Depressive Disorders

© The McGraw-Hill Companies. All Rights Reserved.

Depressive Disorders

Chapter 71

PHARMACOTHERAPY A PATHOPHYSIOLOGIC APPROACH



Abbreviations

APA: American Psychiatric Association DA: dopamineDSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revisionECT: electroconvulsive therapy5-HT: serotoninHAMD: Hamilton depression scaleMAOI: monoamine oxidase inhibitorMDD: major depressive disorderNE: norepinephrineNIH: National Institutes of HealthREM: rapid eye movementSNRI: serotonin-norepinephrine reuptake inhibitorSSRI: serotonin-selective reuptake inhibitorSTAR* D: Sequenced treatment alternatives to relieve depressionTCA: tricyclic antidepressantTRD: treatment-resistant depression



Introduction• Major depressive episode defined by Diagnostic and

Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR) criteria

– Published by American Psychiatric Association

• Depression associated with functional disability, morbidity and mortality

• Newer antidepressants as effective and better

tolerated than older agents

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision. Washington, DC: American Psychiatric Association, 2000.



Epidemiology• True prevalence unknown

• The National Comorbidity Survey Replication

– 16.2% of population studied had history of major depressive disorder

– >6.6% had episode in past 12 months

• Women at increased risk of depression from early adolescence until their mid-50s

– Lifetime rate 1.7 to 2.7 times greater than for menKessler RC, Berglund P, Demler O. The epidemiology of major depressive disorders: Results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289:3095–3105.

Burt VK, Stein K. Epidemiology of depression throughout the female life cycle. J Clin Psychol. 2002;63(Suppl 7):9–15.



Epidemiology• Adults 18 to 29 years: highest rates of major depression

• Estimated lifetime prevalence of MDD in individuals 65 to 80 years

– 20.4% in women

– 9.6% in men

• Depressive disorders common during adolescence

– Comorbid substance abuse

– Suicide attempts

Kessler RC, Berglund P, Demler O. The epidemiology of major depressive disorders: Results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289:3095–3105.

Steffens DC, Skoog I, Norton MC, et al. Prevalence of depression and its treatment in an elderly population. The Cache County study. Arch Gen Psychiatry. 2000;57:601–607.

Kessler RC, Walters EE. Epidemiology of DSM-III-R major depression and minor depression among adolescents and young adults in the National Comorbidity Survey. Depress Anxiety. 1998;7:3–14.



Epidemiology• Depressive disorders and suicide tend to occur within families

– ~8% to 18% of MDD patients have > one 1st-degree relative with history of depression, compared with 5.6% of 1st-degree relatives of those without depression

– 1st-degree relatives of patients with depression 1.5 to 3 times more likely to develop depression than controls


Weissman MM, Gershon ES, Kidd KK, et al. Psychiatric disorders in the relatives of probands with affective disorder. Arch Gen Psychiatry. 1984;41:13–21.

Warner V, Weissman MM, Mufson L, Wickramaratne PJ. Grandparents, parents, and grandchildren at high risk for depression: A three-generation study. J Am Acad Child Adolesc Psychiatry. 1999;38:289–296.



Epidemiology• Prevalence influenced by genetic and

environmental factors– Heritability of liability for major depression

37%

– 63% of variance in liability caused by individual-specific environment

Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: Review and meta-analysis. Am J Psychiatry. 2000;157:1552–1562.



Etiology

• Depressive disorder etiology too complex to be explained by single social, developmental, biologic theory

• Several factors work together to cause/precipitate depressive disorders

• Major depression symptoms consistently reflect changes in brain monoamine neurotransmitters

– Norepinephrine (NE)

– Serotonin (5-hydroxytryptamine [5-HT])

– Dopamine (DA)

Stahl SM. Blue genes and the mechanism of action of antidepressants. J Clin Psychiatry. 2000;61:164–165.

Delgado PL. Depression: The case for a monoamine deficiency. J Clin Psychiatry. 2000;61(Suppl 6):7–11.

Hirschfield RM. History and the evolution of the monoamine hypothesis of depression. J Clin Psychiatry. 2000;61(Suppl 6):4–6.



Pathophysiology



Biogenic Amine Hypothesis• Depression linked to decreased NE, 5-HT, DA in the

brain– Actual cause unknown

• Based on observations from early 1950s • Antihypertensive drug reserpine depletes neuronal

storage granules of NE, 5-HT, DA – produces clinically significant depression >15%

patients

Delgado PL, Moreno FA, Potter R, et al. Norepinephrine and serotonin in antidepressant action: Evidence from neurotransmitter depletion studies. In: Briley M, Montgomery SA, eds. Antidepressant Therapy at the Dawn of the Third Millennium. London: Marin Dunitz, 1997:141–163.



Biogenic Amine Hypothesis• Monoamine (e.g., NE, 5-HT) reuptake blockade occurs

immediately on antidepressant administration

• Antidepressant clinical effects generally not seen until after ~4 weeks

– May be result of cascade of events from receptor occupancy to gene transcription

– caused researchers to focus on adaptive changes induced by antidepressants

Delgado PL. Depression: The case for a monoamine deficiency. J Clin Psychiatry. 2000;61(Suppl 6):7–11.

Baldessarini RJ. Drugs and the treatment of psychiatric disorders: Depression and anxiety disorders. In: Hardman JG, Limbrid LE, Goodman A, et al. eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw-Hill, 2000:447–484.

Stahl SM. Blue genes and the monoamine hypothesis of depression. J Clin Psychiatry. 2000;61:77–78.



Theories of Postsynaptic Changes in Receptor Sensitivity

• Discrepancy between timing of monoamine reuptake blockade (immediate) and measurable improvement in symptoms

• Some theories focus on adaptive/chronic changes in amine receptor systems compared with acute changes

• Mid-1970s: chronic (not acute) antidepressant administration to animals caused desensitization of NE-stimulated cyclic adenosine monophosphate synthesis




Theories of Postsynaptic Changes in Receptor Sensitivity

• Downregulation of β-adrenergic receptors accompanies desensitization for most antidepressants

• Desensitization or downregulation of NE receptors corresponds to clinically relevant time course for antidepressant effects

• Other studies reveal desensitization of presynaptic 5-HT1A autoreceptors following chronic antidepressant administration


Feighner JP. Mechanism of action of antidepressant medications. J Clin Psychiatry. 1999;60(Suppl 4):4–11.

Stahl SM. Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct mechanisms of action. J Clin Psychiatry. 1998;59(Suppl 4):5–14.



Dysregulation Hypothesis• Incorporates diversity of antidepressant activity with

adaptive changes in receptor sensitization over several weeks

• Emphasizes failure of neurotransmitter system homeostatic regulation rather than absolute increases or decreases in activities

• Hypothesis: antidepressants restore efficient regulation to dysregulated neurotransmitter systems

Bryant SG, Brown CS. Current concepts in clinical therapeutics: Major affective disorders, part 1. Clin Pharmacol. 1986;5:304–318.

Siever LJ, Davis KL. Overview: Toward a dysregulation hypothesis of depression. Am J Psychiatry. 1985;142:1017–1031.



5-HT/NE Link Hypothesis• No single neurotransmitter theory adequate

• Maintains serotonergic and noradrenergic systems both involved in antidepressant response

• Consistent with rationale of postsynaptic alteration theory

– Emphasizes importance of β-adrenergic receptor down regulation for antidepressant effect

• Both serotonergic and noradrenergic medications downregulate β-adrenergic receptors

– Link between 5-HT and NE

Feighner JP. Mechanism of action of antidepressant medications. J Clin Psychiatry. 1999;60(Suppl 4):4–11.



