ANTIDEPRESSANT PHARMACOTHERAPY

General approach to Antidepressant Pharmacotherapy
Approach to pharmacotherapy based on coexisting conditions/demographics
Side effects of antidepressants
Specific Antidepressants
"Augmentation" of Antidepressants by combining w/other agents
Drugs for Bipolar Affective Disorder

I. General approach to antidepressant pharmacotherapy

1. All block reuptake of monoamine neurotransmitters (to different degrees), but how this improves depression is not well understood.
2. There is no consistent evidence of any significant difference in overall effectiveness at reducing sx of depression among available antidepressants (see, for instance, JAMA 286:3003, 2001--JW)
3. Dosing
   1. Begin with low dose (1/4 maximal), increase every 2-3d over 2-3wks until reach maximum dose, get relief of sx, or side effects
      1. With tricyclics, dosing of 75-100mg/d may achieve equal improvement in depression sx with lower incidence of side effects, according to one meta-analysis of 6 randomized trials looking at 6-8wk outcomes (BMJ 325:1016, 2002--AFP)
   2. Consider divided doses until 1-2wks at stable dose, then can go to once-daily dosing for most meds (bupropion is one exception)
      1. For elderly pts on older drugs given at bedtime, consider keeping on divided dose, so don't get high levels at night when might have higher risk of falling if need to get out of bed
4. Allow 1-2wks for therapeutic effect to be noticeable
5. If not getting good results:
   1. Consider checking medication blood levels
      1. Reliable therapeutic levels available only for imipramine, desipramine, and nortriptyline
      2. Nevertheless, 10-30-fold difference in individual metabolism for many antidepressants makes levels helpful b/c standard dosing may not fit everyone
   2. Consider changing to or adding new agent
   3. Comparison of various 2nd-line strategies for depression pharmacotherapy: the "Sequenced Treatment Alternatives to Relieve Depression" ("STAR*D") Study:

4. Antidepressant medications in patients with coexistent substance abuse
   1. In a meta-analysis of 14 RCTs of antidepressant medication vs. placebo in pts with unipolar depression and current alcohol or other drug abuse, 
      antidepressant Rx as ass'd with significant improvements in depression sx (as measured by the Hamilton Depression Scale) (JAMA 291:1887, 2004--abst)
5. Duration of treatment
   1. 6-12mos generally recommended if response obtained
   2. 395 pts responding to 12wks of fluoxetine 20mg/d for major depression randomized to another 50wks of placebo, 14wks of fluoxetine + 36wks placebo, 38wks fluoxetine + 12wks placebo, or 50wks fluoxetine. Relapse rate as of 12wks after switching to placebo was 49% in those getting placebo after initial 12wks and 23% in those who got fluoxetine total 26wks--both sig. more than those who continued fluoxetine for longer periods. However, the group that switched to placebo 38wks after randomization had no greater risk of relapse than those who took fluoxetine 50wks, so total 50 wks (initial 12 + 38) may be best initial tx duration; Am. J. Psych 155:1247, 1998--JW)
   3. In a meta-analysis of 31 randomized trials of different durations of treatment with antidepressants for acute depression, with 6-36mo f/u intervals, tx regimens of > 1mo were ass'd with significantly lower risk of relapse (18% vs. 41%)
      (Lancet 361:653, 2003--AFP)
   4. Antidepressant discontinuation syndromes (Adapted by Joe McCreery from Ronald Pies M.D., Ed., "Advances in Psychiatric Medicine: Treatment Challenges in Depressive Disorders," 1998)
      1. Sx/signs reported include: Malaise, agitation, confusion, sleep disturbance, incoordination, tremor, gait disturbance, dizziness, paresthesias, myalgias, HA, rhinorrhea, n/v, diarrhea, abdominal pain, anorexia, diaphoresis
      2. Sx usually start 1-3d after d/c and last 10-14d
      3. Risk increases with use of SRI's > 1mo and TCA's/MAOI's > 2mos
      4. Greater risk with use of meds with short t-1/2 or no active metabolite (e.g. paroxetine and fluvoxamine), less with longer t-1/2 or active metabolites (e.g. sertraline and fluoxetine)
      5. To minimize risk, consider these steps:
         1. Taper over 2-3wks, longer for "high-risk" meds as above
         2. When switching from SSRI to non-SSRI, add in new drug slowly as you taper the SSRI

