Serotonin's Role in Depression and How SSRIs Can Help
Many chemicals in the brain help to either excite or inhibit activity between neurons. These chemicals, called neurotransmitters, play an extremely important role in activities of the brain.
For many years the role of neurotransmitters in muscular movement and nervous intervention of organs in the sympathetic and parasympathetic systems have been well researched (Shepard, 1994). But the role of neurotransmitters in cognitive workings of the cerebrum remained a mystery.
The neurotransmitter serotonin has been linked with depression and suicide and is under close investigation (Asberg, 2011). The evidence obtained through testing and evaluation led to an alarming rise in the prescribing of selective serotonin reuptake inhibitors (SSRIs).
Has the research into serotonin been concrete enough to justify such a sudden wave of SSRI usage? Or are we jumping too quickly onto a cure to depression without thinking of future consequences?
Before one can examine these questions, it is necessary to look at the physiology of neurons and the role of neurotransmitters. One also needs to look at serotonin as a neurotransmitter, and at research exploring the role of serotonin in depression and suicide.
Physiology of Neurons and the Role of Neurotransmitters
Nerve impulses are chemical reactions within nerve cells that cause polarization. When polarization occurs an electrical signal called an action potential is sent through the dendrites and deciphered as a message by a nucleus located in the neuron's cell body (Shepard, 1994).
The nucleus in the cell body decodes messages and sends the decoded message as an action potential through an axon to the end of an axon called the synaptic end bulb (Shepard, 1994).
The synaptic end bulbs contain synaptic vesicles that contain neurotransmitters. The neurotransmitters located in the synaptic vesicles are released into the synpatic cleft by the action potential (Shepard, 1994).
These neurotransmitters are sent throughout the synaptic cleft to react with the neurotransmitter receptors in the plasma membrane of the receiving dendrites (Shepard, 1994).
Neurotransmtters play a dual role in neuron activity. they can either excite another neuron, or organ, or they can inhibit actions of other neurons, or organs. This separates neurotransmitters as either excitatory or inhibitory. Yet, in some cases neurotransmitters can perform both tasks.
The neuron excited by the neurotransmitter opens ion channels in the postsynaptic membrane through which Sodium (Na+) and Potassium (K-) permeability causes the membrane potential to shift into a positive direction (Shepard, 1994).
Each neurotransmitter has a ligand, or molecule that coordinates with a metal ion, to form a complex that opens ion channels by binding with a specific binding site in the presynaptic membrane. This starts the movement of (Na+) and (K-) causing another action potential (Shepard, 1994).
An inhibitory neurotransmitter causes the postsynaptic membrane to reach negative action potential by exceeding the limit of the firing threshold of the neuron. This is achieved by the inhibitory neurotransmitter opening (K+) ion channels in the postsynaptic membrane.
This increase in (K+) causes the neuron to pass beyond its firing potential. The firing potential of a neuron is the maximum amount of membrane potential needed to make the neuron fire. Usually the (K+) ion channels are controlled by Chloride (Cl-) pumps (Shepard, 1994).
The change in the voltage from positive to negative after hyperpolarization is called the inhibitory postsynaptic potential.
Seratonin as a Neurotransmitter
Serotonin, or 5-hydroxytryptamine, is an indole alkyl amine located in platelet mast cells, enterochromaffin cells, and in specific neurons where it acts as an neurotransmitter (Shepard, 1994).
Within the central nervous system serotonin is located in the midbrain and the pons. Serotonin is found specifically in a part of the brain stem called the raphe nucleus. Axons moving out from the raphe nucleus end in the hypothalamus and the thalamus (Shepard, 1994).
The hypothalamus regulates emotional and behavioral patterns, diurnal rhythms, body temperature, and eating and drinking behaviors.
The thalamus provides crude interpretations of touch, pressue, pain, and temperature. It also plays an important role in voluntary motor activity, and arousal (Shepard, 1994).