Role of DA in Depression• Traditional explanations focused on NE and 5-HT

– biogenic amine hypothesis does not distinguish between NE and DA

• Evidence suggests decreased DA transmission in depression

– agents that increase dopaminergic transmission are effective antidepressants

• Studies suggest increased DA transmission in mesolimbic

pathway accounts for part of antidepressant mechanism

Ordway GA, Klimek V, Mann JJ. Neurocircuitry of mood disorders. In: Davis KL, Charney D, Coyle JT, Nemeroff C, eds. Neuropsychopharmacology: The Fifth Generation of Progress. American College of Neuropsychopharmacology. Lippincott Williams and Wilkins: Philadelphia, 2002:1051–1064.



Role of DA in Depression• Mechanisms by which antidepressants alter DA

transmission unclear

– Can be mediated indirectly by actions at NE or 5-HT terminals

• Complexity of interaction between 5-HT, NE, and possibly DA gaining greater appreciation

– Precise mechanism not known

Ordway GA, Klimek V, Mann JJ. Neurocircuitry of mood disorders. In: Davis KL, Charney D, Coyle JT, Nemeroff C, eds. Neuropsychopharmacology: The Fifth Generation of Progress. American College of Neuropsychopharmacology. Lippincott Williams and Wilkins: Philadelphia, 2002:1051–1064.



Biologic Markers• Search for biologic or pharmacodynamic markers to assist in

MDD diagnosis and treatment

• Although no biologic marker has been discovered, several biologic abnormalities are present in many depressed patients

• Sleep studies in MDD patients identified several abnormalities

– More pronounced with advancing age

– Occur in other psychiatric disorders

– Not diagnostic for major depression

Thase ME, Fasiczka AL, Berman SR, et al. Electroencephalographic sleep profiles before and after cognitive behavior therapy of depression. Arch Gen Psychiatry. 1998;55:138–144



Biologic Markers

• ~45% to 60% of MDD patients have a neuroendocrine abnormality

– Cortisol hypersecretion: lack of cortisol suppression after dexamethasone administration

• Indicates hypothalamic-pituitary-adrenal axis overactivity or dysregulation

• High rate of false-positive and false-negative results limits usefulness of testing

• Relative lack of use in clinical practice

– Abnormal/diminished response to thyroid-stimulating hormone



Clinical Presentation

• Withdrawal from substances of abuse (e.g., cocaine) can cause depressive symptoms

• Rule out medical conditions or concomitant medication

– Complete physical exam and medication review

– Mental status examination

– Laboratory workup

• Complete blood count with differential

• Thyroid function tests

• Electrolytes

Sofuoglu M, Dudish-Poulsen S, Poling J, et al. The effect of individual cocaine withdrawal symptoms on outcomes in cocaine users. Addict Behav. 2005;30:1125–1134.

General medical conditions

Endocrine diseases Metabolic disorders

Hypothyroidism Electrolyte imbalance

Addison or Cushing disease Hypokalemia

Deficiency states Hyponatremia

Pernicious anemia Hepatic encephalopathy

Wernicke encephalopathy Cardiovascular disease

Severe anemia Coronary artery disease

Infections Congestive heart failure

AIDS Myocardial infarction

Encephalitis Neurologic disorders

Human immunodeficiency virus Alzheimer's disease

Mononucleosis Epilepsy

Sexually transmitted diseases Huntington's disease

Tuberculosis Multiple sclerosis

Collagen disorder Pain

Systemic lupus erythematosus Parkinson's disease

Malignant disease

Medical Conditions Associated with Depressive Symptoms

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: The McGraw-Hill Companies. 2008. http://www.accesspharmacy.com/.



Substance Use Disorders Associated with Depressive Symptoms

Substance use disorders (including intoxication and withdrawal)

Alcoholism

Marijuana abuse and dependence

Nicotine dependence

Opiate abuse and dependence (e.g., heroin)

Psychostimulant abuse and dependence (e.g., cocaine)




Medications Associated with Depressive Symptoms

Antihypertensives Hormonal therapy

Clonidine Oral contraceptives

Diuretics Steroids/adrenocorticotropic hormone

Guanethidine sulfate Acne therapy

Hydralazine hydrochloride Isotretinoin

Methyldopa Other

Propranolol Interferon-β1a

Reserpine




Clinical Presentation• Stressors/life events trigger depression in

some individuals

• Patients may have >1 recurrent episodes during lifetime


DSM-IV-TR Criteria for MDDA. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

Note: Do not include symptoms that are clearly caused by a general medical condition or mood-incongruent delusions or hallucinations.

1. Depressed mood most of the day nearly every day

2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day nearly every day

3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day

4. Insomnia or hypersomnia nearly every day

5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)

6. Fatigue or loss of energy nearly every day

7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day

8. Diminished ability to think or concentrate, or indecisiveness, nearly every day

9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

C. The symptoms are not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism).

D. The symptoms are not better accounted for by bereavement (i.e., after the loss of a loved one), the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.




Emotional Symptoms• Persistent diminished ability to experience pleasure

• Loss of interest/pleasure in usual activities, hobbies, work

• Appear sad or depressed

– Often pessimistic

– Believe nothing will help them feel better

• Feelings of worthlessness/inappropriate guilt

– Identify patients at risk for suicide

• ~90% of MDD patients have anxiety symptoms

McGirr A, Renaud J, Seguin M, et al. An examination of DSM-IV depressive symptoms and risk for suicide completion in major depressive disorder: A psychological autopsy study. J Affect Disord. 2007;97:203–209.



Emotional Symptoms• Unrealistic guilt feelings

– Can reach delusional proportions• Patients can feel they deserve punishment

– View illness as punishment • MDD patients with psychotic features

– May hear voices (auditory hallucinations) saying he/she is a bad person and should commit suicide

– Can require hospitalization if patient becomes danger to self or others



Physical Symptoms

• Often motivate patients to seek medical attention

• Chronic fatigue

– Often worse in morning; does not improve with rest

– Pain (especially headache) often accompanies fatigue

• Sleep disturbances

– Frequent early morning awakening with difficulty returning to sleep

– Difficulty falling asleep

– Frequent nighttime awakening

– Increased sleep (hypersomnia)



Physical Symptoms• Appetite disturbances

– Decreased appetite

• Can result in substantial weight loss, especially elderly patients

– Other patients overeat/gain weight

• Gastrointestinal complaints

• Cardiovascular complaints

– Palpitations

• Loss of sexual interest/libido

Lebowitz BD, Pearson JL, Schneider LS, et al. Diagnosis and treatment of depression in late life: Consensus statement update. JAMA. 1997;278:1186–1190.

Trivedi MH. The link between depression and physical symptoms. Prim Care Companion J Clin Psychiatry. 2004;6(suppl 1):12–16.



Intellectual/Cognitive Symptoms• Decreased ability to concentrate

• Slowed thinking

• Poor memory of recent events

• Confusion and indecisiveness

• Consider depression when elderly patients

have cognitive symptoms

Lebowitz BD, Pearson JL, Schneider LS, et al. Diagnosis and treatment of depression in late life: Consensus statement update. JAMA. 1997;278:1186–1190.



Psychomotor Disturbances• Psychomotor retardation: noticeably slowed

– Physical movements– Thought processes– Speech

• Psychomotor agitation: purposeless, restless motion – Pacing– Wringing of hands– Shouting outbursts



Suicide Risk Evaluation/Management

• Center for Disease Control lists suicide as

– 3rd leading cause of death in those aged 15 to 24 years

– 2nd leading cause of death in those aged 25 to 34 years

• Widely held myths regarding suicide

– People more likely to commit suicide if asked about it

– People talking about suicide are looking for attention and are not serious

– Suicidal people are crazy

– Most suicides caused by sudden traumatic event

Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. Suicide: Fact Sheet. 2006, http://www.cdc.gov/ncipc/factsheets/suifacts.htm.



Suicide Risk Evaluation/Management• Assess all MDD patients for suicidal potential• Factors increasing suicide risk

– Suicidal plans/attempts– Male gender– Being single or living alone– Inpatient status– Feelings of hopelessness, relationship difficulties – General medical condition, alcohol/substance abuse– More work hours missed in past week

Coryell WH. Clinical assessment of suicide risk in depressive disorder. CNS Spectr. 2006;11(6):137–142.

