MDD 2024 for student.pdf

Pharmacotherapy of Major Depressive Disorder 1  Session Objectives 2  Describe the etiology and pathophysiology of major depressive disorder (MDD).  Discuss the clinical presentation of MDD.  Outline treatment goals for a patient with MDD.  Recommend pharmacotherapy for patie...

Pharmacotherapy of Major Depressive Disorder 1  Session Objectives 2  Describe the etiology and pathophysiology of major depressive disorder (MDD).  Discuss the clinical presentation of MDD.  Outline treatment goals for a patient with MDD.  Recommend pharmacotherapy for patient with MDD.  Develop a monitoring plan  Introduction  Everyone feels “depression" at Symptoms can certain times continue for weeks,  Clinical depression is a serious months, or years at condition that affects a person's untreated patients mind and body.  all aspects of everyday life including eating, sleeping, working, relationships, and how a person thinks about himself/herself is affected.  Introduction … 4  Major depression is characterized by:  Feelings of intense sadness and despair,  mental slowing and loss of concentration,  pessimistic worry,  lack of pleasure,  self-depreciation, and  variable agitation or hostility.  Types of Depression 5 Dysthymic Disorder  2 years of depressed, for more days than not ( mood can be irritable)  Hopelessness  ↓ Energy, easily fatigable  ↓ Self-esteem  ↑↓ Sleep  ↑↓ Appetite  ↓ Decision-making, ↓ concentration  Types of Depression…. 6  Dysthymia……  Low grade but associated w/significant impairment  Chronic  Not reversed spontaneously  Tends to appear earlier  Age of onset…………….. Often develops men experience MDD  Onset : midtwenties  Many patients with MDD have comorbid psychiatric disorders,  anxiety and  substance abuse disorders  the 4th leading cause of the global burden of disease  Etiology 11  Cause of MDD is unknown  probably multifactorial  Several factors appear to work together to cause or precipitate depressive disorders  genetic predisposition  psychological stressors, and  underlying pathophysiology  Etiology 12  Cause of MDD is unknown  probably multifactorial  Several factors appear to work together to cause or precipitate depressive disorders  genetic predisposition  psychological stressors, and  underlying pathophysiology  Etiology… 13  Risk Factors  Genetic predisposition  2.5x greater: 1st degree relative  twins: 65% increases incidence  Gender difference……….. F 25%; M 15%  Age…………Elderly higher incidence  Race…Whites >Native Americans >African Americans  Co morbidity…….  Marital status……….Single>Divorced>Widow  Pathophysiology 14  The actual pathophysiology of depression unknown  Cause of depression was linked to decreased brain levels of the neurotransmitters : norepinephrine (NE), serotonin (5-HT), and dopamine (DA)  Biogenic (monoamine) amine hypothesis  Postsynaptic changes in receptor sensitivity  Dysregulation hypothesis  5-HT/norepinephrine link hypothesis  Pathophysiology… 15 1. Monoamine theory Deficit of monoamines: 1. Inadequate neurotransmitter NA, 5-HT, DA in the. brain signalling  functional deficit of NA, DA and 5-HT  Concentration in the synaptic cleft 2. Cortisol- hormone that the body produces in response to stress  Neurotransmission in depressed patients the brain have a raised baseline cortisol concentration  Pathophysiology… 16 Reducing the central serotonin, noradrenaline, and dopamine concentration can lead to depression Drugs that increase the central serotonin, noradrenaline, and dopamine concentration improve depression!  Pathophysiology… 17  Postsynaptic changes in receptor sensitivity  desensitization or downregulation of NE or 5-HT1A receptors may relate to onset of antidepressant effects.  