Your patient has anxiety, and you’ve tried the usual medications. You’ve rotated through your favorite SSRIs and SNRIs but none have worked out, either due to efficacy problems or side effects. You’ve tried some of the benzodiazepines, but sedation and dependence have become problematic. You’ve even given buspirone a whirl, with the all-too-common results— suboptimal response, dizziness, and sedation.

It’s time to go off-label. Off-label prescribing refers to the use of medication for a condition not named in its FDA approval. Off-label prescribing has come under fire of late, because some large drug companies have been found guilty of illegal drug promotion, but physicians are free to prescribe any medication they want, as long as there is some evidence for usefulness. And remember that the lack of an FDA indication does not necessarily mean lack of efficacy—it sometimes means that no drug company has deemed the investment in clinical trials worth the eventual pay off.

So here is a selective list of possible off-label prescriptions for anxiety, along with suggestions for dosing and an estimation of probable efficacy based on whatever literature exists.

Lyrica (pregabalin). FDA approved indications: postherpetic neuropathy, diabetic neuropathy, and fibromyalgia. Approved for Generalized Anxiety Disorder in Europe but not in U.S. Possible mechanism: GABA reuptake inhibitor. Generalized Anxiety Disorder (GAD): In three Pfizer-funded placebo-controlled trials for GAD, Lyrica was significantly more effective than placebo and as effective as Xanax and Ativan. Start at 100 mg QHS, and gradually titrate to 300 mg BID. Big drawbacks: dizziness in 30% of patients, sedation in 22%, and weight gain of 5 lbs. in many patients. Somewhat addictive, and is a Schedule V controlled substance (same category as cough suppressants with codeine). No drug-drug interactions.

Neurontin (gabapentin). FDA approved indications: epilepsy and postherpetic neuralgia. Possible mechanism: modulator of GABA. Social phobia: One small placebo-controlled trial found Neurontin (average dose 2868 mg/day) superior to placebo for social phobia, but the response rates were low (32% for Neurontin, 14% for placebo) (Pande AC et al., J Clin Psychopharmacol 1999; 19:341-8). Alcohol withdrawal: In one large double blind trial, a rapid four-day taper of Neurontin (from 1200 mg/day to 800 mg/day) was more effective than a taper of lorazepam in terms of preventing relapse (Myrick H et al., Alcohol Clin Exp Res. 2009 Sep;33(9):1582-8. Epub 2009 May 26). Common Neurontin side effects: dizziness and sedation.

Gabitril (tiagabine). FDA approved indications: epilepsy. Mechanism: GABA A reuptake inhibition. GAD: Recently, the results of three placebo controlled trials of Gabitril for GAD were published in one paper (Pollack MH et al., J Clin Psychopharmacol 2008 Jun;28(3):308- 6.) At doses up to 16 mg/day, there was no difference between Gabitril and placebo in any of the 10 week studies, although the subset of patients who could tolerate the medication and stay on it for the full 10 weeks did show some significant improvement. Common side effects included dizziness, headache, nausea, fatigue, and somnolence.

Topamax (topiramate). FDA approved indications: epilepsy and migraine prophylaxis. Mechanism: Unknown. PTSD: In open trials, Topamax at around 50-100 mg/day led to rapid improvement of some PTSD symptoms in non-combat related PTSD (Berlant J et al., J Clin Psychiatry 2002;63(1):15-20), but in placebo controlled trials for chronic combat related PTSD it was ineffective, partly because of a 55% dropout rate due to side effects such as cognitive dulling and sedation (Lindley SE et al., J Clin Psychopharmacol 2007;27(6):677-681). Redeeming quality: one of the few psychotropics to cause weight loss rather than weight gain.

Seroquel XR (quetiapine XR). FDA approved indications: schizophrenia, manic and mixed episodes of bipolar disorder, monotherapy for bipolar depression. GAD: Astra Zeneca conducted three eight-week placebo controlled studies of Seroquel XR for GAD, all of which were submitted to the FDA, one of which has been published (Bandelow B et al., Int J Neuropsycho-pharmacol 2009;20:1-16). All the efficacy data is available in a massive pdf document on the FDA website at http://bit.ly/M7Qu7. A total of about 1800 people were enrolled in these multi-site studies, two in the USA and one international. When dosed at 50-150 mg/day, Seroquel XR was more effective than placebo in all three trials, but 300 mg/day was either ineffective or provided no additional benefit, depending on the trial. Patients on Seroquel had a rate of somnolence/sedation of 51.2% vs. 16.5 % on placebo, and in the longer term trials, Seroquel patients gained an average of 6.6 lbs. The FDA rejected the GAD indication because, while it demonstrated efficacy, the long-term side effects are worrisome. Note also that these studies had very strict exclusion criteria; only patients with GAD and no other psychiatric conditions or medical conditions were allowed. In my practice, I can count such patients with the fingers of one hand. Nonetheless, it’s clearly effective for some patients and worth a try when other treatments have failed.

Hydroxyzine (Atarax, Vistaril). FDA approved indications: Pruritis caused by allergies, and “symptomatic relief of anxiety and tension associated with psychoneurosis” (originally approved in 1956, hence the outdated terminology). Mechanism: antihistamine. GAD: While hydroxyzine is not really an off-label medication for anxiety, I’ve included it here because it is rarely used in practice despite having fairly good efficacy data. For example, in one large randomized placebo controlled trial, patients with GAD randomly assigned to hydroxyzine 50 mg/day did just as well as those assigned to bromazepam 6 mg/day (bromazepam is a benzodiazepine approved in Europe; 6 mg is equivalent to about 10 mg of diazepam). Patients on the benzodiazepine experienced more sedation (Llorca PM et al., J Clin Psychiatry 2002 Nov;63(11):1020-7).