Claassen CA, Trivedi MH, Rush AJ, et al. Clinical differences among depressed patients with and without a history of suicide attempts: findings from the STAR*D trial. J Affect Disord. 2007;97:77–84.



Suicide Risk Evaluation/Management

• High suicide risk: detailed plan with intention and ability to carry it out

• Hints of suicidal ideation used to assess severity of suicidal thoughts – Personality change– Sudden decision to make a will/give away possessions– Recent gun purchase; obtaining large supply of

medications or other potentially toxic substances • Suicide risk can increase as MDD patients develop energy

and capacity to act on a plan made earlier



Treatment



Treatment Goals• Reduce acute symptoms• Facilitate return to level of functioning before illness• Prevent further episodes • Decision to hospitalize based on

– Suicide risk– Physical health– Social support system– Psychotic and/or catatonic symptoms



General Approach to Treatment• Phases of treatment

– Acute phase: 6 to 10 weeks; goal is remission (i.e., absence of symptoms)

– Continuation phase: 4 to 9 months after remission achieved; goal to eliminate residual symptoms or prevent relapse (i.e., return of symptoms <6 months of remission)

– Maintenance phase: >12 to 36 months; goal to prevent recurrence (i.e., separate episode of depression)

American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(4Suppl):1–45.

Mann JJ. The Medical Management of Depression. N Engl J Med. 2005;353:1819–1834.



General Approach to Treatment• Risk of recurrence increases as number of past episodes

increases

• Duration of therapy depends on risk of recurrence

• Some investigators recommend lifelong maintenance therapy for persons at greatest risk for recurrence

– <40 years of age with >2 prior episodes

– Any age with >3 prior episodes

• Educate patient and his/her support system

– Delay in antidepressant effects

– Importance of adherence




Nonpharmacologic Therapy• Psychotherapy and antidepressant effects considered

additive

• Mild to moderate depressive episode: psychotherapy can be 1st line therapy

• Severe and/or psychotic MDD: psychotherapy alone not recommended for acute treatment

• Maintenance psychotherapy generally not recommended as sole treatment to prevent recurrence

Blackburn IM, Moore RG. Controlled acute and follow-up trial of cognitive therapy and pharmacotherapy in outpatients with recurrent depression. Br J Psychiatry. 1997;171:328–334.



Nonpharmacologic Therapy• Electroconvulsive therapy (ECT): safe, effective treatment

for certain severe mental illnesses including MDD

• Candidates for ECT

– Rapid response needed

– Risks of other treatments outweigh potential benefits

– History of poor antidepressant response

– History of good ECT response

– Patient prefers ECT

Klapheke MM. Electroconvulsive therapy consultation: An update. Convuls Ther. 1997;13:227–241.



Nonpharmacologic Therapy• General ECT course

– Unilateral or bilateral 2 to 3 times/week– 6 to 12 treatments

• Rapid therapeutic response (10 to 14 days)• Conditions associated with increased risk

– Increased intracranial pressure, cerebral lesions– Recent myocardial infarction– Recent intracerebral hemorrhage– Bleeding– Unstable vascular condition



Nonpharmacologic Therapy• Anesthetics and nondepolarizing neuromuscular blocking

agents decrease ECT morbidity

• ECT adverse effects

– Cognitive dysfunction

– Cardiovascular dysfunction

– Prolonged apnea

– Treatment-emergent mania

– Headache

– Nausea

– Muscle achesKlapheke MM. Electroconvulsive therapy consultation: An update. Convuls Ther. 1997;13:227–241.



Nonpharmacologic Therapy• Cognitive changes associated with ECT

– Confusion

– Memory disturbance

• Most cognitive disturbances transient

– Some patients report permanent memory loss for events months before, after, during treatment

• Relapse rates high during year following ECT unless maintenance antidepressant prescribed

Klapheke MM. Electroconvulsive therapy consultation: An update. Convuls Ther. 1997;13:227–241.



Nonpharmacologic Therapy• Bright light therapy: patients gaze into 10,000-lux intensity

light box ~30 minutes/day

– Can use with antidepressants

– Effective for seasonal affective disorder (SAD) and adjunctive use in MDD with seasonal exacerbations

– Well tolerated

• Most frequently reported adverse event: minor visual complaints

• Baseline and periodic eye examinations recommended

Lafer B, Sachs GS, Labbate LA, et al. Side effects induced by bright light therapy. Am J Psychiatry. 1994;151:1081–1083.




Pharmacologic Therapy



Adult Dosagesa

Generic Name Trade Name Initial Dose (mg/day)

Usual Dosage Range

(mg/day)

Selective serotonin reuptake inhibitors

Citalopram Celexa 20 20–60

Escitalopram Lexapro 10 10–20

Fluoxetine Prozac 20 20–60

Fluvoxamine Luvox 50 50–300

Paroxetine Paxil 20 20–60

Sertraline Zoloft 50 50–200

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: New York: The McGraw-Hill Companies. http://www.accesspharmacy.com/

aDoses listed are total daily doses; elderly patients are usually treated with approximately ½ of the dose listed.



Adult Dosagesa Generic Name Trade Name Initial Dose

(mg/day)Usual Dosage

Range (mg/day)Serotonin/norepinephrine reuptake inhibitors

Venlafaxine Effexor 37.5–75 75–225

Duloxetine Cymbalta 30 30–90

Desvenlafaxine Pristiq 50 50-100

Milnacipran Savella 12.5 100

Aminoketones

Bupropion hydrochloride

Wellbutrin 150 150–300

Bupropion hydrobromide

Aplenzin 174 174-348

aDoses listed are total daily doses; elderly patients are usually treated with approximately ½ of the dose listed.

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: The McGraw-Hill Companies. http://www.accesspharmacy.com/



Adult Dosagesa Generic Name Trade Name Suggested

Therapeutic Plasma Conc.

(ng/mL)

Initial Dose (mg/day)

Usual Dosage Range (mg/day)

Tricyclics

Tertiary amines

Amitriptyline Elavil 120–250b 25 100–300

Clomipramine Anafranil 25 100–250

Doxepin Sinequan 25 100–300

Imipramine Tofranil 200–350c 25 100–300

Secondary amines

Desipramine Norpramin 100–300c 25 100–300

Nortriptyline Pamelor 50–150 25 50–200

aDoses listed are total daily doses; elderly patients are usually treated with approximately ½ of the dose listed. bParent drug plus metabolite. cIt has been suggested that combined imipramine + desipramine concentrations should fall between 150–240 ng/mL.




Adult Dosagesa Generic Name Trade Name Initial Dose

(mg/day)Usual Dosage

Range (mg/day)Triazolopyridines

Nefazodone Serzone 100 200–600

Trazodone Desyrel 50 150–300

Tetracyclics

Mirtazapine Remeron 15 15–45

Monoamine oxidase inhibitors

Phenelzine Nardil 15 30–90

Selegiline (transdermal) Emsam 6b 6–12b

Tranylcypromine Parnate 10 20–60

aDoses listed are total daily doses; elderly patients are usually treated with approximately ½ of the dose listed. bTransdermal delivery system designed to deliver dose continuously over a 24-hour period.