Dysregulation hypothesis  This theory emphasizes a failure of homeostatic regulation of neurotransmitter systems, rather than absolute increases or decreases in their activities  Pathophysiology… 18  5-HT/norepinephrine link hypothesis:  This theory suggests that 5-HT and NE activities are linked, and that both the serotonergic and noradrenergic systems are involved in antidepressant response.  The role of DA  Evidence suggests that dopamine transmission is decreased in depression and that increased dopamine activity in the mesolimbic pathway contributes to antidepressant activity.  Clinical Presentation And Diagnosis 19  Emotional symptoms:  diminished ability to experience pleasure,  loss of interest in usual activities,  sadness, pessimism,  crying, hopelessness,  anxiety,  guilt, and  psychotic features (eg, auditory hallucinations and delusions)  Clinical Presentation And Diagnosis… 20  Physical (biological )  change in appetite and weight decreased appetite with weight loss (most common) sometimes iincreased appetite with weight gain  loss of energy or fatigue  Lose of sexual interest  unexplained physical problems: headaches, stomach problems, aches and pains, cardiovascular complaints (especially palpitations)  Clinical Presentation And Diagnosis… 21  Physical (biological)…  change in sleep patterns. usually early morning awakening inability to sleep sleeping too much loss of interest in life  Clinical Presentation And Diagnosis… 22  Intellectual or  Psychomotor cognitive symptoms: disturbances:  decreased ability to  psychomotor concentrate, retardation (slowed  poor memory for physical movements, recent events, thought processes, and  confusion, and speech) or  indecisiveness  psychomotor agitation Clinical Presentation And Diagnosis… 23 People who are depressed may not experience all of these symptoms. Some will have many symptoms, others will have just a few.  Diagnostic Criteria 24  4 Criteria 1. Clinical Symptoms 2. Duration of illness 3. Impact of quality of life 4. Absence of other organic diseases  Diagnostic Criteria… 25  I. Five or more of symptoms for at least two- week period.  One of the symptoms is either:  Depressed mood  Loss of interest in pleasurable activities  II. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.  III. Cannot be established that an organic factor initiated or maintained the disturbance Medical Conditions that May Mimic Depression  Central Nervous System  Women’s Health  Alzheimer disease  Premenstrual dysphoric  Cerebrovascular accident disorder  Epilepsy  Antepartum/postpartum  Multiple sclerosis  Parkinson disease  Perimenopause  Cardiovascular  Other  Cerebral arteriosclerosis  Chronic fatigue syndrome  Congestive heart failure  Chronic pain syndrome(s)  Myocardial infarction  Fibromyalgia  Endocrine  Irritable bowel syndrome  Addison disease  Malignancies (various)  Diabetes mellitus (types 1 and 2)  Migraine headaches  Hypothyroidism  Rheumatoid arthritis  Systemic lupus erythematosus  Medications that May Induce Depression  Cardiovascular Agents  Hormonal Agents  b-Blockersa  Anabolic steroids  Clonidine  Corticosteroids  Methyldopa  Gonadotropin-releasing hormone  Reserpine  Progestins  Central Nervous System  Tamoxifen  Barbiturates  Others  Chloral hydrate  Efavirenz  Ecstasy (MDMA)  Interferon  Ethanol  Isotretinoin  Varenicline  Mefloquine  aLipophilic b -blockers (e.g.,  Levetiracetam propranolol) may have higher risk but data are conflicting  Treatment 28  Goals of Treatment:  Resolution of current symptoms (ie, remission) and  the prevention of further episodes of depression (ie, relapse or recurrence)  Approach  Pharmacologic  Non pharmacologic  Non pharmacologic Therapy 29  Electroconvulsive therapy (ECT) - success rate of 78% - ECT for individuals whose depression is severe or life threatening or is effective in cases where antidepressant medications do not provide sufficient relief of symptoms  Non pharmacologic Therapy… 30  Electroconvulsive therapy (ECT) uses a small electric current to produce a generalized cerebral seizure under general anesthesia.  