         3. When switching between SSRI's: Taper and add in new antidepressant gradually.

II. Approach to pharmacotherapy based on coexisting conditions/demographics

1. CHF, CAD, cardiac conduction defects: Consider SRIs or Buproprion over Tricyclics
   1. 81 pts with depression and documented ischemic heart disease randomized to paroxetine 20-30mg/d vs. nortriptyline titrated to 50-150ng/ml x 6 wks; found that resting adverse cardiac events sig. more common in nortriptyline group (2% vs. 18%; mostly sinus tachycardia but also 2 cases of increased ventricular ectopy); no sig. difference in efficacy for depression (JAMA 279:287, 1998--abst)
2. Hypertension treated with alpha-blockers or labetolol
   1. Consider Fluoxetine, bupropion, desipramine, protriptyline, paroxetine (low alpha blockade)
3. Postural hypotension
   1. Avoid imipramine, amitriptyline, MAOIs
4. History of PUD or GI bleeding
   1. Consider avoiding SSRI's (see above)
5. Parkinsonism or tardive dyskinesia
   1. Avoid amoxapine
6. Neurogenic bladder
   1. Trazodone, buproprion, fluoxetine, amoxapine, sertraline (low muscarinic blockade)
7. Angle-closure glaucoma
   1. Trazodone, bupropion, fluoxetine, sertraline
8. Using ergotamines
   1. Avoid SSRIs
9. Elderly patients
   1. Start with lower doses than in younger patients, especially with tricyclics
   2. Both tricyclics and SSRI's are associated with hip fractures in community-dwelling elderly (Lancet 351:1303, 1998--JW) in nursing-home ots.  This is probably related to increased risk of falls (confirmed; NEJM 339:875, 1998--JW) and also reductions in bone mineral density (Arch. Int. Med. 167:188, 2007--JW)
   3. Duration of treatment
      1. In a study in 116 pts > 70yo with major depression who had responded to short-term treatment with paroxetine, randomized to maintenance treatment with paroxetine vs. placebo x 2y, the 2y incidence of recurrence was sig. lower in the paroxetine group (35-37% vs. 58-68% with placebo; this was actually a 2 x 2 study which also compared monthly psychotherapy vs. monthly med-management visits; there was no sig. diff between those two appraoches in incidence of recurrence) (NEJM 354:1130, 2006--JW)
10. Pregnancy
    1. 228 women who used fluoxetine during preg. c/w 254 controls who didn't had similar rate of SpAb and major structural anomalies but higher rate of "minor anomalies" (15.5% c/w 6.5%). However, exposure group was older, had much greater prevalence of depression, and smoked more than controls (NEJM 335:1010, 1996-AFP)
    2. Retrospective study of 135 children age 1-7 whose moms had received either tricyclics (80) or fluoxetine (55) in Canada; compared with 84 unexposed control children had no differences in mean scores for physical development, global IQ, language skills, or behavior (NEJM 336:258, 1997)
    3. Other SSRI's (paroxetine, fluvoxamine, and sertraline): 267 women with 1st TM exposure to these drugs c/w controls not exposed; no association found with risk for major malformations, low birthweight, stillbirth, miscarriage, or prematurity. (JAMA 279:609, 1998--JW)
    4. In a cohort study of 44 children whose mothers had depression in pregnancy, 31 of whom elected to take meds (SSRI's), evaluated at 40mos of age with the Bayley Scales of Infant Development, mental development was similar in both groups but SSRI-exposed children had sig. lower psychomotor development (J. Peds. 142:402, 2003--abst)
    5. In a nonrandomized prospective study comparing infants of 20 mothers taking 20-40mg/d of citalopram or fluoxetine for depression or panic disorder and infants of 20 controls matched for obstetric characteristics, all assessed at age 4 days, 2 weeks, and 2mos, "serotonergic symptom scores" (included BP, HR, temperature, myoclonus, tremor, hyperreflexia, etc.) were sig. higher in the SSRI group at 4d but not at 2wks or 2mos (Arch. Gen. Psychiat. 60:720, 2003--abst)
    6. Case reports exist of "withdrawal-like" phenomena (including seizure) occurring in neonates born to mothers who used SSRIs in pregnancy (Lancet 365:482, 2005--JW; Arch. Pediat. Adol. Med. 160:173, 2006--JW)
    7. In a retrospective study in 4,850 pregnant women, 972 of whom used SSRIs during pregnancy, the SSRI-using group had sig. higher incidence of low birth weight, seizures, preterm birth, and fetal death (Am. J. Obs. Gyn. 194:961, 2006--AFP)
    8. In a case-control study of 377 infants with persistent pulmonary hypertension of the newborn (PPHN) and 836 matched controls born at the same hospitals, maternal use of SSRIs after 20wks gestation was associated, after adjustment for potential confounders, with OR of 6.1 for PPHN (NEJM 354:579, 2006--AFP)