Pharmacologic Therapy• Antidepressants are of equivalent efficacy when

administered in comparable doses

• Initial choice made empirically

• Cannot predict which antidepressant will be most effective in a patient

• Failure to respond to 1 class or 1 drug in a class does not predict failed response to another drug class or another drug within the class



Pharmacologic Therapy• Factors that influence antidepressant choice

– History of response– Pharmacogenetics

• Familial antidepressant response history– Medical history– Symptoms – Potential drug-drug interactions– Adverse events profile– Patient preference– Drug cost



Relative Potencies and Side-Effect Profile

Reuptake AntagonismAnti-

cholinergic Effects

Sedation Orthostatic Hypo-

tension

Seizuresa

Conduction

Abnormalitiesa

NE 5-HT

Selective serotonin reuptake inhibitors Citalopram 0 ++++ 0 + 0 ++ 0Escitalopram 0 ++++ 0 0 0 0 0Fluoxetine 0 +++ 0 0 0 ++ 0Fluvoxamine 0 ++++ 0 0 0 ++ 0Paroxetine 0 ++++ + + 0 ++ 0Sertraline 0 ++++ 0 0 0 ++ 0++++, high; +++, moderate; ++, low; +, very low; 0, absent.aThese are uncommon side effects of antidepressant drugs, particularly when used at normal therapeutic doses.





Reuptake Antagonism

Anti-cholinergic

Effects


tension

Seizuresa

Conduction

Abnormalitiesa

NE 5-HT

Serotonin/norepinephrine reuptake inhibitors

Venlafaxineb ++++ ++++ + + 0 ++ +Duloxetinec ++++ ++++ + 0 + 0 0Aminoketones

Bupropiond + 0 + 0 0 ++++ +++++, high; +++, moderate; ++, low; +, very low; 0, absent.aThese are uncommon side effects of antidepressant drugs, particularly when used at normal therapeutic doses.bPrimarily serotonin (5-HT) at lower doses, norepinephrine (NE) at higher doses, and dopamine (DA) at very high doses.cBalanced 5-HT and NE reuptake inhibition.dAlso blocks dopamine reuptake.





Reuptake Antagonism

Anti-cholinergic

Effects


tension

Seizuresa

Conduction

Abnormalitiesa

NE 5-HT

Tricyclics

Tertiary amines

Amitriptyline ++ ++++ ++++ ++++ +++ +++ +++ Clomipramine ++ +++ ++++ ++++ ++ ++++ +++ Doxepin ++ ++ +++ ++++ ++ +++ ++ Imipramine +++ +++ +++ +++ ++++ +++ +++Secondary amines

Desipramine ++++ + ++ ++ ++ ++ ++ Nortriptyline +++ ++ ++ ++ + ++ ++++++, high; +++, moderate; ++, low; +, very low; 0, absent.

aThese are uncommon side effects of antidepressant drugs, particularly when used at normal therapeutic doses.




Relative Potencies and Side-Effect ProfileReuptake

Antagonism

Anti-cholinergic

Effects


tension

Seizuresa

Conduction

Abnormalitiesa

NE 5-HT

Triazolopyridines

Nefazodone 0 ++ 0 +++ +++ ++ +Trazodone 0 ++ 0 ++++ +++ ++ +Tetracyclics

Mirtazapine 0 0 + ++ ++ 0 +Monoamine oxidase inhibitors

Phenelzine ++ ++ + ++ ++ + Selegiline 0 0 0 + ++ 0 0Tranylcypromine ++ + + + ++ + +++++, high; +++, moderate; ++, low; +, very low; 0, absent.

aThese are uncommon side effects of antidepressant drugs, particularly when used at normal therapeutic doses.




Mixed Serotonin and Norepinephrine Reuptake Inhibitors: TCAs

• Other antidepressants are as effective as TCAs but are safer in overdose and better tolerated than TCAs

• Potentiate NE and 5-HT activity by blocking reuptake– Potency and selectivity vary greatly – Adverse effects common; affect other receptor

systems • Cholinergic• Neurologic• Cardiovascular



Triazolopyridines• Trazodone and nefazodone

– Dual actions on serotonergic neurons

• 5-HT2 receptor antagonists and 5-HT reuptake inhibitors

• Also enhance 5-HT1A-mediated neurotransmission


Ables AZ, Baughman III, OL. Antidepressants: Update on new agents and indications. Am Fam Physician. 2003;67:547–554.



Triazolopyridines• Trazodone blocks α1-adrenergic and histaminergic

receptors – Increased side effects limit use (e.g., dizziness,

sedation)• Nefazodone use declined after reports of hepatic

toxicity – Black box warning: rare cases of liver failure

Ables AZ, Baughman III, OL. Antidepressants: Update on new agents and indications. Am Fam Physician. 2003;67:547–554.




Aminoketone• Bupropion

– No appreciable effect on 5-HT reuptake– Reuptake properties at NE and DA reuptake

pumps

– Unique among currently available antidepressants

Horst WD, Preskorn SH. Mechanism of action and clinical characteristics of three atypical antidepressants: Venlafaxine, nefazodone, bupropion. J Affect Disord. 1998;51:237–254.




Mixed Serotonin-Norepinephrine Effects

• Mirtazapine

– Enhances central noradrenergic and serotonergic activity

• Antagonism of central presynaptic α2-adrenergic autoreceptors and heteroreceptors

– Also antagonizes 5-HT2, 5-HT3, and histamine receptors

• Lower anxiety and gastrointestinal side effects

• Histamine receptor blockade associated with sedative properties


Gorman JM. Mirtazapine: Clinical overview. J Clin Psychiatry. 1999;60(Suppl 17):9–13.



Monoamine Oxidase Inhibitors• Increase NE, 5-HT, DA in neuronal synapse by inhibiting

MAO enzyme

• Chronic therapy changes receptor sensitivity

– Downregulation of β-adrenergic, α-adrenergic, serotonergic receptors

• Phenelzine and tranylcypromine: nonselective MAO-A and MAO-B inhibitors

• Selegiline transdermal patch allows inhibition of brain MAO-A and MAO-B with reduced effects on MAO-A in the gut

Bryant SG, Brown CS. Current concepts in clinical therapeutics: Major affective disorders, part 2. Clin Pharm. 1986;5:385–395.

Patkar AA, Pae C-U, Masand PS. Transdermal Selegiline: The New Generation of Monoamine Oxidase Inhibitors. CNS Spectr. 2006;11:363–375.

http://www.accesspharmacy.com/content.aspx?aID=3205404#3205404



St. John's Wort• Mixed results regarding efficacy

• Herbal medication available over-the-counter

– Not FDA regulated

– Manufacturers not required to provide proof of safety and/or efficacy

– Recommend single-source product from reputable manufacturer

• Significant drug interactions with commonly used medications

Linde K, Mulrow CD, Berner M, Egger M. St. John's Wort for depression. Cochrane Database of Systematic Reviews. 2005, Issue 2 Art. No.: CD000448.



Adverse Effects



TCAs

• Common side effects dose related; associated with cholinergic receptor blockade– Dry mouth– Constipation– Weight gain– Sexual dysfunction– Blurred vision

Bryant SG, Brown CS. Current concepts in clinical therapeutics: Major affective disorders, part 2. Clin Pharm. 1986;5:385–395.

Settle ED Jr. Antidepressant drugs: disturbing and potentially dangerous adverse effects. J Clin Psychiatry. 1998;59(Suppl 16):25–30.

– Urinary retention– Dizziness– Tachycardia– Memory impairment– Delirium at higher doses



TCAs• Orthostatic hypotension common

– Dose-related

– Potentially problematic

– Attributed to affinity for adrenergic receptors

• Cardiac conduction delays

– Heart block in patients with preexisting conduction disorders

– Overdose can produce severe arrhythmias

– Exercise caution if patients have clinically significant cardiac disease

Nemeroff CB. The burden of severe depression: a review of diagnostic challenges and treatment alternatives. J Psychiatr Res. 2007;41:189–206.



TCAs• Abrupt TCA withdrawal

– Cholinergic rebound symptoms

• Dizziness

• Nausea

• Diarrhea

• Insomnia

• Restlessness

– Especially if dose >300 mg/day

– Taper dose over several days

Haddad P. Antidepressant discontinuation reactions. In: Thompson C, chairperson. Discontinuation of antidepressant therapy: Emerging complications and their relevance [academic highlights]. J Clin Psychiatry. 1998;59:541–548.



