Paroxetine (Paxil)

Paxil is another popular SSRI anti-depressant. It works as well as the others with most of the advantages and disadvantages of SSRIs. However, its short half-life means that it has some additional problems when a dose is missed and problems in children born of mothers on paroxetine.  Paxil is now available as an inexpensive generic, but the manufacturer has now come out with a much more expensive long-acting form Paxil XR.  I see no reason to ever start patients on this medication in view of its disadvantages, but patients already doing well on it should continue.

Most patients take 40 mg per day with the typical treatment range 20-60 mg per day. Since paroxetine is shorter acting, patients usually take half their dose in the morning and half in the evening. The time-released Paxil CR has a half-life of 15-20 hours. 

Of 6145 depressed patients in clinical trials worldwide, 20% discontinued paroxetine due to side-effects. The most side-effects reported in clinical trials in their order of occurrence greater than placebo are: nausea (17%), drowsiness (14%), ejaculatory difficulty (13%), other male sexual difficulties (10%), asthenia (9%), sweating (9%), dizziness (7%), insomnia (7%), tremor (6%), dry mouth (6%), constipation (5%), diarrhea (4%), anorexia (4%), yawning (4%), In the 2% to 3% range: palpitations, flushing, flatulence, lump in throat, nervousness, anxiety, tingling, decreased libido, blurred vision, female sexual difficulties, and urinary frequency. Because of paroxetine’s short half-life, there is a high likelihood of side-effects if it is stopped abruptly. Thus, care should be taken not to run out of medicine and when discontinued, patients should be weaned off of paroxetine over several weeks to months.

A recent decision by the English government has asked physicians not to prescribe paroxetine for children.  This is probably related to its shorter half-life.  The problem may not be as marked with Paxil CR.  Still, Paxil CR has no advantage for the average patient over the much less expensive fluoxetine ($100 vs. $3 a month!).

Britain Says Paroxetine Not for Teens: emotional side-effects, ranging from mood swings and increased crying, to suicidal thoughts and self-harm, was twice as high in the Paxil group as in those taking a fake pill. A total of 3.2 percent of patients on Paxil had the emotional side-effects, compared with 1.5% placebo. Study of 1000. British regulators say don’t give to kids. 6/10/03 AP-London, writer Emma Ross

Paroxetine (Paxil) Caused Increased Suicide Attempts in Large Adult Study: In a DB PC study of 916 adults on paroxetine, seven attempted to take their own life vs. one of 550 patients on placebo. Their conclusions are published in the journal Dr Ivar Aursnes, et al. University of Oslo. BMC Medicine 8/21/05. Ed: Paroxetine is the only short-acting SSRI anti-depressant and has long had a serious problem with drug withdrawal symptoms, even between regular doses.

Clomipramine did Better than Paroxetine: DB 120 MDD in-patients. 12 vs 19 dropouts due to side-effects, but clomipramine more effective. Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. Danish University Antidepressant Group. J Affect Disord 1990 Apr;18(4):289-99; Clomipramine is an inexpensive tricyclic.

Paroxetine as Good as Chlomipramine in Teens: In a DB PC study of 121 patients ages 12-20 with major depressive disorder, there was no difference in effectiveness. Side-effects were 69% clomipramine vs. 49% paroxetine. Paroxetine Versus Clomipramine in Adolescents With Severe Major Depression: A Double-Blind, Randomized, Multicenter Trial. Braconnier A, Le Coent R, Cohen D. J Am Acad Child Adolesc Psychiatry 2003 Jan;42(1):22-29. Ed: As noted above, other research has found serious shortcomings for paroxetine with teens.

Paroxetine did Better than Imipramine for Teen Depression: In an 8-week DB PC study of 275 teens with major depressive disorders, paroxetine 20-40 mg/d did better than imipramine 200-300 mg/d, but neither was very impressive. Paroxetine lowered HAM-D depression scores by the psychiatrists of the teens but did no better than placebo on parent or self rating. Imipramine did no better than placebo on anything. The imipramine dropout incredibly high 31% vs. 10% paroxetine and 6% placebo. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. Keller MB, Ryan ND, et al. Brown Univ. J Am Acad Child Adolesc Psychiatry 2001 Jul;40(7):762-72. Ed: This appears to have been an industry-funded study and may have been stacked against imipramine, but tricyclics have long been discouraged for children and teens because of lower effectiveness than with adults.

