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![TREATMENT
RESISTANT
DEPRESSION
The STAR*D
1. switch to a second agent that may be from the same or
different class of antidepressant
2. Augmentation with
a. Bupropion (150–450 mg/day),
b. Lithium (eg, 300–900 mg/day orally),
c. Thyroid medication (eg, liothyronine, 25–50 mcg/day
orally)
d. Second-generation antipsychotic (eg, aripiprazole [5–15
mg/day] or olanzapine [5–15 mg/day]).](https://image.slidesharecdn.com/antidepressants-190321044848/85/Antidepressants-36-320.jpg)
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Antidepressants
- 1. ANTIDEPRESSANTS Dr M.KARTHIGA 2ND YEARPOSTGRADUATE M.D.PHARMACOLOGY
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- 3. DEPRESSION • MOOD • Physicaland cognitive symptoms • NOT JUST BEING SAD !!! • >15% • TYPES • Psychotic major depression • Major depression with atypical feature • Melancholic major depression • Seasonal affective disorder • Major depression with peripartum onset • DISABILITY • MORTALITY • UNDERDIAGNOSED • UNDERTREATED • CO MORBID CONDITIONS
- 4. The Diagnostic andStatistical Manual of Mental Disorders –DSM - V
- 5. PATHOGENESIS • MONOAMINES THEORY– Noradrenaline, Serotonin, Dopamine • Neurotrophic Theory – Brain derived Neurotrophic factors (BDNF) • NMDA glutamatergic receptors with ketamine • Enhancing neurogenesis • Cyclic nucleotide signaling
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- 8. TRICYCLIC ANTIDEPRESSANTS (TCA) • Amitriptyline • Clomipramine •Desipramine • Doxepin • Imipramine • Nortriptyline MONOAMINEOXIDASE INHIBITORS (MAOI) • Phenelzine • Isocarboxazid • Tranylcypromin e • Selegiline • Moclobemide
- 9. • Fluoxetine • Citalopram •Escitalopram • Paroxetine • Sertraline SELECTIVE SEROTONIN REUPTAKE INHIBITORS • Duloxetine • Venlafaxine • Milnacipran • Levomilnacipran SELECTIVE SEROTONIN AND NORADRENALINE REUPTAKE INHIBITORS
- 10. • Trazodone • Nefazodone •Mirtazapine • Mianserin SEROTONIN ANTAGONISTS • Bupropion • Atypical antipsychotics OTHERS
- 12. TRICYCLIC ANTIDEPRESSANTS Neuronal blockof SERT/NET/DAT Inhibit the re-uptake of 5HT/NE/DA Increased concentration in the synaptic cleft. 3-4 weeks H1 Ach α2 Adr
- 13. PHARMACOKINETICS • T1/2- 8–80h • M - CYP 2D6, 2C19, 3A3/4, 1A2 • Patient’s clinical response • 7% -SLOW METABOLISERS d/t a variant CYP2D6 isoenzyme USES Severe major depression
- 14. ADVERSE EFFECTS • Sedation,orthostatichypotension • Blurred vision, dry mouth, tachycardia, constipation, difficulty urinating • Weight gain • Quinidine-like effects • Lower the seizure threshold. DRUG INTERACTIONS • Drugs that inhibit CYP2D6, such as bupropion and SSRIs • Shouldn’t be used within 14days of MAOI • Antipsychotic agents, type 1C CHOLINERGIC REBOUND
- 15. MONOAMINE OXIDASE INHIBITORS •MAO-A and MAO-B 5HT,DA • EXOGENOUS- TYRAMINENE • 3rd line drugs NE HYPERTENSIVE CRISIS 1.Tranylcypromine 2.Phenelzine 3.Isocarboxazid. 4.Selegiline 5.Moclobemide 6.Eprobemide,
- 16. • M -Acetylation. • T1/2 – 24 hrs • Effects – 2 weeks USES • Depression unresponsive/ allergic to TCA • Selegiline- transdermal patch ADVERSE EFFECTS • Hypertensive crisis • Hepatotoxicity. • Sexual disturbances • Weight gain • Cooling measures • BZD • CYPROHEPTADINE
- 17. SELECTIVE SEROTONIN REUPTAKE INHIBITORS •1st drug fluoxetine available in 1988 Inhibits SERT AUTORECEPTOR MECHANISM 5HT1A and 5HT7 autoreceptors reduces 5HT synthesis and release Increase in cAMP signalling Phosphorylation of the nuclear transcription factor CREB >Expression of BDNF >Inc neurogenesis in hippocampus and subventricular zone
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- 19. • Insomnia,irritability • Nausea,Diarrhoea,emesis – 5HT3 • Akathisia , extrapyramidal symptoms • Affect platelet serotonin • Sertraline and citalopram - safest when used with warfarin • Sexual – dec. libido, erectile dysfunction,a norgasmia,ej aculatory delay – 5HT2 • Oral PDE-5 inhibitors ( sildenafil, 25–50 mg; tadalafil, 5-20 mg; or vardenafil, 10–20 mg taken 1 hour prior to sexual activity) • Bupropion (75–150 mg orally daily) Cyproheptadine, 4 mg orally prior to sexual activity, DRUG HOLIDAY
- 20. • Initial dose-typically a therapeutic dose • lower lethality in overdose compared to TCAs or MAO inhibitors. • Shorter t1/2rapid aborting of A/E • SEROTONIN SYNDROME +TCA/MAOI • The SSRIs should not be started until at least 14 days following discontinuation of treatment with an MAOI; this allows for synthesis of the new MAO
- 21. SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS •Both NET and SERT • VENLAFAXINE – 5(11) HRS • DULOXETINE- 12 hrs • CYP2D6,3A4 USES • Depression,Anxiety, • Fibromyalgia and neuropathic pain • Off-label • Stress urinary incontinence (duloxetine) • Autism • Binge-eating disorders, hot flashes • PTSD (venlafaxine) SEROTONIN SYNDROME WASHOUT PERIOD ADVERSE EFFECTS • Nausea, constipation, insomnia, headaches, sexual dysfunction. • DIASTOLIC HYPERTENSION-Venlafaxine • BLEEDING- Milnacipran