SNRIs• Venlafaxine adverse effects similar to those of SSRIs

– Nausea

– Sexual dysfunction

– Activation

– Dose-related increase in diastolic blood pressure

• Baseline blood pressure not useful predictor of occurrence

• Monitor blood pressure regularly

• Reduce dose/discontinue if hypertension sustained


Feighner JP. Cardiovascular safety in depressed patients: Focus on venlafaxine. J Clin Psychiatry. 1995;56:574–579.



SNRIs• Duloxetine relatively well tolerated in short-term clinical

trials– long-term studies in larger patient population will more

clearly define risks and benefits – most common adverse events

• nausea• dry mouth• constipation

decreased appetite insomnia increased sweating

Stahl SM, Grady MM, Moret C, Briley M. SNRIs: Their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. CNS Spectr. 2005;10:732–747.

Bauer M, Moller HJ, Schneider E. Duloxetine: a new selective and dual-acting antidepressant. Expert Opin Pharmacother. 2006;7(4):421–427.



SSRIs• Low affinity for histaminergic, α1-adrenergic, muscarinic

receptors

– Fewer anticholinergic and cardiovascular adverse effects than TCAs

– Not usually associated with significant weight gain

– Common adverse effects generally mild, short lived

• Nausea, vomiting, diarrhea

• Sexual dysfunction

• Headache

• InsomniaGoldstein BJ, Goodnick PJ. Selective serotonin reuptake inhibitors in the treatment of affective disorders: III. Tolerability, safety and pharmacoeconomics. J Psychopharmacol. 1998;12(3 Suppl B):S55–S87.



SSRIs• Discontinuation/withdrawal syndrome can occur

if abruptly discontinued• Longer drug and active metabolite half-life: less

likely withdrawal syndrome will occur • SSRIs improve anxiety symptoms associated

with depression– Some patients experience increased anxiety

symptoms or agitation early in treatment



Triazolopyridines• Trazodone and nefazodone have minimal

anticholinergic effects and 5-HT agonist side effects

• Trazodone adverse effects

– Orthostatic hypotension

– Sedation

– Cognitive slowing

– Dizziness

– Priapism rare, potentially serious



Triazolopyridines• Nefazadone adverse effects

– Light-headedness, dizziness– Orthostatic hypotension– Somnolence– Dry mouth– Nausea – Asthenia (weakness) – Hepatic injury (black box warning)

• Do not initiate in patients with active liver disease or elevated baseline serum transaminases



Aminoketone• Bupropion adverse effects

– Nausea, vomiting– Tremor– Insomnia, activation, agitation – Dry mouth– Skin reactions– Seizures

• Appears to be dose-related• Increased by predisposing factors: history of head

trauma, CNS tumor



Mixed Serotonin-Norepinephrine Effects

• Mirtazapine adverse effects – Somnolence – Weight gain – Dry mouth– Constipation

• Side effects such as weight gain can be less with larger doses – Increased noradrenergic transmission as dose

increasedMasand PS and Gupta S. Long-term side effects of newer-generation antidepressants: SSRIs, venlafaxine, nefazodone, bupropion, and mirtazapine. Ann Clin Psychiatry. 2002;14:175–182.



Monoamine Oxidase Inhibitors• Adverse effects

– Postural hypotension (minimize with divided doses) – Weight gain – Sexual side effects

• Phenelzine: mild to moderate sedation• Tranylcypromine: can be stimulating

– Insomnia – Fever– Myoclonic jerking– Brisk deep tendon reflexes



Monoamine Oxidase Inhibitors• Hypertensive crisis

– Rare– Potentially serious and life-threatening – Can occur when MAOIs taken with certain foods

• High in tyramine or certain medications• 10 mg of tyramine can cause marked pressor

effect• 25 mg can result in serious hypertensive crisis

– Can culminate in cerebrovascular accident and death Neil JF, Licata SM, May SJ, Himmelhock JM. Dietary noncompliance during treatment with tranylcypromine. J Clin Psychiatry. 1979;40:33–37.



Monoamine Oxidase Inhibitors• Hypertensive crisis symptoms

– Occipital headache

– Stiff neck

– Nausea

– Vomiting

– Sweating

– Sharply elevated blood pressure

Neil JF, Licata SM, May SJ, Himmelhock JM. Dietary noncompliance during treatment with tranylcypromine. J Clin Psychiatry. 1979;40:33–37.

Dietary Restrictions for Patients Taking MAOIsa

Aged cheesesb Sardines Pods of broad beans (fava beans)

Sour creamc Anchovies Yeast extract, other yeast products

Yogurtc Snails Meat extract (Marmite)

Cottage cheesec Canned, aged, processed meats

Soy sauce

American cheesec Monosodium glutamate Chocolatee

Mild Swiss cheesec Liver (chicken/beef, > 2 days old)

Coffeee

Wined (especially Chianti, sherry) Fermented foods Ripe avocado

Beer Canned figs Sauerkraut

Herring (pickled, salted, dry) Raisins LicoriceaAccording to the FDA-approved prescribing information for the transdermal selegiline patch, patients receiving the 6 mg/24 h dose are not required to modify their diet. However, patients receiving the 9 or 12 mg/24 h are still required to follow the dietary restrictions similar to the other monoamine oxidase inhibitors (MAOIs).bClearly warrants absolute prohibition (e.g., English Stilton, blue, Camembert, cheddar).cUp to 56 g (2 oz) daily is acceptable.dAn 88 mL (3 oz) white wine or a single cocktail is acceptable.eUp to 56 g (2 oz) daily is acceptable: larger amounts of decaffeinated coffee are acceptable.


Medication Restrictions for Patients Taking MAOIs

Amphetamines Levodopa

Appetite suppressants Local anesthetics containing sympathomimetic vasoconstrictors

Asthma inhalants Meperidine

Buspirone Methyldopa

Carbamazepine Methylphenidate

Cocaine Other antidepressantsa

Cyclobenzaprine Other MAOIs

Decongestants (topical and systemic) Reserpine

Dextromethorphan Rizatriptan

Dopamine Stimulants

Ephedrine Sumatriptan

Epinephrine Sympathomimetics

Guanethidine Tryptophan

aTricyclic antidepressants can be used with caution by experienced clinicians in treatment-resistant populations.




Clinical Controversy

• Numerous FDA reports warn of adverse effects associated with antidepressant use in various populations

• Many warnings accompanied by product labeling changes including black box warnings

• Some warnings not unequivocally supported in scientific literature

– Examine and understand reports

– Consider in context of scientific literature



TCA Pharmacokinetics• Low bioavailability (30% to 70% for most TCAs)

– 1st-pass hepatic effect

– Interindividual variation

• Large volume of distribution– Concentrate in brain and cardiac tissue

• Extensive and strong binding– Plasma albumin– Erythrocytes

– α1-acid glycoprotein

– Lipoprotein



TCA Pharmacokinetics• Major metabolic pathways

– Demethylation

– Aromatic and aliphatic hydroxylation

– Glucuronide conjugation

• Enterohepatic cycling

• Linear metabolism within usual dosage range

• Elimination half-lives vary greatly among individuals



PharmacokineticsGeneric Name Elimination

Half-Life (h)a

Time of Peak Plasma

Concentration (h)

Plasma Protein

Binding (%)

Percentage Bioavailable

Clinically Important

Metabolites

Selective serotonin reuptake inhibitors

Citalopram 33 2–4 80 80 None

Escitalopram 27–32 5 56 80 None

Fluoxetine 4–6 daysb 4–8 94 95 Norfluoxetine

Fluvoxamine 15–26 2–8 77 53 None

Paroxetine 24–31 5–7 95 d None

Sertraline 27 6–8 99 36c None

aBiologic half-life in slowest phase of elimination.b4–6 days with chronic dosing; norfluoxetine, 4–16 days.cIncreases 30–40% when taken with food.dNo data available.





