There are three less commonly used medications that may increase the risk of depression. They are as follows:
Clonidine – (Level of Evidence: C)
Clonidine produces a pharmaceutical effect in patients with high blood pressure by acting on alpha-receptors in blood vessels. When these receptors are blocked, smooth muscles in the blood vessel wall relax. This results in lower blood pressure. However, Clonidine may also work on another subtype of alpha-receptors that regulates the output of a neurotransmitter called norepinephrine. When these receptors are activated, the concentration of norepinephrine decreases and this may contribute to depression. Despite this possible mechanism, there is inconsistent data to indicate a link between clonidine and depression. Larger studies suggest that the risk of depression (1.5% of patients) when using this medication is the same as the risk in the general population.
Guanethidine – (Level of Evidence: C)
Guanethidine reduces the release of norepinephrine at the nerve junction. Norepinephrine usually stimulates blood vessels to contract and increase blood pressure. However, with lower circulating levels, blood pressure is decreased. With prolonged use, guanethidine gradually accumulates in nerve endings and takes the place of norepinephrine, preventing its release. With lower levels of norepinephrine, patients may develop depression. According to case report studies, approximately 1.5% of patients using guanethidine develop depression.
Alpha-methyldopa – (Level of Evidence: B)
Like clonidine, methyldopa works on alpha-receptors to relax blood vessels and decrease blood pressure. However, in the body, it is transformed into a norepinephrine analog and binds to norepinephrine receptors on nerve endings. This norepinephrine analog is less active and does not trigger nerves to fire impulses. This reduction in norepinephrine activity causes depression. Studies in patients taking methyldopa showed that 3.6% of patients developed the condition.
Propanolol – (Level of Evidence Unknown)
Propranolol works on beta-receptors in the heart to slow down heart rate and subsequently decrease blood pressure. Additionally, it binds to serotonin receptors and blocks serotonin (a neurotransmitter) from having its effect. Decreased levels of serotonin may contribute to developing depression. There are several cases in which propranolol-induced depression worsened as the dose increased. Symptoms of depression resolved when the drug was discontinued.