Babatunde Idowu Ogundipe M.D. M.P.H.December 2 2011Comprehensive Clinical Services P.C.

Several forms of depression, the most common of which are major depressive disorder & dysthymic disorder:

(1)Major depressive disorder: Combination of symptoms interfering with person’s

ability to work, sleep, study, eat, & enjoy once-pleasurable activities. Disabling & prevents person from functioning normally. Often recurs in persons life.

(2)Dysthymic disorder: Long-term (> 2 years) but less severe symptoms

that may not disable a person but can prevent one from functioning normally or feeling well.

(3)Psychotic depression: Severe depressive illness accompanied by some form

of psychosis, such as break with reality, hallucinations, & delusions.

(4)Postpartum depression: When new mother develops major depressive

episode within one month after delivery. Estimated that 10-15% women with postpartum depression after giving birth.

(5)Seasonal affective disorder (SAD): Depression during winter months, when less natural

sunlight, that lifts during spring and summer. Half of these cases do not respond to light therapy alone but responsive to combo antidepressants, light, and psychotherapy.

(6)Bipolar disorder: Aka manic-depression. Cycling mood changes from

extreme highs (mania) to extreme lows (depression).

Major depressive disorder is one of the most common illnesses in the US adult population yet is an underdiagnosed & undertreated disorder.

Approximately 19 million people, equivalent to about 10% of U.S population older than age 18 in a given year with depressive disorder.

Over a lifetime about 10 to 20 % of the adult population will have experienced depression.

Risk depression is 2-3 times higher in women versus men.

Risk depression is 2-3 times higher in first-degree relatives of depressed persons.

Suicide is a concern in depressed patients with 15 % of those affected dying by suicide.

Depressed patients with medical problems have higher morbidity & mortality rates when compared with nondepressed patients.

No single cause rather likely a combination of genetic, biochemical, environmental, & psychological factors.

Research indicates depressive illnesses are disorders of the brain. Brain imaging shows brains of people with depression look different from those without. Parts of brain responsible for regulating mood, thinking, sleep, appetite, behavior appear to function abnormally.

Important neurotransmitters (chemicals that brain cells use to communicate-appear to be out of balance).

Genetic research indicates risk depression results from the influence multiple genes acting together with environmental or other factors.

Trauma, loss of a loved one, a difficult relationship, any stressful situation may trigger a depressive episode.

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Initial Screening can be accomplished with Patient Health Questionnaire:

(1) “During the past month, have you often been bothered by feeling down, depressed, or hopeless?” (depressed mood).

(2) “During the past month, have you often been bothered by little interest or pleasure in doing things?” (anhedonia).

A positive response to both with sensitivity of 96% & specificity of 57%.

Negative answers to both make clinically relevant depression unlikely & alternative diagnoses more likely.

If positive on at least 1 of 2 above items then ask additional questions to see if meet criteria Major depression.

If meet 4 more of the following symptoms for at least 2 weeks and have social & occupational impairment then they make the diagnosis :

The other symptoms of depression include: (3)Weight loss or weight gain (or change in appetite) (4)Insomnia or hypersomnia. (5)Psychomotor agitation or retardation. (6)Fatigue or reduced energy. (7)Preoccupation with feelings of worthlessness or

guilt. (8)Poor concentration or indecisiveness. (9)Morbid or suicidal thoughts. (10)Substantial social or occupational impairment.

Remember SIGECAPS : Sleep (inc/dec), Interest (dec), Guilt, Energy (dec), Concentration, Appetite (dec/inc), Psychomotor agitation or retardation, Suicidal ideation.

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TABLE 1. Differential Diagnosis of Depressive SyndromesDepressive symptoms1. Depressed mood2. Decreased pleasure3. Weight loss or weight gain4. Insomnia or hypersomnia5. Psychomotor agitation or retardation6. Fatigue or reduced energy7. Preoccupation with feelings of worthlessness or guilt8. Poor concentration or indecisiveness9. Morbid or suicidal thoughts10. Substantial social or occupational impairmentMajor depressive disorderEither 1 or 2; at least 4 items from 3-9 for at least 2 wk; Dysthymia1; at least 2 items from 2-9 for at least 2 y;Adjustment disorder with depressed moodIdentifiable stressor but symptoms out of proportion to what is expectedNot enough symptoms to meet major depressive disorder criteriaSubstantial social or occupational impairmentStressor within 3 mo, impairment not longer than 6 moBereavementSpecific stressor: death of a loved oneSymptoms resemble major depressive disorder, but patient considersthem appropriateMajor depressive disorder diagnosis is not given unless symptomspersist longer than 2 mo or include guilt not related to thedead, a preoccupation with worthlessness, marked psychomotorretardation, suicidal ideation, and prolonged and marked functionalimpairmentFrom Quick Reference to the Diagnostic Criteria From DSM-IV-TR,8 withpermission.

