Pharmacologic Treatment of Depression

Ten Leading Causes of Disability in the World Type of Disability Cost (in DALYs) Cumulative % of Cost Unipolar major depression 42, Tuberculosis19, Road traffic accidents 19, Alcohol use 14, Self-inflicted injuries 14, Bipolar Disorder 13, War13, Violence12, Schizophrenia12, Iron deficiency anemia 12,

Antidepressants - History  1958Monoamine oxidase inhibitors (MAOIs)  1958 Tricyclics (TCA’s)  1982Trazodone (Deseryl)  1988Fluoxetine (Prozac)  1989Bupropion (Wellbutrin)  1994Nefazodone (Serzone)  1994Venlafaxine (Effexor)  1996 Mirtazapine (Remeron)

Treatment Response Categories STATE OBJECTIVE CRITERION CLINICAL STATUS PREVALENCE IN RCTS Remission HAM-D ≤ 7 No residual psychopathology ~ 40% Response ≥ 50% decrease in HAM-D without remission Substantially improved, but with residual sxs ~ 25% Partial response 25%-50% decrease in HAM- D Mild-moderate improvement ~ 10% Nonresponse < 25% decrease in HAM-D No clinically meaningful response ~ 25%

Efficacy vs Effectiveness

Fig. 1. Survival analysis of weeks to major depressive episode relapse (MDE): comparing patients with unipolar major depressive disorder who recovered from intake MDE with residual subsyndromal depressive symptoms vs. asymptomatic status. Wilcoxon Chi Square Test of Difference=47.96; P< Send feedback to ScienceDirect Software and compilation © 2001 ScienceDirect. All rights reserved. ScienceDirect® is an Elsevier Science B.V. registered trademark.feedback

Why Is Achieving Remission Important? Residual symptoms put patients at high risk of relapse and recurrence Residual symptoms put patients at high risk of relapse and recurrence –Patients with residual symptoms after medication treatment are 3.5 times more likely to relapse compared to those fully recovered (Judd et al, 1998) –This risk is greater than the risk associated with having ≥ 3 prior depressive episodes –Similar finding exists after response to cognitive therapy

Major Depression Syndromal classification with disturbances of mood, neurovegetative and cognitive functioning Syndromal classification with disturbances of mood, neurovegetative and cognitive functioning

Major Depression At least 5 of the following symptoms present for at least 2 weeks (either #1 or #2 must be present): 1) depressed mood 2) anhedonia – loss of interest or pleasure 3) change in appetite 4) sleep disturbance

Major Depression 5) psychomotor retardation or agitation 5) psychomotor retardation or agitation 6) decreased energy 7) feeling of worthlessness or inappropriate guilt 8) diminished ability to think or concentrate 9) recurrent thoughts of death or suicidal ideation

Major Depression Symptoms cause marked distress and/or Symptoms cause marked distress and/or impairment in social or occupational functioning. No evidence of medical or substance- induced etiology for the patient’s symptoms. No evidence of medical or substance- induced etiology for the patient’s symptoms. Symptoms are not due to a normal reaction to the death of a loved one. Symptoms are not due to a normal reaction to the death of a loved one.

Special Diagnostic Considerations Bereavement Bereavement Late life onset Late life onset Subtypes Subtypes Cluster B personality disorders Cluster B personality disorders

Bereavement and Late Life Depression 25 – 35% of widows/widowers meet diagnostic criteria for major depressive disorder at 2 months. 25 – 35% of widows/widowers meet diagnostic criteria for major depressive disorder at 2 months. ~15% of widows/widowers meet diagnostic criteria for major depressive disorder at one year. ~15% of widows/widowers meet diagnostic criteria for major depressive disorder at one year. This figure remains stable throughout the second year. This figure remains stable throughout the second year.

