Alleviation of Hot Flashes With Increase in Venlafaxine Dose

Sir: Venlafaxine, a newer bicyclic antidepressant, acts as a serotonin-norepinephrine reuptake inhibitor (SNRI). Besides improving depressive symptoms, venlafaxine has also been demonstrated to alleviate vasomotor symptoms.¹ It is being increasingly used as a nonhormonal drug to treat hot flashes, mostly in those women with concerns about or contraindications to estrogen-containing preparations.² We report an interesting case of new onset of hot flashes in a postmenopausal woman who was being treated with venlafaxine for chronic depression. The symptoms of hot flashes were alleviated with increase in the dose of venlafaxine and reemerged with decrease in the dose.

Case report. Ms. A is a 54-year-old woman with a longstanding history of schizoaffective disorder, which required more than 10 hospitalizations over the past 20 years. Her psychosis was under good control with aripiprazole, and she had been free of hallucinations and delusions. She had a history of 2 suicide attempts in the remote past. She reported occasional depression, which was well controlled with a small dose of venlafaxine, 75 mg daily, that she had been taking for over a year. No alcohol or drug use has been reported in the last 20 years. Her medical history included seizure disorder, which was well controlled with phenytoin. She had been free of seizure episodes for a year. Other medical illnesses include type 2 diabetes, hypercholesterolemia, gastroesophageal reflux disorder, hypertension, and urinary incontinence. Her medications included venlafaxine 75 mg daily, aripiprazole 30 mg daily, lamotrigine 200 mg twice daily, metoprolol 12.5 mg twice daily, rosiglitazone 4 mg daily, simvastatin 40 mg at bedtime, phenytoin 300 mg at bedtime, and temazepam 15 mg as needed for insomnia.

She complained of new-onset hot flashes at a frequency of 8 to 10 episodes a day over the last 3 months. Each episode lasted for 20 minutes with intense feeling of flushing initially followed by intense feeling of cold. Venlafaxine was increased to 150 mg daily, as a previous report³ has shown benefits of venlafaxine in treatment of hot flashes. With the increase in the dose of venlafaxine, the patient reported reduction in hot flashes both in frequency and severity. The hot flashes decreased in frequency to 2 episodes per day with each episode lasting for only 5 to 10 minutes.

Within a week of increasing the dose of venlafaxine, she reported worsening of the tremor in her hands. She also stated that the jerky movements in her extremities increased. We attributed her increased tremulousness and jerkiness to enhanced nor-adrenergic stimulation from the increased dose of venlafaxine; hence, we decreased the dose of venlafaxine to 75 mg daily. She reported decrease in tremors but an increase in the frequency of hot flashes after 7 days of reducing the dose of venlafaxine. We increased the dose of venlafaxine to 150 mg again, which resulted in a prompt control of hot flashes within a week. We consulted a neurologist for the management of tremulousness.

In addition to its well-established efficacy in treatment of depression, venlafaxine has also been found to be effective in decreasing the number and frequency of hot flashes.⁴ Although estrogen has been used for many years for treating hot flashes, concern about its safety has precluded its use largely due to the findings of the Women's Health Initiative trial.² Newer anti-depressants are being investigated as an alternative means for alleviating hot flashes.⁵ Venlafaxine is one of the newer antidepressants that has also been used as a nonhormonal treatment for hot flashes in cancer survivors⁴ and in postmenopausal women.³ A beneficial effect on vasomotor symptoms with the use of venlafaxine has also been reported in perimenopausal women with depression.¹

In the present case, we observed reappearance of hot flashes in a postmenopausal woman who was being treated with venlafaxine 75 mg daily for a year for depression. Interestingly, increasing the dose of venlafaxine to 150 mg daily alleviated her hot flashes. The exact mechanism of venlafaxine to alleviate hot flashes remains unknown. Venlafaxine is known to affect both serotonin as well as norepinephrine reuptake. Effects of venlafaxine at lower doses are thought to be related to the serotonin reuptake inhibition, and at higher doses its effects are attributed to a combination of both serotonergic and noradrenergic effects.⁶

The physiologic mechanism underlying hot flashes is not completely known. Two hypotheses have been proposed for the mechanism of hot flashes.³ According to one theory, changes in estrogen levels at menopause alter central nervous system adrenergic neurotransmission and cause abnormal thermoregulation. Another hypothesis is that decreased estrogen levels at menopause lowers serotonin levels, and the changes in serotonergic neurotransmission might cause hot flashes. In the present case, the new onset of hot flashes while being treated with a lower dose of venlafaxine is probably related to its effect on serotonin reuptake inhibition. The alleviation of hot flashes at a higher dose may involve its action on both serotonergic and noradrenergic pathways or on a predominantly adrenergic pathway.

A possibility of drug-drug interaction should also be noted in this report, as the patient was taking phenytoin. Phenytoin is a potent cytochrome P450 3A4 inducer and can decrease the levels and effects of venlafaxine. However, the patient had been on the same dose of both phenytoin and venlafaxine over the last year. Therefore, in the present case, the new onset of hot flashes cannot be explained by the drug interaction. No other drug-drug interactions were found regarding venlafaxine.

In conclusion, although venlafaxine has shown success as a treatment for hot flashes in postmenopausal women, this response could be dose related.