Darkeyes & Fayerody - The Depakote (Epival - divalproex) is probably the main culpert in the weight gain department, but antidepressant doses of Elavil (amitriptyline - 200mg - 250mg/day) also caused weight gain. I used to see a lot of people gain in the pre-SSRI days (pre-1990s), but the mechanism was probably different and the gains were not as drastic as we are seeing today with the SSRIs.

The weight gain with the TCAs (tricyclic antidepressants) like Elavil was due to the drugs' binding to a number of secondary receptors, other than those thought to be responsible for the antidepressant action. Similar to Effexor (venlafaxine), Elavil increases concentrations of both serotonin and norepinephrine (via reuptake blockade). Unlike Effexor, Elavil also binds to and blocks histamine-H1 receptors, which is notorious for causing weight gain. Elavil also blocks muscarinic-cholinergic (M1) receptors resulting in water retension (ie. bloating), and since it also blocks alpha-1-adrenergic receptors leading to profound drowsiness. Both of these side effects can indirectly lead to weight gain.

Acs an aside, many psychiatrists think that the TCAs are much better antidepressants than the SSRIs, but the profound drowsiness, dizziness, and cardiotoxic effects (which cause fatalities in overdose) seriously limit their use. The trade-off with the SSRIs is their relative safety in overdose, and relatively benign side effects profile (moderate weight gain is not ordinarily lethal).

The weight gain associated with Depakote is mainly due to an increase in appetite. I am not certain of the mechanism of appetite increase, but the drug has also been shown to increase testosterone in some teenage girls with epilepsy. The testosterone increases can lead to polycystic ovarian syndrome resulting in menstrual problems, unwanted hair growth, and obesity (ie. hyperandrogenism)

A 2001 University of Toronto study of women aged 18-50 years with bipolar disorder compared lithium and divalproex. Half of those taking divalproex (Depakote) had menstrual irregularities compared to 15% of those taking lithium. Weight gain was also prevalent among those taking divalproex. Blood tests also showed that those taking divalproex had higher bloods levels of androgens (eg. testosterone) and leptins (which is associated with weight gain), than those taking lithium.

When I read the report of this study, I thought, "Wow! No female should be taking Depakote for bipolar disorder!", but then I looked up the actual study, I found that it was presented at the annual meeting of the Canadian Psychiatric Association in 2001. The study consisted of only 38 women (18 taking divalproex and 20 taking lithium). When they concluded that 50% reported menstrual abnormalities, this meant only 9 women. So, when they said that half of the women taking divalproex who were overweight AND had menstrual irregularities, also had increased blood levels of androgens (ie. hyperandrogenism), they were referring to only 2 or 3 women. I don't know how you can make any generalizations from sample sizes this small (but when you use percentages, it does look impressive and convincing).

BTW - I read somewhere that the hyperandrogenism can be averted by simply taking birth control pills when taking Depakote. I don't know if this would prevent the increase in appetite or weight gain associated with the drug ..... I doubt it.

I hope that this is of some help, or interest. - Cam