  41 Cont’d Atypical antidepressants Side effects Atypical Agent specific SE Antidepressants Dissociation Headache Dizziness Dysgeusia Nausea Hypoesthesia Esketamine Vertigo Anxiety Sedation Lethargy Presyncope Drowsiness Brexanolone Sedation Vertigo Xerostomia  42 Serotonin modulators Serotonin Metabolism and Administration DDI modulators elimination CYP3A4 inhibitor Liver Nefazodone (Serzone®) BID P-glycoprotein inducer Trazodone P-glycoprotein Liver (Desyrel®) BID inducer None Liver Vilazodone QD (Viibryd®) None Liver Vortioxetine QD (Trintellix ®)  43 Cont’d Serotonin modulators First-line treatment if the drug has a desirable characteristic Use Nefazodone ➔ major depression and premenstrual syndrome Trazodone ➔ major depression, functional dyspepsia, hypnotic to treat insomnia in the context of depression, as well as insomnia associated with antidepressants Vilazodone ➔ MDD NOT FIRST LINE!!! Vortioxetine ➔ MDD  44 Cont’d Serotonin modulators Atypical Antidepr. Pharmacology Antagonizes and down regulates postsynaptic 5-HT2A receptors, and weakly inhibits presynaptic serotonin and norepinephrine reuptake ➔ increase activity at the serotonin Nefazodone 5-HT1A receptors Little to no affinity for alpha-adrenergic receptors, cholinergic,DA-2, and histamine H1 receptors Acts upon postsynaptic 5-HT2A and 5-HT2C receptors and weakly inhibits presynaptic 5HT reuptake ➔ dose dependent effects such that at low doses the drug acts as a 5HT antagonist and at high doses as a 5HT agonist Trazodone Effects on NE and DA reuptake are minimal Blocks postsynaptic alpha-adren receptors (OH &priapism) & H1 receptors (sedation) Does not affect cholinergic receptors Inhibits presynaptic reuptake of serotonin and also acts as a partial agonist at Vilazodone postsynaptic serotonin 5-HT1A receptors Inhibition of NE and DA reuptake is minimal 5HT reuptake inhibitor (SRI) 5-HT1A receptor high-efficacy partial agonist/near-full agonist Vortioxetine 5-HT1B receptor partial agonist / 5-HT3A receptor antagonist / 5-HT7 receptor antagonist Affinity for the β1-adrenergic receptor → only likely to contribute to side effects  45 Cont’d Serotonin modulators Serotonin Agent specific SE Common SE modulators Anticholinergic Nefazodone CAUTION: can cause liver failure Drowsiness QT Prolongation OH Weight gain GI toxicity Trazodone Sexual Dysfunction (Priapism) Sedation Insomnia/agitation Vilazodone GI toxicity (higher rates of N/V/D) Sexual Dysfunction GI Toxicity Vortioxetine  46 Tricyclic antidepressants (TCAs) Metabolism Type of Adminis TCAs MOA MOA: blocks DDI and amine tration elimination H 1 and M1 Liver Amitriptyline (has active (Tryptizol®) More potent in metab: blocking reuptake nortript) of 5-HT compared H 1 and M1 Liver Clomipramine with NE (Anafranil®) Tertiary Strongest H1 Liver Doxepin 5HT > NE (sed/wt) & M1 QD Substrate (Doxepin®) Alpha, H1, & Liver Imipramine M1 (has active (Tofranil®) metab: desipramine) H1 and less Liver Trimipramine M1  47 Cont’d Tricyclic antidepressants (TCAs) Metabolism Type of Adminis TCAs MOA MOA: blocks DDI and amine tration elimination Less H1 & M1 Liver Desipramine (Desipramine®) (active metab More potent in of imipramine) blocking reuptake of NE than 5-HT Less H1 & M1 Liver Nortriptyline Secondary (active metab of amitriptyline) NE > 5HT Less H1 & M1 Liver Protriptyline QD Substrate Tetracyclic H1 Liver Maprotiline (Ludiomil®) More Potent NE DA Liver reuptake inhibitor Different than 5-HT Amoxapine type of (NE>5HT) amine and blocks postsynaptic DA receptors  48 Cont’d Tricyclic antidepressants (TCAs) Use 1958 ➔ TCAs were first-line treatment for depression for 30 years, until SSRIs were introduced Major depression, panic