A Generalist’s Guide to Treating Patients With DepressionWith an Emphasis on Using Side Effects to Tailor Antidepressant Therapy

Other differential to major depression could include: (1)Substance-induced mood disorder (i.e.illicit drugs,

beta blockers). (2)Mood disorder due to a medical condition: I.e.many nonpsychiatric disorders present with

complaints of fatigue, insomnia, & difficulty concentrating: endocrinopathies (hypothyroidism, hyperparathyroidism, Cushing, and Addison’s diseases), frontal lobe disease, right hemispheric stroke, occult tumors outside the brain, & infections of the brain.

i.e. Anemia, hypoglycemia, & hyperglycemia may also appear clinically like depression.

As generalist physicians we have 4 options:(1)Watchful waiting.(2)Psychopharmacologic treatment.(3)Psychotherapy(4)Referral to a Psychiatrist.

What is your opinion?:Do generalist tend to diagnose depression

when its not there?Do generalist tend to not diagnose depression

when its there?Do you think there is more antidepressants

being prescribed by generalists than necessary based on above?

If so what are your thoughts on alternative ways to manage symptoms that may not fully constitute depression?

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Dose (mg/d)Antidepressant Starting Therapeutic MaximumSelected first-generation antidepressants:TricyclicsTertiary amine: Amitriptyline 25 50-200 300 Clomipramine (Anafranil) 25 50-200 300 Doxepin (Sinequan) 25 50-200 300 Imipramine (Tofranil) 25 50-200 300Secondary amine: Desipramine (Norpramin) 25 50-200 300 Nortriptyline (Pamelor) 25 50-150 150Selected second-generation antidepressants:SSRIs Citalopram (Celexa) 10 10-60 80 Escitalopram (Lexapro) 10 10-20 40 Fluoxetine (Prozac) 10 20-60 80 Paroxetine (Paxil) 10 20-50 60 Sertraline (Zoloft) 25 25-200 200SNRIs Desvenlafaxine (Pristiq) 50 50-100 100 Duloxetine (Cymbalta) 30 30-90 120 Venlafaxine (Effexor XR) 37.5 37.5-375Serotonin antagonist Mirtazapine (Remeron) 7.5 15-45 45Norepinephrine and dopaminereuptake inhibitors Bupropion SR (Wellbutrin) 100 100-400 400 Bupropion XL (Wellbutrin) 150 150-450 450SNRI = serotonin and norepinephrine reuptake inhibitor; SR = sustained release; SSRI =selective serotonin reuptake inhibitor; XL = extended release. All doses are for oral preparationtaken once daily except for bupropion SR, which is taken twice daily, and venlafaxine(Effexor SR), which can be taken once a day or in divided doses.

A Generalist’s Guide to Treating Patients With DepressionWith an Emphasis on Using Side Effects to Tailor Antidepressant Therapy

Pharmacotherapy key points: All classes of antidepressants demonstrate comparable

efficacy in treating depression. Second generation (SSRI’s, SNRI’s, Serotonin

antagonist’s, & Norepinephrine & dopamine reuptake inhibitors). antidepressants have become first-line treatment given marketing claims that they promote better adherence & are safer in overdose than first generation drugs (TCA’s).

Choosing which antidepressant to use should be based on differences in side effects amongst the available antidepressants.

Managing side effects can enhance comfort & function and ultimately improve adherence & premature discontinuation.

Side effects can be of therapeutic value.

Pharmacotherapy key points continued: Treatment should be continued for at least 6

months. These medications take at least 2 months to reach an adequate response so once a patients depression is treated & in remission the current antidepressant should be continued at the same dose ( as long as well tolerated) for > 6 months to 1 year to decrease the chance of relapse.

Patients with just 1 episode of depression can be taken off medication after 1 year but those with > 2 episodes should be kept on the antidepressant indefinitely.

Psychotherapy combined with pharmacotherapy is substantially faster & more effective in gaining response or remission than either alone.

Electroconvulsive therapy for refractory or catatonic depression, acute mania, or acute psychosis.

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Selective Serotonin Reuptake Inhibitors:

Citalopram (Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft), Fluvoxamine (Luvox).

Mechanism: Selectively block serotonin reuptake pump on presynaptic terminal increased serotonin levels available in synapse

Applications: first line therapy for depression + many anxiety disorders.

Interactions: Can increase warfarin levels given P-450 interactions.