Imipramine as Good as Paroxetine in Maintenance: In a 6-week DB PC study of 734 patients with the 219 responders in another DB PC study of 1 year of follow-up. Equal efficacy was found but there was higher imipramine dropout and paroxetine was favored by the paroxetine-funded researchers. A double-blind comparison of paroxetine with imipramine in the long-term treatment of depression. Houston: Claghorn JL, Feighner JP. J Clin Psychopharmacol 1993 Dec;13(6 Suppl 2):23S-27S

Imipramine as Good as Paroxetine for Elderly Depression: 198 MDD >60yo DB imipramine 50-100/d vs paroxetine 20-40/d. No difference in depression or frequency of side-effects but abstracts singles out anti-cholinergic (13% vs 6%) and serious side-effects (8% vs 4%) as more common with imipramine. A double-blind comparison of the efficacy and safely of paroxetine and imipramine in the treatment of depression with dementia. Katona CL, Hunter BN, Bray J. Int J Geriatr Psychiatry 1998 Feb;13(2):100-8

Imipramine as Good as Paroxetine in Chinese Depression: 40 pt MDD DB. 6 weeks. Imipramine 100mg vs paroxetine 20-30/d. Response rate 65% vs. 67%. Authors say paroxetine better because fewer side-effects. Taipei. Paroxetine in the treatment of Chinese patients with depressive episode: a double-blind randomized comparison with imipramine. Chiu HJ, Hong CJ, Chan CH. Zhonghua Yi Xue Za Zhi (Taipei) 1996 Jun;57(6):418-23

Imipramine/Paroxetine Combo Helped only Low Lithium Bipolar Depression: DB PC 117 bipolar depressed on lithium. Some also on valproic or carbamazepine. Only those on lithium under 0.8 mEq/L helped by anti-depressant. Nemerodd C et al: Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Amer J Psyc 01;158:906-12. Emory U & GlaxoSmithKline

Paroxetine as Good as Nefazodone: 206 DB MDD mod-severe out-patients England. No difference in efficacy or dropouts due to side-effects (13% and 14%). A multicenter double-blind comparison of nefazodone and paroxetine in the treatment of outpatients with moderate-to-severe depression. Baldwin DS, Hawley CJ, Abed RT, Maragakis BP, Cox J, Buckingham SA, Pover GH, Ascher A. J Clin Psychiatry 1996;57 Suppl 2:46-52

Paroxetine as Good as Venlafaxine for BAD Depr, Venlafaxine More Mania: 55 pt blind investigator random assign 6 wk study aver 30mg paroxetine or 180 venlafaxine. 43% & 48% responded with 33% both groups remitting. 3% v 13% became manic or hypomanic despite mood stabilizer. J Clin Psych 02;63:508.

Trazodone Just as Good as Paxil for Depression: In a 6-week DB PC study of 108 adults with major depression, trazodone prolonged release 150-450 mg/day did just as well as paroxetine 20-40 mg/day. There were no significant differences between the groups at endpoint in efficacy measures, and in percentage of responders (> 85%) or patients in remission (> 65%). Sleep disorders (HAM-D subset) were significantly less evident for patients in the trazodone group at the end of the study (p < 0.05). Adverse drug reactions were reported by 35% of trazodone-treated patients (mainly of the nervous system) and 26% of paroxetine-treated patients (mainly gastrointestinal), although none was considered to be serious. A comparative, randomised, double-blind study of trazodone prolonged-release and paroxetine in the treatment of patients with major depressive disorder. Kasper S, et al. Medical University, Vienna, Austria. Curr Med Res Opin. 2005 Aug;21(8):1139-46. Ed: The so-called SSRI magic bullet for depression has been disproven for the umpteenth time. Don't trust pharmaceutical companies! For more, see Depression.

Early Improvement Good Predictor for Either Paroxetine or Mirtazapine: Improvement (20% decrease in HAM-D) occurred in a majority of the analyzed patients within 2 weeks (mirtazapine: 72.7% of 109 patients; paroxetine: 64.9% of 103 patients). Early improvement was a highly sensitive predictor of later stable response or stable remission for both drugs. NPV approached maximum values as early as week 2 for mirtazapine and week 3 for paroxetine. After 2 weeks of treatment with mirtazapine and 3 weeks with paroxetine, almost none of the patients who had not yet improved became a stable responder or stable remitter in the later course. U Mainz. Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression. Szegedi A, Muller MJ, Anghelescu I, Klawe C, Kohnen R, Benkert O. J Clin Psychiatry. 2003 Apr;64(4):413-20

Lithium-Paroxetine Serotonin Syndrome: 17 patients given both with four developing some symptoms of syndrome and two more going manic. J Clin Psychopharm 01;21:474

Withdrawal Symptoms: Often dizzy, nausea, diarrhea. May include headache, light-headed, vertigo, anorexia, myalgia, fatigue. More common than with fluoxetine or sertraline due to short half-life. Psyc Drug Alerts 5/97

Prophylactic Paroxetine for Interferon Depression: Interferon-alpha used for malignant melanoma & hepatitis C and frequently causes major depression leading to d/c. DB PC 40 scheduled for high-dose interferon rx paroxetine 10mg/d up to 40 for 14 weeks starting two weeks before interferon. 11% vs 45% on placebo developed major depression with 5% and 35% having interferon stopped.Musselman D et al: Paroxetine for the prevention of depression induced by high-dose interferon alfa. NEJM 01;344:961, Emory

Paroxetine Safer than Nortriptyline with Coronary Heart Disease: 81 depressed with CHD. 61% v55% improvedbut1/41 v 7/40 with adverse cardiac event. Roose JAMA ’98;279:287-91