attacks, GAD, PTSD, bulimia nervosa, smoking cessation, chronic daily headache and neuropathy Taken once a day, usually at bedtime because of sedating SE Response: 4 weeks ➔ after reaching therapeutic dose, response should occur after at least 4 weeks Adequate trial: 12 weeks ➔ after reaching therapeutic dose, 12 weeks should elapse before determining whether the medications have sufficiently relieved symptoms or not Amoxapine ➔ antipsychotic effects  49 Cont’d Tricyclic antidepressants (TCAs) Side effects Tertiary amines generally cause more SE compared with secondary amines More anticholinergic side effects (eg, constipation or blurred vision) + highly sedating (central effects on histamine) Heart block, ventricular arrhythmias, and sudden death ➔ Before initiating treatment with any of the cyclic antidepressants, patients must be screened for cardiac conduction system disease, which precludes the use of these medications Patients ≥ 40 years should have a baseline ECG for this purpose Cardiac Patients < 40 can be screened by history for evidence of cardiac disease and do not require an ECG if the history is negative Orthostatic hypotension (alpha block)  50 Cont’d Tricyclic antidepressants (TCAs) Side effects Blurred vision, constipation, dry mouth (which may lead to dental caries), urinary retention, Anticholinergic tachycardia, ocular crisis in patients with narrow- angle glaucoma, confusion and delirium Antihistaminic Sedation, increased appetite leading to weight gain, confusion, and delirium Other Decreased seizure threshold, sexual dysfunction, diaphoresis, and tremor Toxicity Dangerous in overdose by suicidal patients  51 Monoamine oxidase inhibitors (MAOIs) Metabolism and Drug Administration DDI elimination MAO inhibitor Tranylcypromine BID Urine CYP inhibitor Phenelzine TID MAO inhibitor Urine Selegiline MAO inhibitor (Transdermal QD Liver and kidney CYP inhibitor patch: EMSAM®)  52 Cont’d MonoAmine Oxidase Inhibitors (MAOIs) Use Not considered first-line antidepressant Dietary restrictions Drug-drug interactions Extensive side-effects Useful for "atypical" depression Depression with hyperphagia, hypersomnia, leaden paralysis (depressed patients who have a sense of heaviness in arms & legs), and rejection sensitivity (anxiously expect, readily perceive, and overreact to social rejection) Effective in treatment-resistant depression  53 Cont’d MonoAmine Oxidase Inhibitors (MAOIs) Pharmacology Inhibit MAOa and MAOb MAOa: preferentially deaminates 5HT, melatonin, epinephrine, NE, DA, trace amines (like Tyramine) MAOb: preferentially deaminates phenylethylamine, DA, and other trace amines (like Tyramine)  54 Cont’d MonoAmine Oxidase Inhibitors (MAOIs) Pharmacology Tranylcypromine Irreversible inhibitor of MAOa Irreversible inhibitor of MAOb to a degree Blocks reuptake of serotonin and catecholamines Phenelzine Irreversible inhibitor of MAOa and MAOb Selegeline Selective MAOb inhibitor at low doses and a non-selective MAO inhibitor at higher doses Transdermal patch form “EMSAM” ➔ approved by FDA in 2006 for treatment of depression (bypasses gut)  55 Cont’d MonoAmine Oxidase Inhibitors (MAOIs) Side effects Serotonin Syndrome Sexual dysfunction, sleep disturbance, dry mouth, GI upset, urinary hesitancy, headache, and myoclonic jerks Hypertensive Crisis Blockade of MAOa in the GI tract is responsible for the "cheese reaction“ Severe hypertensive crisis that can occur after patients on MAOIs ingest foods containing the sympathomimetic tyramine Tyramine is usually metabolized in the GI tract by MAOa Blockade of MAOa allows it to flow into the general circulation  56 Cont’d MonoAmine Oxidase Inhibitors (MAOIs)  57 Cont’d MonoAmine Oxidase