Half-Life (h)a

Time of Peak Plasma

Concentration (h)

Plasma Protein Binding

(%)


Clinically Important Metabolites

Serotonin/norepinephrine reuptake inhibitor

Venlafaxine 5 2 27–30 45 O-Desmethylvenlafaxine

Desvenlafaxine 11 7.5 30 80 O-Desmethylvenlafaxine

Duloxetine 12 6 90 50 None

Milnacipran 6-8 2-4 13 85-90 None

Aminoketone

Bupropion 10–21 3 82–88 b Hydroxybupropion

Threohydrobupropion

Erythrohydrobupropion

aBiologic half-life in slowest phase of elimination.bNo data available.





Half-Life (h)a

Time of Peak Plasma

Concentration (h)


(%)



Triazolopyridines

Nefazodone 2–4 1 99 20 Meta-chlorophenylpiperazine

Trazodone 6–11 1–2 92 b

Meta-

chlorophenylpiperazine

Tetracyclics

Mirtazapine 20–40 2 85 50 None

aBiologic half-life in slowest phase of elimination.bNo data available.





Half-Life (h)a

Time of Peak Plasma

Concentration (h)


(%)



Tricyclics

Tertiary amines

Amitriptyline 9–46 1–5 90–97 30–60 Nortriptyline

Clomipramine 20–24 2–6 97 36–62 Desmethylclomipramine

Doxepin 8–36 1–4 68–82 13–45 Desmethyldoxepin

Imipramine 6–34 1.5–3 63–96 22–77 Desipramine

Secondary amines

Desipramine 11–46 3–6 73–92 33–51 2-Hydroxydesipramine

Nortriptyline 16–88 3–12 87–95 46–70 10-Hydroxynortriptyline

aBiologic half-life in slowest phase of elimination.




SNRI Pharmacokinetics• Venlafaxine metabolized to active metabolite O-

desmethylvenlafaxine– Lowest plasma protein binding of any antidepressant

(27%–30%)– Different formulations have different pharmacokinetics

and adverse-effect profiles• Venlafaxine extended-release: sustained plasma

concentrations associated with higher rates of sexual dysfunction (37%) compared to immediate release (6%)

Olver JS, Burrows GD, Norman TR. The treatment of depression with different formulations of venlafaxine: a comparative analysis. Hum Psychopharmacol. 2004;19:9–16.



SSRI Pharmacokinetics• SSRIs have diverse pharmacokinetics • Pharmacokinetic attributes can guide treatment• Extensively distributed to tissues• Nonlinear drug accumulation with long-term

administration

– Possible exceptions: citalopram, sertraline• Relationship between dose and observed effect (e.g.,

side effects) can change over time for nonlinear SSRIs

DeVane CL. Metabolism and pharmacokinetics of the selective serotonin reuptake inhibitors. Cell Mol Neurobiol. 1999;19:443–466.

Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors: An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet. 1997;32(Suppl 1):1–21.



Bupropion Pharmacokinetics• Metabolized to multiple active metabolites

• 3 formulations considered bioequivalent – Immediate release, sustained release, extended

release– Peak plasma concentrations lower for sustained-

release formulation

• Believed to contribute to lower seizure risk

Jefferson JW, Pradko JF, Muir KT. Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations. Clin Therp. 2005;27:1685–1695.

Dunner DL, Zisook S, Billow AA, et al. A prospective safety surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry. 1998;59;366–373.



Mirtazapine Pharmacokinetics

• Extensive biotransformation to several metabolites

– Primarily renal elimination

– Metabolites present at low plasma concentrations

• Minimally contribute to overall pharmacologic profile

Timmer CJ, Sitsen JM, Delbressine LP. Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet. 2000;38:461–474.



TCA Altered Pharmacokinetics• Factors that influence plasma concentration

– Disease states, e.g., hepatic disease

– Genetics

– Age

– Cigarette smoking

– Concurrent drug administration

– Renal failure does not alter nortriptyline metabolism

• 10-hydroxy metabolite can accumulate

• Protein binding can be diminished: enhanced drug

sensitivity Wells BG. Tricyclic antidepressants. In: Taylor WJ, Caviness MHD, eds. A Textbook for the Clinical Application of Therapeutic Drug Monitoring. Irving, TX: Abbott Laboratories, 1986:449–465.



SSRI Altered Pharmacokinetics

• Hepatic impairment – Twofold increase in paroxetine plasma concentrations

• Cirrhosis– Fluoxetine and norfluoxetine t1/2 increased to 7.6 and 12

days, respectively

– Sertraline t1/2 2.5 times greater than in patients without liver disease

DeVane CL. Metabolism and pharmacokinetics of the selective serotonin reuptake inhibitors. Cell Mol Neurobiol. 1999;19:443–466.

Krastev Z, Terzivoanov D, Vlahov V, et al. The pharmacokinetics of paroxetine in patients with liver cirrhosis. Acta Psychiatr Scand. 1989;350(Suppl):91–92.

Demolis JL, Angebaud P, Grange JD, et al. Influence of liver cirrhosis on sertraline pharmacokinetics. Br J Clin Pharmacol. 1996;42:394–397.



Altered Pharmacokinetics• Renal impairment

– Two- to fourfold increase in paroxetine plasma concentrations compared with normal volunteers

• Clearance of venlafaxine, mirtazapine and their metabolites

– Reduced by hepatic or renal disease

– Adjust dose accordingly

Krastev Z, Terzivoanov D, Vlahov V, et al. The pharmacokinetics of paroxetine in patients with liver cirrhosis. Acta Psychiatr Scand. 1989;350(Suppl):91–92.

Kent JM. SNaRIs, NaSSAs, and NaRIs: New agents for the treatment of depression. Lancet. 2000;355:911–918.



Plasma Concentration and Clinical Response

• Clinical response dictates dosage adjustments• Correlation not established between plasma

concentration and clinical response or adverse effects for newer antidepressants

• Nortriptyline, desipramine, imipramine, and amitriptyline have evidence to support association between plasma concentrations and clinical response

• Plasma concentration monitoring not routinely performed

Watanabe MD, Winter ME. Tricyclic antidepressants: amitriptyline, desipramine, imipramine, and nortriptyline. In: Winter ME, ed. Basic Clinical Pharmacokinetics, 4th ed. Baltimore, MD: Lippincott Williams and Wilkins, 2004:423–437.



TCA Plasma Concentration Monitoring

• Indications – Inadequate response, relapse– Serious or persistent adverse effects– Higher than standard doses– Suspected toxicity– Elderly patients– Pregnancy– Cardiac disease– Suspected nonadherence or drug interactions

Watanabe MD, Winter ME. Tricyclic antidepressants: amitriptyline, desipramine, imipramine, and nortriptyline. In: Winter ME, ed. Basic Clinical Pharmacokinetics, 4th ed. Baltimore, MD: Lippincott Williams and Wilkins, 2004:423–437.