Paroxetine/Donepezil Toxicity: 2cases patients on paroxetine developing insomnia, diarrhea, and agitation with 5 mg donepezil. Paroxetine inhibits P450 2D6. J Amer Geriatrics Soc 99;47:1037

Paroxetine Reduced Suicide Attempts: 1-year DB PC paroxetine (40 mg/day) 91 patients who had recently attempted suicide for at least a second time. None of the patients had experienced a major depressive episode or had any other major DSM-III-R axis I diagnoses. At least one cluster B personality disorder was present in 74 patients. RESULTS: With adjustment for the number of previous suicide attempts, paroxetine showed significant efficacy in the prevention of recurrent suicidal behavior. Among the patients who had attempted suicide fewer than five times, 12 (36%) in the placebo group (N = 33) and five (17%) in the paroxetine group (N = 30) made a subsequent suicide attempt. Paroxetine was also significantly more effective in patients who met fewer than 15 criteria for cluster B personality disorders than in those who met more than 15 criteria. Overall, paroxetine was not significantly different from placebo in its effect on depressive mood, hopelessness, and anger. However, the data suggest that paroxetine may have some temporary effect in reducing anger. Reduction by paroxetine of suicidal behavior in patients with repeated suicide attempts but not major depression. Verkes RJ, Van der Mast RC, Hengeveld MW, Tuyl JP, Zwinderman AH, Van Kempen GM. Am J Psychiatry 1998 Apr;155(4):543-7

Paroxetine Withdrawal in New Borns and Enterocolitis: Four neonates with jitteriness, irritability, vomiting, and/or hypoglycemia linked to paroxetine use by the mother are reported. Between days 2 and 5, two had necrotizing enterocolitis. Two were still irritable and lethargic at day 22 although other two were better in a few days. Possible cholinergic rebound and serotonin platelet aggregation. Stiskal J, et al: Neonatal paroxetine withdrawal syndrome. Arch Disease Childhood Fetal Neonate 01;84:F134-5

Paroxetine May Cause Complications for Newborns: Of 55 exposed to paroxetine in 3^rd trimester, 22% required intensive and prolonged hospitalizations after birth for respiratory distress, hypoglycemia or jaundice. Only 6% of control group had complications. Premature birth occurred in 20% paroxetine vs. 4% of controls. Of 36 breastfeeding mothers on paroxetine, 22% reported symptoms in controls vs. 0% of control breastfeeders. Paroxetine shortest half-life and most specific SSRI. Costei A, et al: Perinatal outcome following third trimester exposure to paroxetine. Arch Pediatric and Adolescent Med 2002;156:1129-32. Univ Toronto.

Paroxetine/Tramadol Sertotonin Syndrome: Two elderly with MDD rx tramadol for bone pain = nausea, diaphoresis, irritable, weak, confused, fever, agitation, restless. Stop both and better. Cyproheptadine (serotonin receptor antagonist) also used for one. Tramadol (Ultram) analgesic that inhibits reuptake of serotonin and norepinephrine. Internatl J Ger Psych 98;13:343

Paroxetine Withdrawal But Not Fluoxetine, Citalopram or Sertraline: 85 pt in DB studies had DB 4-7 substitution of placebo for med. Only paroxetine patients suffered noticeable withdrawal effects: cognitive failures (P = 0.007), poorer quality of sleep (P = 0.016), and an increase in depressive symptoms, as rated both subjectively, using the Zung scale (P = 0.006) and by the clinician, using the Montgomery-Asberg Depression Rating Scale (P = 0.0003) and Clinical Global Impression (P = 0.0003). These cleared on restarting med. U Surrey. Abrupt and brief discontinuation of antidepressant treatment: effects on cognitive function and psychomotor performance. Hindmarch I, Kimber S, Cockle SM. Int Clin Psychopharmacol 2000 Nov;15(6):305-18

Paroxetine Side-Effects Higher with 5HT2a variant: DNA from 246 people, aged 65 and older, with depression in DB PC 8 weeks of paroxetine (Paxil) or mirtazapine (Remeron) determined for the 102 T/C single nucleotide polymorphism (SNP) in the serotonin 2A (5-HT(2A)) locus (HTR2A), previously associated with psychotropic medication treatment outcome. Discontinuations due to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype. There was a significant linear relationship between the number of C alleles and the probability of discontinuation. HTR2A 102 T/C genotype had no effect on mirtazapine side effects. CYP2D6 genotype did not predict treatment outcome for either medication. Pharmacogenetics of antidepressant medication intolerance. Murphy GM Jr, Kremer C, Rodrigues HE, Schatzberg AF. Am J Psychiatry. 2003 Oct;160(10):1830-5

Apolipoprotein E epsilon4 Patients Respond Slower to Paroxetine Than to Mirtazapine: The apolipoprotein E epsilon4 allele and antidepressant efficacy in cognitively intact elderly depressed patients. Same study as above with 16 week open extension. Biol Psychiatry. 2003 Oct 1;54(7):665-73 Murphy GM, Kremer C, Rodrigues H, Schatzberg AF; Mitrazapine versus paroxetine Study Group.