Dr. Bob's Psychopharmacology Tips

Topiramate

Date: Fri, 03 Oct 1997 23:34:07 +0200
From: Leigh Janet <leigh@lia.net>
Subject: Topiramate

I have used lamotrigine, gabapentin and topiramate extensively over the past 2 years. Most patients managed with these agents suffer from bipolar spectrum disorders, and many also meet diagnostic criteria for borderline personality disorder. Many patients have explosive irritable temperaments, and most have experienced massive interpersonal difficulties, especially in their domestic lives.

The usual presentation is treatment refractory mood disorder, mostly depression, but many have, in addition, histories of significant anxiety disorders (usually OCD, panic disorder with or without agoraphobia, or multiple social phobias), substance abuse, prior hypomanic episodes, and brain trauma, and many have abnormal EEGs, especially temporal lobe electrical abnormalities.

Some (female) patients have post partum onset or worsening of their disorders, and many have thyroid anomalies. All patients have been extensively worked up from a medical perspective at some stage. All patients have extensive prior psychiatric treatment histories, with failure to respond to multiple prior interventions.

Common features almost inevitably include rapid shifts in mood, from depression to euthymia, from hypomania to depression, etc., and many have developed ultra-rapid mood cycling, even patients that were maintained well for years on antidepressants or lithium. Reversed vegetative features are common in many (but not all) episodes -- even within individual patients' histories.

Many patients are notably dysphoric during their mood episodes.

All patients are fully informed about the current status of these drugs as far as their use in mood disorders is concerned. Generally I am dealing with a well informed population, but many are prepared to undergo management with novel treatments as they have failed to respond to multiple other treatments. I give each patient a detailed exposition of the side effects of each drug. All patients are able to give informed consent.

Experience with Topiramate

My initial experience with topiramate is in patients who have failed to respond to all other management, including lamotrigine and gabapentin. This is a core group which poses seriously difficult management problems. They have all had numerous interventions (all have had ECT, some even maintenance ECT at some stage), multiple hospitalizations, multiple treating persons, etc.

The known pharmacological action of topiramate suggests potential usefulness in management of mood disorders.

Topiramate proved to be a difficult agent to initiate, with my first 7 patients failing to establish recommended therapeutic dose levels due to non-tolerance. The side effects were psychological or vague physical complaints, varying from "spaced out" to awful, agitated, or unpleasant feelings. Many patients complained of excessive sedation. Coming from patients that had been exposed to most of the drugs known to psychopharmacology, these reactions were surprising.

I tried introducing the drug more slowly, and this allowed most patients to settle on therapeutic doses.

Using very gradual build up schedules of 25 mg per week, there have been few adverse events with topiramate, and 3 of my core non-responders are currently doing very well on topiramate regimens, one in combination with olanzapine and valproate, one with tranylcypramine and gabapentin, and one with lithium. 2 of these patients relapsed dramatically when I tried to reduce the topiramate, and recovered when the topiramate was re-instated.

Although my n = 15 and only 3 have shown definite response, these responses are significant in context. 5 of the fifteen are still in the build-up phase and cannot be considered in this discussion. I have managed to build up the topiramate dose to 400 mg/day quite quickly in hospitalized patients, and am still in the process of evaluating the optimal rate of build up.

One interesting feature of the side effect profile of topiramate is anorexia and weight loss, which 2 patients have experienced -- much to their pleasure! I remain suspicious about psychotropic agents and weight reduction, so will need a lot more convincing, but topiramate may offer an advantage for patients who have significant weight increase with other agents.

Paraesthesiae are a common complaint, especially affecting the hands and feet. Depression is listed as one of the side effects of the drug, so patients have to be carefully monitored. Patients should be advised to maintain adequate hydration to minimize the risk of nephrolithiasis. I avoid the drug in patients with a prior history of "stones".

Other precautions with topiramate include the possibility of reversal of efficacy of oral contraceptive activity (increased clearance of oestrogen), which, combined with the risk of teratogenicity, means that additional contraceptive advice is necessary.

Topiramate does not seem to interact with valproate, but may increase phenytoin levels, which, as everyone knows, may rapidly lead to toxic phenytoin levels. The mechanism of this increase is proposed to be inhibition of a specific polymorphic CYP2C [meph] isoenzyme.

Carbamazepine may reduce topiramate levels, and topiramate may reduce digoxin levels.

Date: Mon, 23 Feb 1998 20:31:28 -0800
From: Frank Feiner <nfrank@pol.net>
Subject: Topiramate and weight loss

Most of my patients on Depakote (divalproex) gain weight -- sometimes enormous amounts. Some complain of ravenous appetites...

--Ed Gordon MD

Date: Tue, 24 Feb 1998 13:02:40 -0500
From: Ziad Nahas <nahasz@smtpgw2.musc.edu>
Subject: Topiramate and weight loss

Topamax (topiramate) has not been established as an effective mood stabilizer. However anacdotal reports as an add on to Depakote in an attempt to control weight gain appear interesting. If a patient is doing well on Depakote, one might think about this as an alternative before switching.

Date: Wed, 17 Jun 1998 21:39:00 -0400
From: Ivan Goldberg <Psydoc@psycom.net>
Subject: Topiramate

I have been using topiramate together with lamotrigine to help control mixed states or rapid cycling in some patients with hard to treat bipolar disorder. Weight loss is a frequent side effect.

From: johncarp@webtv.net (john carpenter)
Date: Wed, 17 Jun 1998 21:56:27 -0700
Subject: Topiramate

In the June 1998 newsletter Currents interview with Paul Keck, M.D., it was stated that topiramate had "two-for-one" effects providing mood stabilization and weight loss. Sounds too good to be true! It's supposed to be safe when added to lithium or valproate. We have a lot of patients who might benefit from this, but need to find out more about dosing, side effects, etc.

Date: Thu, 18 Jun 1998 22:17:15 -0400
From: Ivan Goldberg <Psydoc@psycom.net>
Subject: Topiramate

When lamotrigine has been increased to the maximally effective or tolerated dose I will start topiramate 20 mg once a day and increase the dose in increments of 25 mg until the patient is taking 100 mg qid. Improvement may be seen at a total daily doses of 50 to 400 mg/day. Generally I increase the dose every four or five days. While I have seen some ataxia and have heard of some drowsiness, topiramate is usually well tolerated. Appetite and weight reduction are often seen at doses of 200 mg/day and over.

From: "John G. Wagnitz, MD, MS, FAPA" <neurosis@ac.net>
Subject: Topiramate
Date: Thu, 18 Jun 1998 22:27:25 -0400

At APA in Toronto, Susan McEvoy (Cincinnati) gave a industry-sponsored presentation in which she discussed its use in weight reduction caused by other mood stabilizers. Others I spoke to later advised caution, particularly with cognitive difficulties.

The idea of a mood stabilizer which might not cause weight gain is certainly interesting.

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