Side effects: Sexual dysfunction (decreased libido, anorgasmia, genital arousal problems, increased ejaculation latency or absence) nausea, diarrhea, anorexia, headache, anxiety, tremor, sleep disturbance.

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Atypical Antidepressants: Mirtazapine (Remeron) = Serotonin antagonist. Mechanism: An alpha-2 antagonist that enhances

norepinephrine (NE) & 5-HT. Side effects: Sedation (treatment insomnia)-

blockade 5-HT2shortened sleep onset latency, increased total sleep time, & improved sleep efficiency(take at bedtime), weight gain(increases appetite), minimal sexual side effects.

Interactions: contraindicated with MAOI’s, benzodiazepines, alcohol.

Bupropion(Wellbutrin) = Norepinephrine & Dopamine reuptake inhibitors.

Applications: First line therapy for depression & smoking cessation. Effective for patients who have had sexual side effects from other antidepressants.

Atypical Antidepressants: Side effects: anxiety, insomnia, agitation. Lowers

seizure threshold, especially in setting rapid or large dose increases. Associated with weight loss, not gain.

Relative Contraindications: history of seizure disorder, eating disorder, head trauma, MAOI’s & meds that lower seizure threshold.

Venlafaxine(Effexor) = Serotonin & norepinephrine reuptake inhibitor.

Applications: Major Depression, GAD. More rapid response than SSRI’s.

Side effects: diastolic hypertension (monitor blood pressure, can cause slow increase in blood pressure in those already hypertensive).

Atypical Antidepressants: Side effects continued: insomnia, nervousness,

sedation, sexual dysfunction (same as SSRI’s), anticholinergic effects, nausea.

Contraindications: MAOI’s. Trazodone Mechanism of Action: serotonin antagonist & reuptake

inhibitor. Uses: At low doses may be helpful in insomnia (especially in early stages treatment can give in low dose to act as adjunct to another antidepressant).

Side effects: sedation (block histamine receptors in hypothalamic wake-promoting center-along with doxepin), priapism(alpha adrenergic blockade undesired painful erection that begins with nonischemic state & progresses to vaso-occlusion, acidosis, anoxia, & ischemia, rare), postural hypotension.

Tricyclic Antidepressants (TCA’s):

Nortriptyline (Pamelor), Desipramine (Norpramin), Imipramine(Tofranil), Amitriptyline, Clomipramine (Anafranil), Doxepin (Sinequan)

Mechanism: block reuptake of serotonin & norepinephrine.

Applications: useful for chronic pain & migraines. Second line depression. Amitriptyline used in low dose for treatment chronic pain. Clomipramine for OCD.

Interactions: levels increase when used with SSRI’s due to P-450 competition. cnsforum.com

Side effects: (1)Anticholinergic effects = > remember “hot as a

stove, red as a beat, dry as a bone, mad as a hatter”: fever, skin flushing, dry mucous membranes (dry mouth), psychosis, mydriasis(dilated pupils), tachycardia, urinary retention, constipation/paralytic ileus, blurry vision /acute glaucoma.

(2)Cardiac => orthostatic hypotension, cardiac conduction delays with prolonged PR & QRS intervals & (TCA overdose can prolonged QT interval fatal ventricular arrhythmia’s)reentrant arrhythmias like ventricular tachycardia, ventricular fibrillation, & torsades de pointes.

TCA’s contraindicated in patients with h/o heart block, heart disease, & those at high risk suicide.

TCA’s highly protein bound in alkaline environment. Low pH increase free drug concentrationscardiac toxicity. Thus treat with sodium bicarbonate-alkalinize plasma to target pH > 7.45 to prevent/reduce side effects.

Lidocaine antiarrhythmic DOC for TCA –induced ventricular dysrhythmias.

(3)Sedation (Doxepin –high affinity for histamine receptor thus in low dose good for sleep induction)

(4)Weight gain (tertiary amines i.e. amitryptyline/imipramine > secondary amines i.e.nortriptyline & desipramine).

Caution in elderly as can induce confusion. Nortriptyline with slightly fewer sedative & anticholinergic side

effects. Amitriptyline with strongest anticholinergic + sedative

properties. Remember Tri –C’s: Convulsions, Coma, Cardiac arrythmias

Monoamine Oxidase Inhibitors (MAOI’s): Phenelzine, selegiline, & tranylcypromine Use: second line antidepressants Side effects: orthostatic hypotension, insomnia,

weight gain, edema, & sexual dysfunction. Tyramine-induced hypertensive crisis. Aged

cheeses, red wine, sour cream, yogurt, pickled herring, cured meats used with MAOI’s.

MAOI’s combined with SSRI’s, TCA’s, meperidine, fentanyl, or indirect sympathomimetics (i.e.OTC cold remedies) may potentially fatal serotonin syndrome.