ECT increases release of monoamine neurotransmitters, particularly dopamine and serotonin enhances monoamine transmission by desensitizing presynaptic adrenergic autoreceptors.  ECT provides a rapid clinical response and may thus be indicated as first-line treatment in certain urgent clinical situations : o Severe suicidality o Severe psychosis o Catatonia  Non pharmacologic Therapy… 31  Psychotherapy  learning about their disorder,  learning to identify and avoid situations that may induce another depressive episode,  view themselves and their situations more realistically, and  to improve their interpersonal relationship skills. Non pharmacologic Therapy…  Most popular remedy in the world  Appears effective for milder depression  Side effects: phototoxicity  available without prescription (USA,…and,..)  900-1800mg/day is recommended dose St. Johns Wort  Antidepressants 33 Antidepressants Selective Monoamine Tricyclic serotonin Mood oxidase antidepressants reuptake stabilizer/ inhibitors TCAs inhibitors other drugs MAOIs SSRIs  Antidepressants… 34 Classification of Antidepressants Based on Site of Action  Drugs that Selectively Block Re-Uptake of 5-HT (SSRIs) (Fluoxetine; Paroxetine; Sertraline; Citalopram)  Drugs that Block the Re-uptake of NE and 5- HT ( e.g.:Most tricyclics)  Drugs that Block Presynaptic α2-adrenoceptors (e.g.:Mirtazapine).  Drugs that Inhibit MonoAminoOxidase (MAOIs, Phenelzine, Tranylcypraine, Moclobemide)  SSRIs 35  Replaced the TCAs  safe,  better tolerability,  less severe side effects  Less toxic in overdose than TCAs  Do not require blood monitoring  Often takes………. 4-6 weeks for response  SSRIs Dosage 36  Fluoxetine 10-80 mg/d  Paroxetine 10-50 mg/d  Sertraline 25-200 mg/d  Fluvoxamine 50-300 mg/d  Citalopram 20-50 mg/d  Initial response 2-4 wks  If there is a response but not adequate response after 3-6 wks dose.  If no response at all, switch.  SSRIs… 37  Paroxetine  Also used to treat panic disorder, OCD, generalized anxiety disorder  Fluoxetine  Also used to treat OCD, bulimia, and panic disorder.  Long half-life; less withdrawal when medication is stopped.  SSRI 38  Fluvoxamine  primarily used in the treatment of OCD,  it can be used for depression. If daily dose is greater than 100 mg, give in equally divided doses or give larger dose at bedtime not to exceed 300 mg per day.  Sertraline  Also used to treat panic disorder, OCD, premenstrual dysphoric disorder.  Dosing is 50-200 mg per day and should be titrated upward. case1 39  A patient with MDD was started with sertraline 100 mg q.d. for 4-6 weeks with minimum or no change in his symptoms. Your recommendation is:  A. switch to another SSRI (fluoxetine)  B. increase the dose of sertraline  C. wait for another week  D. none of the above  Which SSRI does not need tapering before discontinuation of therapy? 40 5-HT DA NE Half-life Fluoxetine +++ + + 45 (24-144) Norfluoxetine 200 hrs Sertraline +++ ++ 0 26 (23-26) Desomethylsertraline 71 Paroxetine +++ + ++ 18 (7-65) Fluvoxamine +++ 0 + 15 (9-28) Citalopram ++++ 0 0 33 (23-45)  SSRI’s Side Effects 41  GI: N/V/diarrhea  Fluoxetine/sertraline  Constipation (paroxetine)  Central nervous system:  Nervousness, insomnia………fluoxetine  Somnolence ………..paroxetine  HA, tremor, dry mouth …………..paroxetine  Sexual dysfunction  All, but minimum with fluoxetine SSRIs and Sexual Dysfunction 42  Common………..class effect  Affects both……….men and women  Reduced libido  Orgasmic dysfunction  delayed ejaculation  anorgasmia  Erection difficulties ……..minimal  decreased arousal and lubrication for females 43  SSRI – Serotonin Syndrome Serotonin syndrome is a potentially life-threatening 44  condition associated with increased serotonergic activity in the central nervous system (CNS)  A "serotonin syndrome" may occur, where mental status changes along with ………  Agitation sweating  Shivering tremors (nervousness)  Diarrhea uncoordination  fever may develop  This syndrome may be life-threatening.  