- 22. SEROTONIN RECEPTOR ANTAGONISTS •Trazodone,Nefazadone,Vilazadone Blocks 5HT2 and α1 adrenergic receptors. • Mirtazapine and mianserin- H1> 5HT2A, 5HT2C, and 5HT3 • Vortioxetine - potent SERT inhibitor partial agonist at 5HT1A, 5HT1B Antagonist at 5HT1D, 5HT3, and 5HT7 receptors PHARMACOKINETICS MIRTAZIPINE 16-30 hrs TRAZADONE 6 hrs NEFAZADONE 2-4 hrs
- 23. ADVERSE EFFECTS • Mirtazapine-somnolence,increased appetite, and weight gain. Agranulocytosis. • Trazodone - priapism • Nefazodone - Liver failure
- 24. BUPROPION • Inhibition ofDAT and NET • Hydroxybupropion • T1/2- 21 hrs • CYP2B6 • Cautious in renal and hepatic impaired • EXTENDED RELEASE
- 25. BUPROPION • ADVERSE EFFECTS •Anxiety, mild tachycardia, hypertension, irritability, and tremor. • Headache, nausea, dry mouth, constipation, appetite suppression, insomnia, • Aggression, impulsivity, and agitation • Seizures -dose and Cp, (>450 mg/day) . • USES • Depression • Seasonal depressive disorder, • Smoking cessation treatment • ADHD • Off label- neuropathic pain and weight loss
- 26. ATYPICAL ANTIPSYCHOTICS • Aripiprazoleor Quetiapine • Olanzapine and the SSRI fluoxetine • Treatment resistant depression • Combined with SSRI and SNRI FDA
- 27. STIMULANTS AND OTHERDRUGS • Dextroamphetamine (5–30 mg/day orally) and methylphenidate (10–45 mg/day orally) - short-term treatment in medically ill and geriatric patients. • Rapid onset of action (hours) • tachycardia, agitation • two divided doses early • Intravenous infusion of the dissociative anesthetic ketamine • . The effects of a single treatment are short- lived (about 3–7 days • NMDA antagonists -
- 28. RECENT DRUGS • Esketamineintranasal • Noncompetitive NMDA receptor antagonists - memantine, dextromethorphan/quin idine, dextromethorphan/bupropion, and lanicemine), • NR2B subunit-specific NMDA receptor antagonists (traxoprodil, MK-0657), • NMDA receptor glycine site partial agonists (D- cycloserine, rapastinel), • metabotropic glutamate receptor (mGluR) antagonists (basimglurant, declogurant) Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, Thase ME, Winokur A, Van Nueten L, Manji HA, Drevets WC: Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 2018; 75: 139–148.
- 30. The American PsychiatricAssociation (APA) Practice Guideline for the Treatment of Patients with Major Depressive Disorder(2011) • .CUSTOMIZATION • Hamilton or Montgomery-Asberg clinician-administered rating scales or the self-administered Patient Health Questionnaire • Columbia-Suicide Severity Risk Scale Clinical assessment Reactions to previous treatment Patient preference Stressors Presence of other disorders
- 31. DIFFERENTIAL DIAGNOSIS • Schizophrenia,partial complex seizures, organic brain syndromes, panic disorders, and anxiety • Thyroid dysfunction and other endocrinopathies • Malignancies, including central and gastrointestinal tumors • Strokes, particularly dominant hemisphere lesions • Medication-induced depressive symptoms
- 33. • Lag 2–12weeks • SATISFACTORYcontd for 6-12 months • Indefinite fixed dose SWITCHING OVER • Adequate washout – atleast 2 weeks • Not required if of the same group • If Antipsychotics look for body mass index, lipids, and glucose • 1st episode at <20/>50 age • 2 episodes >40 • 3 episodes – any age • Chronic depression >2 yrs
- 34. TAPERING • Over severalweeks. • counseled about the potential for relapse, • plan should be established for seeking treatment if symptoms recur. • Patients should be monitored for several months
- 36. TREATMENT RESISTANT DEPRESSION The STAR*D 1. switchto a second agent that may be from the same or different class of antidepressant 2. Augmentation with a. Bupropion (150–450 mg/day), b. Lithium (eg, 300–900 mg/day orally), c. Thyroid medication (eg, liothyronine, 25–50 mcg/day orally) d. Second-generation antipsychotic (eg, aripiprazole [5–15 mg/day] or olanzapine [5–15 mg/day]).
- 37. • PREGNANT 1. Psychotherapy 2.ECT and BRIGHT LIGHT THEARAPY SSRI – Persistent Pulmonary hypertension Neonatal withdrawal symptoms POST PARTUM DEPRESSION • 1st episodes of depression-, 6-12 months • Recurrent major depression following pregnancy, long- term maintenance treatment with an antidepressant
- 40. REFERENCES • The Pharmacologicalbasis of therapeutics,Goodman and Gilman, 13 th edition • Current Medical Diagnosis and Treatment ,2019 • Basic and Clinical Pharmacology,Katzung,14th edition • Gabbards treatment of Psychiatric disorders • American Psychiatric Association Guidelines
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