Subtypes of Depression Atypical Atypical Reverse neurovegetative symptoms Reverse neurovegetative symptoms Mood reactivity Mood reactivity Hypersensitivity to rejection Hypersensitivity to rejection MAO-I’s and SSRI’s are more effective treatments MAO-I’s and SSRI’s are more effective treatments

Subtypes of Depression Psychotic (~10% of all MDD) Psychotic (~10% of all MDD) Delusions common, may have hallucinationsDelusions common, may have hallucinations Delusions usually mood congruentDelusions usually mood congruent Combined antidepressant and antipsychotic therapy or ECT is necessaryCombined antidepressant and antipsychotic therapy or ECT is necessary

Subtypes of Depression Melancholic Melancholic No mood reactivityNo mood reactivity AnhedoniaAnhedonia Prominent neurovegetative disturbanceProminent neurovegetative disturbance More likely to respond to biological treatmentsMore likely to respond to biological treatments

Subtypes of Depression Catatonic Catatonic Motoric immobility (catalepsy)Motoric immobility (catalepsy) MutismMutism Ecolalia or echopraxiaEcolalia or echopraxia

What is the course of antidepressant response?

Why a temporal delay for maximal therapeutic benefit   -adrenergic receptor down- regulation  5-HT 2 receptor down-regulation

Tricyclic Antidepressants (TCAs)  Characteristic three-ring nucleus  Clinical effects  Normalization of mood and resolution of neurovegetative symptoms  Biochemical effects  Inhibit monoamine uptake at nerve terminals  May potentiate action of drugs that cause neurotransmitter release  Temporal delay of weeks for clinical effects, although biochemical effects are immediate

Mechanism of action of TCAs “Tertiary” TCAs  Inhibit 5-HT uptake imipramine(weaker inhibition of NE uptake) amitriptyline clomipramine “Secondary” TCAs  Inhibit NE uptake desipramine (weaker inhibition of 5-HT uptake) nortriptyline

TCA Metabolism N CH 3 H 3 C N N CH 3 H 3 C N N CH 3 H N CH 3 H nortriptyline imipramine amitriptyline desipramine tertiary aminessecondary amines

In vivo action of TCAs If one administers a tertiary TCA  there is always both the tertiary and the secondary amine in the circulation If one administers a secondary TCA  there is only the secondary amine in the circulation.

Neuropharmacology of TCAs  Inhibit monoamine uptake (NE and 5- HT)  Muscarinic cholinergic antagonism  H 1 histamine antagonism   1 -adrenergic antagonism

Tricyclics- Contraindications QTc greater than 450 msec QTc greater than 450 msec Conditions worsened by muscarinic blockade (eg myasthenia gravis, BPH) Conditions worsened by muscarinic blockade (eg myasthenia gravis, BPH) pre-existing orthostatic hypotension pre-existing orthostatic hypotension Seizure disorder Seizure disorder

Side effect profile of TCAs  Dry mouth  Constipation  Dizziness  Tachycardia  Urinary retention  Impaired sexual funtion  Orthostatic hypotension

Low therapeutic index of TCAs  Cardiotoxicity: resulting from combination of:  Conduction defects, arrhythmias  Delirium Potentiation of effects of other sedating drugs Potentiation of effects of other sedating drugs  Consequences  suicide  requires care in prescribing  monitoring drugs that might have synergistic effects on monoamine function

Monoamine Oxidase Inhibitors (MAOIs)  Irreversibly inhibit monoamine oxidase enzymes  Effective for major depression, panic disorder, social phobia  Drug interactions and dietary restrictions limit use

Biochemistry of MAO  Occurs as two isoenzymes  MAO-A – Oxidizes norepinephrine, serotonin, tyramine Oxidizes norepinephrine, serotonin, tyramine  MAO-B selective for dopamine metabolism selective for dopamine metabolism

Dietary and Drug Interactions  Increased stores of catecholamines sensitize patients to effects of sympathomimetics  Accumulation of tyramine (sympathomimetic) = high risk of hypertensive reactions to dietary tyramine  requires dietary restrictions  Interactions with other sympathomimetic drugs  Antidepressants  OTC cold remedies phenylpropanolamine phenylpropanolamine  Meperidine  L-dopa

Examples of MAOIs  Irreversible, non-selective MAOIs  phenelzine  isocarboxazid  tranylcypromine  Selective MAO-B inhibitors  deprenyl (selegiline)  loses its specificity for MAO-B in antidepressant doses  Reversible monoamine oxidase inhibitors (RIMAs)  Moclobemide – not approved  Appears to be relatively free of food/drug interactions