Drug Interactions



TCA Drug Interactions• Metabolized in liver through cytochrome P450 system

– interact with drugs that modify hepatic enzyme

activity or hepatic blood flow • Extensively protein bound • Certain SSRIs and TCAs (e.g. paroxetine, fluoxetine)

– inhibit cytochrome P450 (e.g., CYP2D6)– increase TCA plasma concentrations

• MAOIs and TCAs can be coadministered – severe reactions/fatalities reported – monitor carefully

Pharmacokinetic Drug Interactions Involving TCAs

Elevates plasma concentrations of TCAs

Lowers plasma concentrations of TCAs

Cimetidine Barbiturates

Diltiazem Carbamazepine

Ethanol, acute ingestion Ethanol, chronic ingestion

SSRIs Phenytoin

Haloperidol Elevates plasma concentrations of interacting drug

Labetalol Hydantoins

Methylphenidate Oral anticoagulants

Oral contraceptives Lowers plasma concentrations of interacting drug

Phenothiazines Levodopa

Propoxyphene

Quinidine

Verapamil


Pharmacodynamic Drug Interactions Involving TCAs

Interacting Drug Effect

Alcohol Increased CNS depressant effects

Amphetamines Increased effect of amphetamines

Androgens Delusions, hostility

Anticholinergic agents Excessive anticholinergic effects

Bepridil Increased antiarrhythmic effect

Clonidine Decreased antihypertensive efficacy

Disulfiram Acute organic brain syndrome

Estrogens Increased or decreased antidepressant response; increased toxicity

Guanadrel Decreased antihypertensive efficacy

Guanethidine Decreased antihypertensive efficacy

Insulin Increased hypoglycemic effects

Lithium Possible additive lowering of seizure threshold


Pharmacodynamic Drug Interactions Involving TCAs

Interacting Drug Effect

Methyldopa Decreased antihypertensive efficacy; tachycardia; CNS stimulation

Monoamine oxidase inhibitors

Increased therapeutic and possibly toxic effects of both drugs; hypertensive crisis; delirium; seizures; hyperpyrexia; serotonin syndrome

Oral hypoglycemics Increased hypoglycemic effects

Phenytoin Possible lowering of seizure threshold and reduced antidepressant response

Sedatives Increased CNS depressant effects

Sympathomimetics Increased pharmacologic effects of direct-acting sympathomimetics; decreased effects of indirect-acting sympathomimetics

Thyroid hormones Increased therapeutic and possibly toxic effects of both drugs; CNS stimulation; tachycardia




SSRI Drug Interactions• CYP2D6 and CYP3A4 responsible for metabolism

>80% of currently marketed drugs

• Patients receiving stable dose of medication known to interact with SSRIs

– Low SSRI starting dose

– Titrate carefully to evaluate importance of interaction

DeVane CL. Differential pharmacology of newer antidepressants. J Clin Psychiatry. 1998;59(Suppl 20):85–93.

SNRI Drug Interactions

Anti-depressant

Interacting Drug/Drug Class

Effect

Venlafaxine MAOIs Potential for hypertensive crisis, serotonin syndrome, delirium

Sibutramine Serotonin syndrome

Triptans Serotonin syndrome

Duloxetine MAOIs Potential for hypertensive crisis, serotonin syndrome, delirium


Thioridazine Thioridazine Cmax increased; prolonged QTc interval



SSRI Drug Interactions

Anti-depressant

Interacting Drug/Drug Class Effect

Citalopram and escitalopram

MAOIs Hypertensive crisis, serotonin syndrome, delirium

Linezolid (MAOI effects) Serotonin syndrome


Triptans Serotonin syndromeSertraline Linezolid (MAOI effects) Serotonin syndrome

MAOIs Potential for hypertensive crisis, serotonin syndrome, delirium




SSRI Drug InteractionsAnti-depressant


Fluoxetine Alprazolam Increased plasma concentrations and half-life of alprazolam; increased psychomotor impairment

Antipsychotics (e.g., haloperidol, risperidone)

Increased antipsychotic concentrations; increased extrapyramidal side effects

β-Adrenergic blockers Increased metoprolol serum concentrations; increased bradycardia; possible heart block

Carbamazepine Increased plasma concentrations of carbamazepine; symptoms of carbamazepine toxicity



Phenytoin Increased plasma concentrations of phenytoin; symptoms of phenytoin toxicity

TCAs Markedly increased TCA plasma concentrations; symptoms of TCA toxicity







Paroxetine Antipsychotics (e.g. haloperidol, perphenazine, risperidone)

Increased antipsychotic concentrations; increased central nervous system and extrapyramidal side effects

β-Adrenergic blockers Increased metoprolol serum concentrations; increased bradycardia; possible heart block



TCAs Markedly increased TCA plasma concentrations; symptoms of TCA toxicity







Effect

Fluvoxamine Alosetron Increased alosetron AUC (sixfold) and half-life (threefold)

Alprazolam Increased AUC of alprazolam by 96%, increased alprazolam half-life by 71%; increased psychomotor impairment

β-Adrenergic blockers Fivefold increase in propranolol serum concentration; bradycardia and hypotension

Carbamazepine Increased plasma concentrations of carbamazepine; symptoms of carbamazepine toxicity

Clozapine Increased clozapine serum concentrations; increased risk for seizures and orthostatic hypotension

Diltiazem Bradycardia


Methadone Increased methadone plasma concentrations; symptoms of methadone toxicity

Ramelteon Increased AUC (190-fold) and Cmax (70-fold)


TCAs Increased TCA plasma concentration; symptoms of TCA toxicity

Theophylline and caffeine

Increased serum concentrations of theophylline orcaffeine; symptoms of theophylline or caffeine toxicity


Warfarin Increased hypoprothrombinemic response to warfarinDiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: The McGraw-Hill Companies. http://www.accesspharmacy.com/

Drug InteractionsAnti-depressant


Effect

Tetracyclics

Mirtazapine Carbamazepine Mirtazapine concentration decrease (60%)

MAOIs Theoretically central serotonin syndrome could occur

Aminoketone

Bupropion MAOIs Potential for hypertensive crisis

Medications that lower seizure threshold

Increased incidence of seizures




CYP450 Enzyme Inhibitory PotentialCYP Enzyme

Drug 1A2 2C 2D6 3A4

Bupropion 0 0 + 0

Citalopram 0 0 + 0

Escitalopram 0 0 + 0

Fluoxetine 0 ++ ++++ ++

Fluvoxamine ++++ ++ 0 +++

Mirtazapine 0 0 0 0

Nefazodone 0 0 0 ++++

Paroxetine 0 0 ++++ 0

Sertraline 0 ++ + +

Venlafaxine 0 0 0/+ 0

++++, high; +++, moderate; ++, low; +, very low; 0, absent




SSRI Pharmacodynamics

• SSRI pharmacodynamic drug interactions can occur– Require close monitoring– Combining an SSRI with another drug that augments

serotonergic function (e.g., linezolid) can lead to serotonin syndrome

• Symptoms: clonus, hyperthermia, mental status changes

• 2 to 5 week wash out period (depends on SSRI t1/2) can be necessary before initiating another serotonergic medication

Boyer EW, Shannon M. Current Concepts: The Serotonin Syndrome. N Engl J Med. 2005;352:1112–1120.



Pharmacodynamics • Drug interactions of newer-generation

antidepressants (venlafaxine, duloxetine, mirtazapine, bupropion) primarily pharmacodynamic

• Relative lack of cytochrome P450 inhibition compared to SSRIs



Special Populations



Elderly Patients• Depression often inadequately treated or

missed/mistaken for another disorder• Depressed mood can be less prominent than other

symptoms; frequently somatic complaints– Loss of appetite– Cognitive impairment– Sleeplessness– Anergia

– Loss of interest in/enjoyment of normal pursuits

Otong D. The art of prescribing. Antidepressants in late-life depression: prescribing principles. Perspect Psychiatr Care. May 2006;42(2):149–153.



Elderly Patients• Important to recognize/treat depression

– Individuals >65 years have highest suicide rate compared to other age groups

– Increased suicidal attempts

• Firearm access

• Diminished cognitive functions

• Sleep disruptions

• Poor social interactions, inattention from caregivers

• SSRIs usually first-choice in elderly patients

Turvey CL, Conwell Y, Jones MP, et al. Risk factors for late-life suicide. A Prospective, Community-Based Study. Am J Geriatr Psychiatry. 2002;10:398–406.



Pediatric Patients• Symptoms vary from accepted diagnostic criteria;

nonspecific

– Boredom

– Anxiety

– Failing adjustment

– Sleep disturbance

• Sparse data supporting efficacy of antidepressants in children and adolescents

• Fluoxetine FDA-approved for depression in patients <18 years; other antidepressants have been studied

Cosgrave E, McGorry P, Allen N, Jackson H. Depression in young people: A growing challenge for primary care. Aust Fam Physician. 2000;29:123–127.



