Serotonergic Medications

Serotonin, or 5-Hyrdoxytryptamine, 5-HT, is a neurotransmitter synthesized by serotonergic neurons in the central nervous system (brain). It is believed to play an important role in a number of biological processes, including body temperature regulation, mood, aggression, sexuality, and appetite. It is sometimes referred to as the “food and mood” chemical. Low levels of serotonin are symptomatic of a number of psychological conditions, including depression and anxiety disorders. Several obesity medications work by increasing levels of serotonin, as this been shown to reduce appetite and food intake. Several classes of serotonergic medications are available for different indications. Selective serotonin reuptake inhibitors are widely used for the treatment of depression. Serotonin 5HT1b/1d agonists are used for the treatment of migraine. Serotonin reuptake inhibitors with additional activities (fenfluramine and sibutramine) are effective for weight loss.

Fenfluramine is a mixture of two chiral isomers, while dexfenfluramine is one of the two isomers. Fenfluramine and dexfenfluramine are the first serotonergic agents used for weight loss. Fenfluramine and its metabolite norfenfluramine have multiple biological activities, including serotonin transporter inhibitor, 5HT releaser, and agonist at several serotonin receptors. Fenfluramine has also been used in combination with phentermine in an off-label fashion. Although fenfluramine is an effective weight loss agent, its long-term use is associated with the development of valvular heart disease. This serious side effect led to the withdrawal of both fenfluramine and dexfenfluramine worldwide in 1997.

Fluoxetine is the first selective serotonin reuptake inhibitor (SSRI) and it is indicated for the treatment of depression. Early clinical studies indicated that short-term use of fluoxetine or other SSRIs is associated with modest weight loss. However, long-term studies showed that the weight loss is transient, and in some cases, long-term weight gain has been observed.

Sibutramine is the only serotonergic agent currently approved for the treatment of obesity. It is a serotonin and norepinephrine transporter inhibitor, along with weak activity at the dopamine transporter. Sibutramine reduces appetite and body weight. Weight loss has been demonstrated in clinical trials lasting two years. Unlike fenfluramine, sibutramine has not been associated with valvular heart disease. While sibutramine at the therapeutic doses is well tolerated, increase in blood pressure has been observed in some patients. Regular monitoring of blood pressure is required when prescribing sibutramine.