Inhibitors (MAOIs) Hypertensive Crisis Drug Restrictions Cold remedies/asthma inhalants Appetite suppressants (Sibutramine) Methyldopa/reserpine Narcotic pain killers (Opioids) Amphetamines Other MAOIs Other antidepressants Vasoconstrictors/ sympathomimetics All stimulants  58 Cont’d MonoAmine Oxidase Inhibitors (MAOIs) Side effects Hypertensive Crisis Signs and Symptoms Headache/neck stiffness or soreness Nausea/vomiting Sweating Dilated pupils/photophobia Sudden nose bleed Tachycardia/bradycardia/chest pain Management Withhold medication and notify MD Monitor vital signs Sublingual captopril/nifedipine Stand up and walk  59 Cont’d MonoAmine Oxidase Inhibitors (MAOIs) Discontinuation From Duration to wait To Antidepressants 2 weeks MAOI Fluoxetine 5 weeks MAOI Antidepressants OR MAOI 2 weeks stopping MAOI diet  60 Antidepressants Selecting an antidepressant Mild to moderate unipolar major depression First line options: SSRIs SNRIs Other options based on preference General order of preference in choosing an AD: SSRI ➔ SNRI ➔ atypical antidepressant ➔ serotonin modulator ➔ TCA ➔ MOAI  61 Cont’d Antidepressants Selecting an antidepressant Given the lack of clear superiority in efficacy among antidepressants, selecting a drug is based upon other factors such as: Patient response to antidepressants during prior depressive episodes Safety Side effect profile Specific depressive symptoms Comorbid illnesses Concurrent medications and potential DDI Family (eg, first-degree relative) history of response to antidepressants Ease of use (eg, frequency of administration) Patient preference Cost Example: Bupropion ➔ patients who prefer to avoid sexual dysfunction or want treatment for comorbid tobacco dependence Citalopram and escitalopram ➔ less likely to cause DDI Mirtazapine ➔ not used in patients who prefer to avoid weight gain  62 Cont’d Antidepressants Side effects Diarrhea occurs more often with sertraline than bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, and venlafaxine (16 vs 8% of patients). Nausea and vomiting occurs more often with venlafaxine than SSRIs as a class (33 vs 22%). Sexual dysfunction occurs less often with bupropion than escitalopram, fluoxetine, paroxetine, and sertraline (6 vs 16%; paroxetine is especially problematic). Somnolence occurs more often with trazodone than bupropion, fluoxetine, mirtazapine, paroxetine, and venlafaxine (42 vs 25%). Weight gain is greater with mirtazapine (0.8-3 kg after 6-8 weeks of treatment) than fluoxetine, paroxetine, trazodone, and venlafaxine.  63 Cont’d Antidepressants Dose Starting at low doses in order to reduce side effects and improve adherence For depressed patients who do not respond to the minimum therapeutic dose of SSRIs, most clinicians increase the dose within the therapeutic dose range Some patients benefit from doses that exceed the maximum therapeutic dose, provided the drug is safely tolerated Pharmacogenetics Patients may rapidly metabolize drugs due to genetic polymorphisms of hepatic enzymes ➔ Require larger doses Other hepatic isoenzymes may lead to slow metabolism of antidepressants ➔ Need lower doses  64 Cont’d Antidepressants Response to antidepressants Response is seen after 4 weeks of treatment at adequate doses Duration of an adequate trial Adequate trial is usually 12 weeks of treatment at adequate doses Partial Response Patients who show little improvement (eg, reduction of baseline symptoms ≤25%) after 4-6 weeks If patient cannot tolerate a drug due to side effects or intolerance, then switch to a different antidepressant  65 Psychotherapy Types Cognitive-behavioral therapy (CBT) Interpersonal psychotherapy Family and couples therapy Problem solving