SSRI – Serotonin Syndrome… 45  SSRIs should not be used with any drug that increases serotonin concentrations, including….  MAO inhibitors  Tramadol  Meperidine  Sumatriptan  Lithium  St. John's wort  Some anti-psychotic agents.  Tricyclic Antidepressants (TCAs) 46  Chemical structure with characteristic three-ring nucleus  Originally developed as Imipramine antipsychotics (1949), but were found to have no effect in this indication.  Tricyclic Antidepressants…. 47  Principal mechanism of action:  Blockade of re-uptake of NE and 5-HT by competition for binding site of the carrier protein.  In most TCA, other receptors (incl. those outside the CNS) are also affected: blockade of H1-receptor, -receptors, M-receptors  TCA’s 48  Tertiary amines  amitriptyline …………….25-300 mg  imipramine ………………..50-300 mg  doxepine ……………………..50-300 mg  Secondary amines  nortriptyline…………………………50-150 mg  desipramine (Norpramine)…… 50-300 mg  protryptline ………………………….. 15-60 mg Tricyclic Antidepressant Other Indications 49  Anxiety (Panic)  Chronic pain  Migraine  Neuropathy  Eating Disorder  Most Common Side effects Reported 50 Percentage of people taking TCAs  Dry mouth - 74%  Drowsiness - 52%  Dizziness - 38%  Constipation - 29%  Confusion - 14%  Drowsiness may wear off over time.  The other side effects probably won't, however.  TCA’s - Adverse effects  Anticholinergic..  Serotonergic effect  Dry mouth, blurred  Sexual dysfunction vision, constipation,  Loss of libido, urinary retention impaired erection (more in amitriptyline,  Withdrawal symptoms less in imipramine) 51  TCA’s - Adverse effects 52  Antihistamine  alpha-adrenergic blockage  Palpitations, tachycardia  Postural (orthostatic) hypotension  TCA Overdose & Acute Intoxication 53  Unfortunately TCA have…… a low therapeutic index:  Target systems (toxicity) – the CNS and heart  Initially excitement, hallucinations and delirium is observed, may be accompanied with convulsions.  Coma and respiratory depression may follow. TCA Overdose & Acute Intoxication... 54  Cardiac dysrrhythmias are very common – tachycardia  Ventricular fibrillation and sudden death may occur.  Hypotension  Serotonin-norepinephrine reuptake 55 inhibitors (SNRIs)  Venlafaxine: Also used to treat generalized anxiety disorder.  Dose 37.5 mg …..Maximum dose 375 mg in XL form.  Blood pressure should be monitored as this medication can increase it.  Case 2 56  A 29 year old female with history of CHF and Atrial fribrillation come to hostital with diagnosis of MDD.  What is the drug of choice for this patients?  A.amitriptyline  B. Sertaline  C. duloxetine  D. all of the above SNRI antidepressants (Venlafaxine, Duloxetine, etc.) and Worsening of Heart Failure 57  There are reports of ………  heart failure exacerbations in patients shortly after starting venlafaxine or duloxetine.  Not well proven – Depression itself can also worsen heart failure.  SNRI Worsening of Heart Failure…  58 To be safe ……….  suggest using an SSRI (sertraline, fluxetine, etc) for initial treatment of depression in heart failure patients.  Counsel heart failure patients to report …  right away any fatigue, edema, trouble breathing, etc after starting an SNRI.  SNRI antidepressants worsening of Heart Failure…. 59  All SNRI can increase heart rate and blood pressure... which can cause problems for patients with advanced or unstable heart failure. 60 SNRI Worsening of Heart Failure…  Heart failure patients have ……..  high circulating levels of NE to compensate for poor cardiac output.  