1. Norepinephrine reuptake blockade causes
   1. Tremors
   2. Tachycardia
   3. Erectile and ejaculatory dysfunction
   4. Blocks antihypertensive effects of guanethidine and guanadrel
   5. Augments pressor effects of sympathomimetic amines
2. Serotonin reuptake blockade causes
   1. GI sx (nausea, diarrhea)
   2. Insomnia
   3. "Jitteriness"
   4. Fatigue
   5. Sexual dysfunction (erectile dysfunction and delayed ejaculation in men (the latter more with Paroxetine than others--J Clin. Psychopharmacol. 18:274, 1998--Med Lett.), anorgasmia in women, decreased libido in both)
   6. Extrapyramidal side effects (rare)
   7. Interactions with ergotamines ("serotonin syndrome"), L-tryptophan, and MAOIs
   8. May slow growth rate in children, by decreasing growth hormone secretion, per case reports (Arch. Ped. Adol. Med. 156:696, 2002--JW)
   9. May be associated with GI Bleeding b/c decreases platelet serotonin levels
      1. SRI use ass'd with RR of 3.0 (after adjusting for confounders) for upper GIB in a case-control study of 1899 pts with GI bleeding and 10,000 age- and sex-matched controls; crude incidence est'd at 1 case per 1300 pts; RR for pts using SRI's and NSAIDs concurrently was 15.6 (BMJ 319:1106, 1999--JW)
      2. In a retrospective cohort study of pts > 65yo tx'd with serotonin-inhibiting antidfepressants, the degree of serotonin-uptake inhibition (calculated from pt's regimen & doses) was ass'd with sig. increased risk for GI bleeding (BMJ 323:655, 2001--JW)
      3. In a case-control study of 196 pts hospitalized for abnormal bleeding and 972 age- and sex-matched controls, risk for such hospitalization was sig. greater in pts using antidepressants providing intermediate (OR 1.9) or high (OR 2.6) degrees of serotonin inhibition vs. those on antidepressants with low degrees of serotonin inhibition (Arch. Int. Med. 164:2367, 2004--abst)
      4. In a case-control study in 579 pts hospitalized with GI hemorrhage and 1000 controls matched for age, sex, and date of hospitalizations, SSRI use was associated with sig. increased risk of lower GI hemorrhage (OR 1.8) but not upper GI hemorrhage (Aliment. Pharmacol. Ther. 23:937, 2006--JW)
   10. May be associated with increased risk for Osteoporosis in postmenopausal women
       1. In a prospective, nonrandomized study in 2,722 postmenopausal women, use of SSRIs was associated with sig. greater decrease in hip BMD than tricyclic antidepressants (mean decrease 0.77%/yr vs. 0.49%/yr; Arch. Int. Med. 167:1240, 2007--AFP)
3. Dopamine reuptake blockade causes
   1. Psychomotor activation
   2. Antiparkinsonian effect
   3. Aggravation of psychosis
4. Direct receptor blockade can cause other side effects
   1. Histamine 1-produces sedation, weight gain, hypotension (among the tricyclics, least likely with nortriptyline)
   2. Muscarinic-produces dry mouth, blurred vision, constipation, urinary retention
   3. Alpha-1 adrenergic-produces orthostatic hypotension, potentiates alpha-blocker antihypertensives
   4. Dopamine-2-amoxapine blocks it (and thus is used mostly in psychotic depressions), causes extrapyramidal sx, sexual dysfunction in males
5. Effect on cardiac conduction-similar to IA antiarrhythmics; only in the tricyclics
6. MAOI's
   1. Avoid over-the-counter sympathomimetics, Demerol, imipramine, clomipramine, SSRI's
   2. Allow washout if switching to/from any meds that might interact
   3. Elderly us. need only 1/2 of the us. adult daily dose

IV. Specific Antidepressants

*-Refers to selectivity at blocking reuptake of serotonin over norepinephrine
**-Can increase risk of seizures; contraindicated in pts at high risk for seizures
***-Causes more anticholinergic side effects than other SSRI's
****-Despite low H1-blockade, does cause significant drowsiness! Also associated with priapism and hepatotoxicity

#-Fluoxetine notes: Can alter (lengthen or shorten) menstrual cycles in women (Obs. Gyn 90:590, 1997--AFP); Available in a Qwk 90mg fomualtion but leads to greater fluctuations in serum concentration and higher relapse rates than daily dosing (Med. Lett. 43:27, 2001)
##--Tends to stimulate appetite and cause more weight gain than other antidepressants
###-Inhibits reuptake of serotonin and norepinephrine; Can elevate diastolic blood pressure