therapy Psychodynamic psychotherapy Supportive psychotherapy Efficacy of psychotherapy Efficacious for the initial treatment of mild to moderate unipolar major depression, based upon randomized trials Compared with antidepressants Comparable efficacy of psychotherapy compared with antidepressants at the end of treatment  66 Classification MILD TO MODERATE MAJOR DEPRESSION SEVERE MAJOR DEPRESSION  67 Severe major depression Clinical features include: Suicidal or homicidal behavior or ideation with a specific plan and intent Psychotic features (eg, delusions or hallucinations) Catatonia Poor judgement that places the patient or others at imminent risk of being harmed Grossly impaired functioning (eg, food and fluid refusal leading to malnutrition and dehydration) Severely ill patients should be referred to a psychiatrist for management and generally require hospitalization  68 Cont’d Severe major depression Choosing treatment Initial treatment ➔ Combination of pharmacotherapy (SNRI or SSRI or other antidepressant) + psychotherapy Alternative ➔ Pharmacotherapy alone Another alternative ➔ Electroconvulsive therapy (ECT) Especially for patients who require a fast response (eg, patients with suicidal ideation or behavior that is life-threatening) General order of preference in choosing an AD: SSRI or SNRI ➔ atypical antidepressant ➔ serotonin modulator ➔ TCA ➔ MOAI  69 St. JOHN’s Wort Hypericum perforatum OTC product Has affinity to many neurotransmitter receptors Efficacy studies have been conflicting Significant drug interactions Safety issues??? Never used in combination with other antidepressants  70 Treatment approach Treatment Acute Continuation Maintenance phases Duration 12 weeks 4-9 months 12-36 months Induce Preserve Prevent Goal Remission Remission Recurrence  71 Treatment failure If no response at therapeutic doses in 12 weeks or intolerance to antidepressant Several options Switch to an agent from the same class Switch to an agent from a different class If failure after 2 different agents from different classes 1. Augmentation therapy 2. Electroconvulsive therapy 3. Combination therapy General order of preference in choosing an AD: SSRI ➔ SNRI ➔ atypical antidep ➔ 5HT modulator ➔ TCA ➔ MOAI General order of preference in choosing an ADJUNCTIVE MEDICATION: SGA ➔ Lithium ➔ Thyroid hormone ➔ 2nd AD from a different class Last  72 Augmentation therapy Drugs added to therapy if response to antidepressants is inadequate Several options Second Generation Antipsychotics SGA (Risperidone, aripiprazole, brexpiprazole Lithium (resistant depression) Thyroid (add to TCAs) Anticonvulsants (CBZ, VA, Lamotrigine) → Mood stabilizers Buspirone → serotonin agonist 73  74 Special populations Elderly Start at lower doses Avoid TCAs Medication monotherapy is preferred in older adults in order to minimize drug side effects and drug-drug interactions SSRIs (1st line), SNRIs (2nd line), avoid TCAs Pregnancy Pregnancy does not protect against depression Weigh risks vs. benefits Options for treating depressed pregnant patients include psychotherapy and pharmacotherapy Moderate to severe maternal major depression poses risks to both the mother and fetus that often outweigh the possible risks associated with antidepressants  75 Cont’d Special populations Pediatrics Antidepressants increase the risk of suicidal thinking/behavior in children, adolescents and young adults Antidepressants have a Black Box warning from the FDA Monitor patients closely Drug Use in Children Citalopram Off label Escitalopram FDA ≥ 12 years Sertraline Not for MDD → Given for OCD Paroxetine Not for MDD Fluoxetine FDA ≥ 8 years Fluvoxamine Not for MDD → Given for OCD  76 THANK YOU…