Remember 6 H’s: Hepatocellular (jaundice, necrosis), Hypotension (postural), Headache, Hypereflexia, Hallucinations, Hypomania.

Side effects seen in treatment with antidepressants: Sometimes within hours, self-limiting: nausea,

headache; those that arrive early & persist: sexual dysfunction or fatigue; those that emerge gradually & accrue: weight gain.

Early side effects result from AD synaptic effects on neurotransmitter reuptake and receptor blockage, whereas those emerging later stem from such slow-to-develop neuroplastic adaptations as receptor desensitization and downregulation that are hypothesized to reverse depression.

Studies have shown that drowsiness, sexual dysfunction, & weight gain are the three most bothersome side effects that may impact patients willingness to continue use of antidepressants.

MAOI’s + SSRI’s or MAOI’s + Venlafaxine or less commonly SSRI’s + Levodopa, SSRI’s + lithium, or SSRI’s + atypical antipsychotic. All may excessive increase in serotonin levels in brain “Serotonin Syndrome”:

Symptoms of delirium, agitation, tachycardia, diaphoresis, & diarrhea.

Signs of myoclonus (muscle rigidity) & hyperreflexia.

Also possible but rare: hyperthermia, seizures, rhabdomyolysis, renal failure, cardiac arrhythmias, & DIC.

Treat by stopping offending drug, treat symptoms + give serotonin antagonist = cyproheptadine.

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Complication use of antipsychotic medications & can occur at any time during course of treatment. Biggest risk is rapid administration high potency nueroleptic (i.e. high doses IM haldol).

May also be precipitated by abrupt withdrawal Levodopa(dopamine precursor) in Parkinson’s patients.

Mortality 10-20 %. Symptoms: muscular rigidity & dystonia, akinesia,

mutism, obtundation, & agitation. Autonomic symptoms: high fever, diaphoresis,

hypertensive episodes, & tachycardia. Other findings: elevated CPK, elevated liver enzymes.

May progress to rhabdomyolysis & or renal dysfunction.

Anticholinergics that promote heat retention (i.e.benztropine) contraindicated in patients with neuroleptic malignant syndrome due to fever & autonomic stability.

Treat by stopping offending medication & giving dantrolene (muscle relaxant), bromocriptine (dopamine agonist) or amantadine .

SSRI Atypicals: MAOI’s: TCA’s:

Sexual Dysfunction:

Fluoxetine (if so switch to mirtazapine/bupropion(inc dopamine-sex fctn) or decrease dose or add sildenafil) or buspirone Paroxetine(most of all SSRI’s).May be useful in men with premature ejaculation given delayed orgasm.

Venlafaxine. yes Introduced in more sexually repressed 1950’s. yes.

Weight Gain:

Paroxetine(most of all SSRI’s), citalopram, sertralineFluoxetine anorexia weight loss.Escitalopram-weight neutral.

Mirtazapineincreased appetiteincreased weight.Bupropionweight loss.

yes Amitriptyline, Imipramine weight increased after 6 months of use.

Sedation:

Paroxetine(most of all SSRI’s)-thus only one taken at night. Other SSRI’s energizing thus taken in morning.

Bupropioninsomnia, may be beneficial in patient with lassitude. Mirtazapine-may be beneficial in patients with insomnia. Trazodone- insomnia (especially in early stages treatment can give in low dose to act as adjunct to another antidepressant).

Amitriptyline. May be beneficial in patients with insomnia. Doxepin –high affinity for histamine receptor thus in low dose good for sleep induction

Anticholinergic

Venlafaxine. Amitriptyline with strongest anticholinergic effect

Other:

Bupropionlowers seizure threshold.Venlafaxine increased diastolic BP.Trazodone priapism + postural hypotension.

Tyramine-induced hypertensive crisis-aged cheeses & red wine. MAOI’s combined with SSRI’s, TCA’s, meperidine, fentanyl, or indirect sympathomimetics (i.e.OTC cold remedies) may potentially fatal serotonin syndrome.

Orthostatic hypotension, Cardiac conduction delays, overdose fatal ventricular arrythmias

Text: Pharmacology of Antidepressants. Mayo Clinic

Proceedings. 2001. Elliott Richelson. FIRST AID for the USMLE 3, Tao Le, Vikas Bhushan,

Robert W. Grow, Veronique Tache. A Generalist’s Guide to Treating Patients With

Depression With an Emphasis on Using Side Effects to Tailor Antidepressant Therapy. Mayo Clinic Proceedings.2010. J. Michael Bostwick, MD.

National Institute of Mental Health. http://www.nimh.nih.gov/health/publications/depression/complete-index.shtml