Serotonin syndrome  Evoked by interaction between serotonergic agents  e.g., SSRIs and MAOIs  Combination of increased stores plus inhibition of reuptake after release  Symptoms  Hyperthermia  Muscle rigidity  Myoclonus  Rapid changes in mental status and vital signs  Can be lethal

Selective Serotonin Uptake Inhibitors (SSRIs)  Currently marketed medications  fluoxetine (Prozac).  sertraline (Zoloft).  paroxetine (Paxil)  fluvoxamine (Luvox)  citalopram (Celexa)  escitalopram (Lexapro)  Selectively inhibit 5-HT (not NE) uptake  Differ from TCAs by having little affinity for muscarinic, as well as many other neuroreceptors

Selective Serotonin Uptake Inhibitors (SSRIs)  Much higher therapeutic index than TCAs or MAO-I’s  Much better tolerated in early therapy  Equal or almost equal in efficacy to TCAs

Side effects associated with SSRIs  Nausea  Sexual dysfunction  Delayed ejaculation/anorgasmia  Anxiety  Insomnia

Selective Norepinephrine- Serotonin Reuptake Inhibitors  Venlafaxine (Effexor) Duloxetine (Cymbalta):  relatively devoid of antihistaminergic, anticholinergic, and antiadrenergic properties  nonselective inhibitor of both NE and 5- HT uptake. Adverse effects: GI, Sexual dysfunction, hypertension (venlafaxine) Adverse effects: GI, Sexual dysfunction, hypertension (venlafaxine)

Other antidepressants  Trazodone  mixed 5-HT agonist/antagonist  1 antagonist  1 antagonist H 1 antagonist H 1 antagonist  Nefazodone (Serzone)  5 HT 2 antagonist  Bupropion (Wellbutrin; Zyban)  Inhibits uptake of DA and NE  antismoking properties probably involves parent molecule  Lacks sexual side effects  Seizure risk

 Mirtazapine (Remeron)   2 antagonist  5H 2 and 5HT 3 antagonist  Net effect selective increase in 5HT 1A function  H 1 antagonist advantages: sedation, no adverse sexual effects advantages: sedation, no adverse sexual effects

Antidepressants and drug interactions  Pharmacodynamic –Additive effects with alcohol and other sedating drugs –MAOI interactions  Pharmakokinetic –Cytochrome P450-2D6 inhibition Fluoxetine and paroxetine Fluoxetine and paroxetine Increased levels of TCAs, antipsychotics, warfarin Increased levels of TCAs, antipsychotics, warfarin –Cytochrome P450-3A4 inhibition Nefazodone and fluvoxamine Nefazodone and fluvoxamine Increased levels of terfenadine, astemizole, cisapride – can cause fatal arrhythmias Increased levels of terfenadine, astemizole, cisapride – can cause fatal arrhythmias

Other uses for antidepressants  Panic Disorder  Obsessive Compulsive Disorder  Only the ADs that inhibit serotonin reuptake  Social Phobia  Post Traumatic Stress Disorder  Premenstrual Dysphoric Disorder  Chronic pain syndromes

Treatment Course One episode – 50% chance of reoccurence One episode – 50% chance of reoccurence Two episodes – 70% chance of reoccurence Two episodes – 70% chance of reoccurence Three or more episodes - >90% chance of reoccurence Three or more episodes - >90% chance of reoccurence

When Do You Characterize a Response As Treatment Resistant? After a patient has been on an antidepressant at for a reasonable amount of time at an adequate dose After a patient has been on an antidepressant at for a reasonable amount of time at an adequate dose No commonly accepted time point No commonly accepted time point –Most drug trial data comes from 8 week long studies –If no onset of response by weeks 4 or 6, there is a % chance of not having onset of response by end of 8 wk trial (Nierenberg et al, 2000), so 4 weeks is a reasonable point to increase dose –An 8-12 week course is consistent with acute treatment framework and allows patients 8 weeks at a dose expected to produce response