NE helps to make the heart pump faster and more forcefully. Tetracyclic antidepressants (TeCAs) 61  Mirtazapine MOA: increased release of NE and 5HT Others Amoxapine Maprotiline Mianserin Mirtazapine Side Effects 62  Sjogren’s (shō'grənz) Syndrome (rare)  Minimal sexual dysfunction  Increased appetite and weight gain:  The odd thing about mirtazapine is in Europe people do not gain weight. ……..but………  In the placebo-controlled trials in the US …………the rates of weight gain was around 10%  MonoAmine Oxidase Inhibitors (MAOI) 63 - Were the first class of antidepressants in clinical use. They were discovered in 1952 after iproniazid (a derivative of the antibiotic isoniazid) was found to be ineffective for treating tuberculosis, but was a potent antidepressant agent). Agents Initial MD Dose (mg/day)  Selegiline 5 mg 10-30  Isocarboxazide 10 mg 30-60  Phenelzine 15 mg 45-90  Tranylcypromine 10 mg 20-40  MAOIs 64 Mechanis of action: * Irreversibly blocking monoamine oxidase, the enzyme responsible for the oxidative deamination of neurotransmitters such as serotonin, norepinephrine, and dopamine.  ADR *Hypertensive crisis, hepatotoxicity, insomnia  MOAIs….Interaction with foods 65  The most serious problem of this class of drugs  Tyramine „cheese and wine“ reaction  some kind of foods contain high amounts of tyramine (natural indirect sympathomimetic produced during fermentation), which is however normally metabolized by MAO in the gut and liver.  Interaction with foods 66  In depressed patients treated with MAOI, these enzymes are also inhibited bioavailability of tyramine is significantly higher which together with pharmacodynamic synergism strikingly increased noradrenaline transmission results in hypertensive crisis, severe headache and potentially fatal intracranial haemorrhage or other organ damage.  Dietary precautions: restriction in the consumption of some maturing cheeses, wine, beer, yogurts, bananas,  Other and atypical antidepressants 67  Noradrenaline Reuptake Inhibitors (NaRI) reboxetine Maprotiline  Miscellaneous St John´s wort (Hypericum perforatum) – a herb containing number of active compounds (among other hyperforin a MAOI). It was proved to be clinically effective and well tolerated, but it induces CYP450 (risk of drug interactions! )  Treatment Resistant Depression 78  Antidepressant treatment at an adequate dose for at least four to eight weeks is necessary before deeming a patient nonresponsive or only partially response to a medication.  Higher doses may be an option, but this risks more frequent and severe adverse effects.  Treatment Resistant Depression… 79  The practice guideline of the American Psychiatric Association recommends that after 6 to 8 weeks of antidepressant treatment, partial responders should consider  changing the dose,  augmenting the antidepressant, or  adding psychotherapy or ECT  For those with no response, options include  changing to another antidepressant or  the addition of psychotherapy or ECT  Discontinuation of Antidepressants 80 Evaluation of Therapeutic Outcomes 81  Monitoring parameters  plasma concentrations  adverse effects  remission of target symptoms, and  changes in social or occupational functioning Evaluation of Therapeutic Outcomes 82  Assure regular monitoring for several months after discontinuation of antidepressants.  Regularly monitor blood pressure of patients given serotonin- norepinephrine reuptake inhibitors  Order a pretreatment ECG  before starting TCA therapy in children, adolescents, and patients over 40 years of age, and  perform follow-up ECGs periodically Evaluation of Therapeutic Outcomes… 83  Monitor for emergence of  suicidal ideation after initiation of any antidepressant, especially in the first few weeks of treatment.  In addition to the clinical interview,  use psychometric rating instruments to rapidly and reliably measure the nature and severity of depressive and associated symptoms.