How high can we safely dose common psychotropics? Given the poor performance of medication combinations in recent studies, it’s time for a close look at the safety and efficacy of raising doses, sometimes known as “dose optimization.”

Since there are few controlled studies of very high doses, we are likely to make plenty of inferential errors when we find our patients responding to heroic doses. While they might, indeed, be responding to “dose optimization,” they might also be responding to nonspecific factors such as the passage of time, our irritation that they are not getting better, or the enhanced placebo effect of knowing that they are getting “special treatment.”

In general, it’s fair to say that there is no such thing as a “maximum” dose; there are ineffective doses, effective doses, and intolerable doses. The maximum dose has to be individually determined for each patient. For example, some patients are unable to tolerate 20 mg/day of fluoxetine, no matter at how gradually it is titrated, while other patients may only do well with doses over 200 mg/day.

It’s also important to keep in mind that the mere passage of time can be a great healer. Two little known studies endorse the value of staying the course with a given dose, even if our patients are champing at the bit for us to do something. In one large study involving 840 depressed patients on fluoxetine, 41% of non-responders at 6 weeks of treatment remitted by 12 weeks (Quitkin FM, et al., Am J Psychiatry 2003; 160: 734-741). Another study showed that after 6 weeks of sertraline non-response at 100 mg/day, simply continuing the same dose for 5 more weeks was more effective than increasing to 200 mg/day (Licht RW, Psychopharmacology 2002; 161: 143-151).

The information that follows is culled from a few controlled trials, many published case reports, and an informal poll of members of Ivan Goldberg’s psychopharmacology listserv (www.psycom.net). In this poll, I asked simply for clinicians to list the highest doses of various meds that they have safely prescribed for patients. Some of these doses are “heroic” and I am not endorsing them, but I list them purely to give you an idea of what some of your colleagues have found helpful in some treatment-resistant patients.

Antidepressants

SSRI controlled studies. In one study, increasing the dose of fluoxetine from 20 mg/day to 40-60 mg/day worked somewhat better than either adding desipramine at a low dose (25-50 mg/day) or adding lithium at a lowish dose (300-600 mg/day) (Fava M et al.,

J Clin Psychopharm 2002;22(4):379-387). But another study of 91 depressed outpatients found no efficacy difference between sertraline 50 mg/day and 150 mg/day for initial non-responders – both achieved an overall remission rate of 40% (Schweizer E et al., Int Clin Psychopharm 2001;16(3):137-143).

SSRI case reports. In 1991, researchers at McLean published a case series of 27 patients who had been treated with very high doses of fluoxetine (Stoll AL et al., J Clin Psychopharmacol 1991;11(3):225-226). The mean dose was 125 mg/day, and the range was from 100 mg to a whopping 320 mg/day. 63% of patients reported a “fair” or “good” response, and almost half (48%) reported no adverse events. Three of the 27 developed transient hypomania or mania, though all three of these patients had a prior diagnosis of bipolar disorder. A single case of a patient with refractory OCD reported an effective dose of 160 mg of citalopram (Bejerot S, et al., Acta Psychiatr Scand. 1998 Nov;98(5):423-4.)

Psychopharm listserv maximum doses reported (all doses are mg/day unless stated otherwise): Citalopram (PDR max 60) 160, escitalopram (PDR 20) 60, fluoxetine (PDR 80) 220, paroxetine (PDR 60) 140, sertraline (PDR 200) 500.

Duloxetine (Cymbalta). (PDR max: 60 for depression, 120 for GAD). One Eli Lilly-sponsored study of drug safety gave 117 healthy women high doses of duloxetine, starting them at 60 mg BID and escalating to 200 mg BID. High-dose patients had statistically significant rises in blood pressure and in pulse rate, both of which normalized after discontinuation of the medication.  Subjects reported a variety of side effects, including headache, nausea, dizziness, insomnia, sedation, and orthostatic hypotension, but nobody required medical attention for these symptoms (Wernicke JF et al., Expert Opin. Drug Saf. 2005:4(6):987-993).

Psychopharm listserv max: 120.