Pediatric Patients• March 2004: FDA issued black box warning for increased risk

of suicidal ideation and behavior with antidepressants in pediatric and adolescent patients

– Retrospective longitudinal reviews found no significant increase in risk of suicide attempts or death

– Untreated adolescents may successfully commit suicide

– Further study needed to resolve controversy

Olfson M, Marcus SC, Shaffer D. Antidepressant drug therapy and suicide in severely depressed children and adults: A case-control study. Arch Gen Psychiatry. 2006;63(8):865–872.

Valuck RJ, Libby AM, Sills MR, et al. Antidepressant treatment and risk of suicide attempt by adolescents with major depressive disorder: a propensity-adjusted retrospective cohort study. CNS Drugs. 2004;18(15):1119–1132.Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry. 2006;163(1):41–47. Hallfors DD, Waller MW, Ford CA, et al. Adolescent depression and suicide risk: Association with sex and drug behavior. Am J Prev Med. 2004;27(3):224–231.Haavisto A, Sourander A, Ellila H, et al. Suicidal ideation and suicide attempts among child and adolescent psychiatric inpatients in Finland. J Affect Disord. 2003;76(1–3):211–221.



Pediatric Patients• Cases of sudden death reported in children and

adolescents taking antidepressants such as desipramine

– Baseline electrocardiogram (ECG) recommended before TCA initiation

– Many clinicians recommend additional ECG when steady-state plasma concentrations achieved

Leonard HL, Meyer HC, Swedo SE, et al. Electrocardiographic changes during desipramine and clomipramine treatment in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1995;34:1460–1468.



Pregnant and Lactating Patients• ~14% of pregnant women develop serious depression• Women who discontinued antidepressant therapy 5

times more likely to relapse during pregnancy than those who continued treatment in one study

• Prenatal SSRI exposure – Risk of low birth weight and respiratory distress– Relationship remained after accounting for maternal

illness severity Oberlander TF, Warburton W, Misri S, et al. Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry. 2006;63:898–906.

Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499–507.



Pregnant and Lactating Patients• Weigh risks and benefits of drug therapy during pregnancy

• Risks of untreated depression

– Low birth weight due to poor maternal weight gain

– Suicidality

– Potential hospitalization

– Potential marital discord

– Inability to engage in appropriate obstetric care

– Difficulty caring for other children

• Do not underestimate or minimize risks of not treating

Hendrick V, Altshuler L. Management of major depression during pregnancy. Am J Psychiatry. 2002;159:1667–1673.



Pregnant and Lactating Patients• Possible approaches

– Discontinue antidepressant before conception if patient stable and appears likely to remain well while not taking antidepressant

– Continue antidepressant until conception – Continue antidepressant throughout pregnancy in

patients with history of relapse after medication discontinuation

– Further evaluations of newer antidepressant agents needed to understand risks at various stages of gestation



Refractory Patients• Most "treatment-resistant" depressed patients likely result

of inadequate therapy (relative resistance)• Sequenced treatment alternatives to relieve depression

(STAR* D) – National Institutes of Health (NIH)-sponsored study– 1 in 3 patients who did not achieve remission using an

antidepressant became symptom-free with an additional medication

– 1 in 4 patients achieved remission after switching to a different antidepressant

Sequenced Treatment Alternatives to Relieve Depression (STAR*D). Available at http://www.edc.gsph.pitt.edu/stard/. (Accessed February 12, 2007)

http://www.edc.gsph.pitt.edu/stard/



Refractory PatientsAssessing treatment refractory patients

1. Correct diagnosis?

2. Psychotic depression?

3. Adequate treatment dose/duration?

4. Do adverse effects preclude adequate dosing?

5. Patient adherence?

6. Stepwise treatment approach used?

7. Treatment outcome adequately measured?

8. Coexisting or preexisting medical/psychiatric disorder?

9. Do other factors interfere with treatment?



Refractory Patients• Non-drug modalities often beneficial

– Environmental manipulation– Family counseling – Cognitive therapy– Interpersonal psychotherapy

• >40% of MDD patients do not achieve remission even after 2 optimal antidepressant trials

Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T3 augmentation following two failed medication treatments for depression: A STAR*D Report. Am J Psychiatry. 2006;163:1519–1530.




Clinical Controversy• No universally agreed upon algorithms/guidelines for

treatment-resistant depression (TRD)– Patients do not achieve remission even after 2 optimal

antidepressant trials• Approaches

– Stop current antidepressant, initiate trial with unrelated agent

– augment current antidepressant with another agent • Lithium, T3, atypical antipsychotic

– Combination antidepressant therapy

Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T3 augmentation following two failed medication treatments for depression: A STAR*D Report. Am J Psychiatry. 2006;163:1519–1530.

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Clinical Application: Dosing

• Elderly patients: start with ½ usual starting dose, increase slowly

• Use caution when switching from one antidepressant to another

– 3 to 4 weeks usually required before mood-elevating response is seen

– Adequate trial: 6-weeks at maximum dosage

• Counsel patients about expected lag time before onset of clinical response to improve adherence




Therapeutic Outcome Evaluation• Monitoring parameters

– Adverse effects

– Target symptom remission

– Changes in social/occupational functioning

– Blood pressure for patients receiving venlafaxine

– ECG for patients >40 years before starting TCA therapy with periodic follow-up

– Suicidal ideation after initiation



Therapeutic Outcome Evaluation• Psychometric rating instruments

– Patient- and clinician-rated scales

– Rapid, reliable measurement of symptom nature and severity

– Administer prior to treatment, 6 to 8 weeks after initiation of therapy, then periodically

• Interview family member/friend (with patient's permission) regarding symptoms and daily functioning



Therapeutic Outcome Evaluation• Psychometric scale definitions

– Nonresponse: <25% decrease in baseline symptoms

– Partial response: 26% to 49% decrease in baseline symptoms

– Partial remission/response: >50% decrease in baseline symptoms

– Remission: return to baseline functioning; no symptoms


Mann JJ. The Medical Management of Depression. N Engl J Med. 2005;353:1819–1834.



Collaborative Practice• Pharmacists can play a crucial role in screening,

recognition, treatment

• High index of suspicion for MDD in certain patients

– Adolescents, young adults

– Family or personal history of depression

– Chronic illness/pain

– Perception or experience of recent loss

– Sleep disorders

– Multiple unexplained somatic complaints

U.S. Preventive Services Task Force. Guide to Clinical Preventive Services, 2nd ed. Baltimore, MD: Williams and Wilkins, 1996:541–546.



Collaborative Practice• Pharmacists play a crucial role in ensuring

medication adherence

– Assess willingness and ability to take medications

– Assess financial viability

– Patient education regarding dosing, side effects, drug interactions

– Guidance regarding follow-up appointments with prescribers

Finely P, Rens HR, Pont JT, et al. Impact of a collaborative pharmacy practice model on the treatment of depression in primary care. Am J Health Syst Pharm. 2002;59:1518–1526.



Conclusions• MDD remains one of the most commonly occurring

mental illnesses in adults– Often undiagnosed and untreated

• Pharmacologic intervention is cornerstone of treatment • Antidepressants have broad spectrum of neurochemical

effects and influence variety of receptors peripherally and centrally

• Safe/effective antidepressant use requires thorough understanding of pharmacology and principles of monitoring efficacy/adverse effects



Acknowledgements

Prepared By/Series Editor: April Casselman, Pharm.D., CGP, BCPS

Editor-in-Chief: Robert L. Talbert, PharmD, FCCP, BCPS, FAHA

Chapter Authors: Christian J. Teter, PharmD, BCPP

Judith C. Kando, PharmD, BCPP

Barbara G. Wells, PharmD, FASHP, FCCP, BCPP

Peggy E. Hayes. PharmD

Section Editor: Barbara G. Wells, PharmD, FASHP, FCCP, BCPP

Depressive Disorders

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