Antidepressant Medication Use in Pregnancy

Barbara Hackley, CNM, MSN


J Midwifery Womens Health. 2010;55(2):90-100. 

In This Article

Physiology of Depression

Little is understood about the physiology of normal mood, much less the physiology associated with mental illness. Twin studies have clearly documented that genetics play an important, but not exclusive, role in the lifetime risk of developing depression; genetic effects have been estimated to account for 37% (95% confidence interval [CI], 31%–42%) of the risk of developing depression compared to 63% (95% CI, 58%–67%) for individual risk factors.[11] Indeed, it appears that the etiology of depression is multifactorial (i.e., some environmental insult, such as severe stress or illness, interacts with an underlying vulnerability and leads to the development of depression).[12]

Unlike other neurologic diseases, such as Parkinson disease, which tend to affect an identified region of the brain, depression seems to affect multiple areas of the brain including the prefrontal cortex, hippocampus, amygdala, and thalamus.[12] Depression results from abnormalities in the interactions between neurotransmitters and hormones in the brain, such as the hypothalamus-pituitary-adrenal (HPA) axis; noradrenergic, serotonergic, and dopaminergic systems; neuropeptides; and brain-derived neurotrophic factor (BDNF), and can lead to structural changes in the brain.[13]

The serotonergic, nonadrenergic, and dopaminergic systems work closely together, but each is thought to have slightly different effects.[13] Key neurotransmitters in these systems include serotonin, norepinephrine, and dopamine.[14] Serotonin is formed from the essential amino acid tryptophan. Serotonin is found in highest levels in the basal ganglia, frontal cortex, hypothalamus, and limbic system. It is thought to regulate sleep, pain sensitivity, sexual function, and appetite, and helps to maintain the integrity of the synaptic junction. Both norepinephrine and dopamine are formed from tyrosine. Norepinephrine-sensitive neurons are found in the fore- and midbrain, locus coeruleus, cerebellum, and spinal cord. The nonadrenergic system is thought to work in concert with the prefrontal cortex in modulating behavior and attention and with the amygdala to impart an emotional component to memory. Dopamine neurons are found mainly in the midbrain and pituitary gland and in the nigrostriatal, mesolimbic, and mesocortical pathways. These pathways are critical and affect motor function, reward and motivation centers, memory, and attention.

Each system is comprised of two different types of pre-and postsynaptic receptors: excitatory and inhibitory.[15] For example, when under stress, serotonin is released into the synaptic cleft, where it binds to the postsynaptic receptors on other neurons and transmits the signal onward. Some serotonin will also be transported back into the presynaptic receptors from which it was originally released by serotonin transporters.[16] This completes the feedback loop. Serotonin is then stored in presynaptic receptors for future use or is metabolized by monamine oxidase and excreted in urine.[16] The other neurotransmitters act similarly. Serotonin receptors appear to be more numerous and heterogeneous than norepinephrine receptors.[15]

In depression, the noradrenergic system is hyperresponsive to stress and fear stimuli, whereas the serotonin system is hyporesponsive and consequently fails to inhibit the stress response.[15] Antidepressants are thought to decrease norepinephrine turnover and receptor sensitivity while increasing serotonin turnover and receptor sensitivity.[15]

While serotonin, norepinephrine, and dopamine are the primary neurotransmitters, their function is affected by other cotransmitters, the neuropeptides. The neuropeptides are released more slowly than the neurotransmitters and may account for the slow but steady response to antidepressants, which often take up to 3 months of use to reach full therapeutic effect. Neuropeptides are found throughout the brain and are thought to counteract the anxiogenic effects of cortisol-releasing factor in the amygdala, hippocampus, and locus coeruleus, and seem to improve cognition under stress.[13]

Antidepressants are thought to increase the amount of BDNF, one of the most prevalent neurotrophic factors in the brain.[12] While the role of BDNF is not well elucidated, it is thought to play opposing roles in different regions of the brain. In depression, levels appear to be lower in the hippocampus but higher in the nucleus accumbens.[13] These complex interactions in multiple areas in the brain help explain the symptomatology of depression: namely sleep disturbances, impaired memory, motor retardation, and depressed mood.

Excess stress also appears to play a role in the development of depression and can cause dysregulation of the HPA axis. Patients with major depression have been found to have elevated plasma and urinary cortisol levels as well as elevated corticotropin-releasing hormone and decreased levels of BDNF.[14] Prolonged severe stress is thought to damage hippocampal neurons and to reduce the inhibitory control exerted by the HPA axis in regulating glucocorticoid levels.[12] Individuals with chronic depression have been found to have smaller hippocampal volumes, suggesting that neurochemical changes in depression affect neuroplastic and neurogenic processes and can result in atrophy in certain types of neurons and lasting changes in both anatomy and function of the brain.[13,14]


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