Venlafaxine XR (Effexor XR) (PDR max 225). In one controlled trial, 232 outpatients with major depression, all of whom did not respond to a previous trial of an SSRI, were randomly assigned to either a low dose venlafaxine XR (up to 150 mg/day) or high dose (up to 375 mg/day). Patients in the higher dose group showed a better response on some secondary measures at 8 weeks. However, the following side effects occurred more frequently in the high dose group: hypertension, constipation, agitation, sweating, and urinary frequency (Thase ME et al., J Clin Psychopharm 2006;26(3):250-258). A case series reported on 40 patients with depression who had been on high doses (mean, 346 mg/day, range 225-525 mg) for at least 12 months. Five of these patients (12.5%) developed hypertension after starting Effexor. ECGs were done on 37 patients, and all parameters were normal with the exception of one patient who had mildly prolonged QTc interval (Mbaya P et al., Hum Psychopharm 2007;22:129-133).

Psychopharm listserv max: 1200

Tranylcypromine (Parnate) (PDR max 60). One case series reported on treatment refractory patients who were given doses from 90-170 mg/day, with significant improvement (Amsterdam JD, et al., Pharmacopsychiat 1989;22:21-25). These scary doses were well-tolerated, and no tyramine-induced reactions were reported.

Psychopharm listserv max: 220

Psychopharm listserv max for some other antidepressants: Bupropion (Wellbutrin) SR (PDR max 400) 900, bupropion XL (PDR 450) 1200, desipramine (PDR 300) 500, imipramine (PDR 300) 600, mirtazepine (Remeron, PDR 45) 180, phenelzine (Nardil, PDR 90) 240, trazodone (PDR 600) 900.

Stimulants

In one study of mixed amphetamine salts XR (Adderall XR, PDR 30), the best results for adults were achieved at 60 mg/day (Weisler RH, et al., CNS Spectr 2006;11:625-639). In another adult study, patients were assigned to high dose methylphenidate OROS (Concerta, PDR 72), receiving an average of 82 mg/day, and did well (Spencer T, Biol Psychiatry 2005;57:456-463.

Psychopharm listserv max: Amphetamine (PDR 30) 60, methylphenidate (PDR 60) 120, methylphenidate OROS (PDR 72) 180, mixed amphetamine salts XR (PDR 30) 430 (yes, 430 mg, but split into three doses).

Antipsychotics

A review was published in 2005 which focused on the safety of higher-than-approved doses of atypical antipsychotics (Goodnick PJ, Exp Op Drug Saf  2005;4:653-668). One case report described a 21 year old woman who took aripiprazole (Abilify, PDR 30) at 75 mg/day; aside from sinus tachycardia, she did well (Duggal HS,  J Clin Psych 2006;67:674-675). Two case series have documented the safety of high doses of olanzapine (Zyprexa, PDR 20) up to 60 mg/day in treatment refractory schizophrenia (Sheitman B et al., Am J Psychiatry 1997;154:1626; Mountjoy C et al., Am J Psychiatry 1999;156:158-159). Quetiapine (Seroquel, PDR 800) was dosed effectively up to 2400 mg/day in a case series of 7 patients, with non-critical side effects such as sedation and orthostasis (Pierre JM et al., Schiz Res 2005;73:373-375). One case series of 15 patients showed no change in QT intervals with ziprasidone (Geodon, PDR 160) doses in the range of 240 to 320 mg/day (Levy WO et al., J Psychiatric Practice 2004;10(4):227-232).

Psychopharm listserv max: Aripiprazole (PDR max 30) 60, olanzapine (PDR 20) 100, quetiapine (PDR 900) 2000, ziprasidone (PDR 160) 320.

Other Psychotropics. We didn’t have time or space to review the literature on high dose benzodiazepines and mood stabilizers, but here are some of the highest doses reported by the psychopharm listserv: alprazolam (Xanax, PDR 4) 22, buspirone (BuSpar, PDR 60) 240 split QID, clonazepam (Klonopin, PDR 20 for seizures, 4 for anxiety) 20, desipramine (PDR) 500, imipramine (PDR) 600, lamotrigine (Lamictal, PDR 500) 1200, modafinil (Provigil, PDR 400) 800, topiramate (Topamax, PDR 400) 900.

In sum, the literature on dosing high is somewhat more robust than we would have predicted, and it appears that doses double the PDR recommended doses are frequently used, with some effectiveness and little in the way of catastrophic side effects.

 
TCPR Verdict:

Go ahead - dose high (with caution)