The anterior nucleus of the thalamus functions in emotions and memory, also in cognition and awareness. The raphe nucleus's connection with the hypothalamus and thalamus plays an important role in this involvement (Shepard, 1994).
Serotonin was first isolated in the blood in 1948. In the central nervous system amino acids are used for cell-to-cell signalling in neurotransmission. The neurotransmitters that use amino acids for cell-to-cell signaling are called biogenic amines (Shepard, 1994).
Serotonin is a biogenic amine derived from tryptamine. Tryptamine is an amino acid that is transported into the brain where it is the primary substrate for the synthesis of serotonin (Shepard, 1994).
After being used in neurotransmission between neurons, serotonin is not broken down but reabsorbed; this is why the use of SSRIs is effective in increasing the amount of serotonin in the brain (Shepard, 1994).
The most commonly prescribed SSRIs are fluoxetine, sertraline, cetalopram, and peroxetine.
Research of Serotonin as Playing a Role in Depression and Suicide
In 1975, Swedish researcher Marie Asberg attempted to measure the levels of serotonin in the brain. These researchers took samples of cerebrospinal fluid from the spines of human subjects and measured the levels of a substance known as Hydroxyindoleacetic Acid or 5-HIAA. 5-HIAA is a metabolite of serotonin and can be measured to obtain a quantitative level of serotonin in a human subject (Asberg, 2011).
An interesting connection was made when the researchers noticed that subjects with low levels of 5-HIAA were committing suicide. This connection was noticed by psychiatrist Marie Asberg who began to study how low levels of 5-HIAA were related to suicides (Asberg, 2011).
During the same time as Asberg's studies, researchers in Finland were studying violent criminal behaviour. They discovered that men who committed impulsive unpremeditated murder had low levels of 5-HIAA. Those who killed more than once had levels of 5-HIAA lower than those who had only killed once (Asberg, 2011).
Victoria Arango examined twenty suicide victims with twenty controls. She found that suicide victims had a significantly larger number of binding sites for serotonin in the brain than that of the controls. The large number of binding sites indicated that the suicide victim's brain had been overcompensating for the lack of serotonin in the brain (Arango, 2002).
Herman Van Praag hypothesized that disturbances in the brain's use of serotonin was the root for mood and aggression disturbances. Praag stated that levels of 5-HIAA below 92.5 mmol/L caused "major depressive episodes" and "dysthmic disorders" (Arango, 2002).
Symptoms common in patients with proposed Serotonin Depletion Syndrome include chronic daily headaches, mood disorders, carbohydrate craving, decreased sexual drive, and difficulties with memory and concentration.
The increase of serotonin research in certain disorders including depression and suicide since 1975 has grown exponentially. Along with SSRIs as a quick fix for everything from headaches to stress related anxiety.
The research performed by Asberg and others strongly suggests that serotonin plays an important role in mood and aggression. Yet, on the other hand, physiologists have proven that serotonin is used in the parts of the brain that play other roles: For example, diurnal rhythms, eating and drinking patterns, and voluntary motor activities.
Do physicians worry about any long-term consequences of elevating serotonin levels in the brain?
Studies have proven that some aggressive patients have actually exhibited more aggressive and confused behaviour after the use of SSRIs.
What happens to patients who may have normal serotonin levels, yet are fed large numbers of SSRIs for a headache?
Could these excessive levels of serotonin cause disorders in the brain that have not been noticed yet?
- Arango V. Underwood MD, Boldrini M, Tamir H, Hsuing S, CHen I, Man JJ: Serotonin 1A receptors, serotonin transporter binding and mRNA expression in the brainstem of depressed suicide victims. Neuron 2002; 34:349-356.
- Asberg, Marie:CSF 5-HIAA and childhood expression of interpersonal violence in suicide attempts. Journal of Affective Disorders Feb 2011; 132(1-2): 173-8.
- Shepard, Gordon M, Neurobiology. Oxford University Press, 1994; 3.
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© 2012 Jamie Lee Hamann