1. S-adenosylmethionine ("SAM-E")
   1. An endogenous compound marketed as a dietary supplement for depression
   2. Little evidence for adverse effects or toxicity as of 1999 (Med. Lett. 41:107, 1999)
   3. In a meta-analysis of 28 randomized controlled trials of SAMe (400-1600mg PO QD) vs. placebo for depression, SAMe was ass'd with sig. improvement @ 3wks on Hamilton Rating scores for depression (mean 6 point improvement); in studies comparing prescription antidepressantes to SAMe, no sig. diff. in outcomes (incidence of 25% or 50% improvement in Hamlton Rating Scale scores (Evidence Report/Technology Assessment: Number 64. AHRQ Publication No. 02-E033, August 2002. http://www.ahrq.gov/clinic/epcsums/samesum.htm)

1. Lithium
2. Beta-Blockers
   1. 111 pts with major depression randomized to fluoxetine 20 QD plus either placebo or pindolol (an antagonist of beta-adrenergic receptors and serotonin "autoreceptors") 7.5mg QD. Followed for 6wks with Hamilton or Montgomery-Asberg depression-rating scales; "Treatment response" 75% vs. 59% with pindolol vs. placebo; p = 0.04. Sustained response 69% vs. 48%; p = 0.03; no sig. diff. In time-to-onset of clinical improvement (Lancet 349:1594, 1997-abst)
3. Tri-iodothyronine (T3)--see also Thyroid Disease
   1. Abnormalities in the hypothalamic-pituitary-thyroid axis are common in Depression (loss of nocturnal TSH surge, transient elevation of T4, blunting of thyroid's response to TRH, increased prevalence of autoimmune thyroiditis)
   2. In the several small placebo-controlled trials done as of 1995, there is no consistent evidence for a benefit to T3 augmentation of antidepressant Rx in euthyroid patients with unipolar depression (summarized in J. Clin. Endo. Metab. 80:2879, 1995)
4. Folic Acid
   1. Supplementation of fluoxetine with folic acid 500ug/d was ass'd with higher response rate than fluoxetine alone in a randomized trial of 69 women with severe depression (J. Affect. Disord. 60:121, 2000--FP News)

V. Drugs for Bipolar Affective Disorder--May require an additional antidepressant, though Lithium has intrinsic antidepressant activity

1. Lithium 1.5g/d in divided doses

1. Monitor levels (check 12h after last dose; should by 0.8-1.2mEq/l for acute tx; 0.6-0.7mEq/l for maintenance)
2. May cause nau, fatigue, tremor, thirst, polyuria, edema, and weight gain; confusion and ataxia can occur
3. Chronic treatment can cause renal damage (interstitial fibrosis, tubular lesions)
4. Mild hypothyroidism is a common side effect
5. Can cause or worsen acne and folliculitis
6. Relapse occurs more frequently with abrupt than with gradual discontinuation

2. Valproic Acid (Depakote, divalproex sodium)
   1. Dosing--Start at 750 BID and titrate dose every few days to therapeutic trough levels 50-125 ug/ml; typical dose to achieve these levels is 1000-2500mg/d
   2. Shown to be effective in tx of acute mania though not shown to be effective at maintaining remission as of 2000 (Med. Lett. 42:114, 2000)
   3. Side effects include sedation, GI upset, rash, alopecia, tremor, weight gain, hepatotoxicity (usually just mild elevations of transaminases) and Polycystic Ovary Syndrome in women
3. Carbamazepine (Tegretol) 400 BID--Effective for acute mania, less effective than Lithium for maintenance tx for bipolar (Med. Lett. 42:114, 2000); may cause leukopenia and induce activity of hepatic enzymes
4. Lamotrigine (Lamictal) --Effective for acute mania, may also improve depression sx; side f/x include rash (up to 10%; can progress to Stevens-Johnson), dizziness, ataxia, somnolence, blurred vision, and nystagmus; does not require blood monitoring (unlike Valproic Acid or Carbamazepine)
5. Oxycarbazepine (fewer side f/x than carbamazepine; may improve manic and depressive sx)
6. Gabapentin (Neurontin)--Less evidence to support its use than with other anticonvulsants as of 2005; may improve anxiety symptoms
7. Antipsychotics e.g. haloperidol used for severe acute mania; newer antipsychotics (e.g. olanzepine, risperidone, quetiapine) may be of benefit particularly in combination with antidepressants