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(10) Bipolar Disorder

What chemical imbalance occurs in bipolar disorder?

Thousands of different chemicals participate in brain function and fall into different groups based on their chemical structure, mechanism of action, psychotropic effects, or where they come from in the body.


The chemicals affecting emotional states in the brain consist of three broad types of compounds: neurotransmitters, which are chemically derived from single aminoacids, the core constituents of proteins; neuropeptides, small links of amino acids that together form a protein with psychoactive effects; and hormones, chemicals made in different regions throughout the body that are released into the blood stream and also have psychoactive effects.

Neurotransmitters are chemically derived from single amino acids, the core constituents of proteins, and exist throughout the body. They are the principal actors affecting brain function, and they fall into categories based on their chemical structure. The catecholamines include dopamine and norepinephrine.

The indoleamines include serotonin. Together these compounds make up the group biogenic amines. Additionally, amino acid transmitters are located in the brain in far greater quantities than neurotransmitters.

Because amino acids are the building blocks of proteins used by all cells of the brain, it is difficult to demonstrate that any particular amino acid is a transmitter substance. Eight amino acids have been discovered that serve as transmitters, two of them the best understood in relation to emotion. These include glutamate, the brain’s major excitatory neurotransmitter, and gamma-aminobutyric acid (GABA), the brain’s major inhibitory neurotransmitter.

The biogenic amines are made within small regions of the brain known as nuclei, which are concentrated areas of nerve cell bodies that act as factories of production.

Axons from the nuclei in those areas of the brain act like highways that disseminate the neurotransmitters more widely throughout the brain. All three of the noted biogenic amines are involved in the regulation of mood.

Dopamine, for example, is implicated in the brain’s natural reward system and, therefore, is seen as pleasure generating.

Norepinephrine is linked to the hormone epinephrine, also known as adrenaline. Adrenaline is associated with all risk-taking activities that cause a “rush.” Serotonin was traditionally linked to activities involving sleep, appetite, and sexual function, better known in psychiatry as vegetative activities, but more recently has been implicated in control of mood and anxiety.

All three biogenic amines have a large body of evidence supporting their roles in mood regulation, although ongoing research is investigating the role of various other neurotransmitters in bipolar disorder as well. Where does the evidence come from? Basically, the evidence stems from four sources: primarily from our understanding of the biological and clinical effects of various psychoactive agents on the brain; secondarily from postmortem human studies; thirdly, from experimentation with animal models; and finally, from newer imaging studies that allow mapping of neurotransmitter systems throughout the brain. Some of the evidence includes the following:

• Depletion of serotonin, norepinephrine, and dopamine (by other medications such as certain antihypertensives) can precipitate depression. Patients who have successfully committed suicide by violent means have evidence of reduced serotonin levels in the central nervous system, based on postmortem analyses.

• Antidepressant medications increase the functional capacity of dopamine, serotonin, and norepinephrine to varying degrees in the brain. These medications, while effective in treating depression, can cause patients to switch into a manic state.

• Some drugs of abuse, particularly the stimulants, which increase the neurotransmitter dopamine in the brain, can trigger mania in bipolar patients and can mimic mania in non-bipolar patients.

• Some prescription medications, such as corticosteroids, used to treat various inflammatory and pulmonary diseases, can precipitate manic symptoms.

• The class of mood stabilizers known as the atypical antipsychotic medications block dopamine receptors and a subclass of serotonin receptors.

• The class of mood stabilizers known as anticonvulsant medications work to stabilize brain activity by increasing GABA and decreasing glutamate.

• Magnetic resonance spectroscopic imaging (MRSI), a form of magnetic resonance imaging (MRI) that allows clinicians to image not only anatomical structures but also physiologic functions. Concentrations of one particular metabolite were significantly higher in the right frontal white matter of bipolar patients compared with control subjects. In addition, two other metabolites were significantly lower in another area of the brain of bipolar patients compared with normal control subjects.

In depression, the biogenic amines are believed to be insufficient in quantity within the synaptic cleft, and thus proper communication to the receiving neuron does not occur. In mania, the biogenic amines are thought to be in too high a quantity and/or the neurons are too sensitive to their effects. Additionally, mania can be precipitated by sleep deprivation, strongly suggesting that the brain’s biological clock plays a role in its development. Medications used as treatment for mania, particularly the mood stabilizers known as the anticonvulsants and lithium, stabilize the neuronal cell membranes, making them less sensitized between nerves. Additionally, many medications work by increasing the amount of GABA, the brain’s major inhibitory neurotransmitter, which also makes the neurons less sensitive to stimulatory neurotransmitters.

A secondary effect occurs as well. Chronic blockade of receptors with the atypical antipsychotic medications or decreased sensitivity from anticonvulsants leads to alterations in the numbers of receptors available to receive these neurotransmitters. Think of the body as continually adjusting itself in order to maintain a proper balance: any change in the system in one direction causes a change in the other direction to balance out the relationship between the two systems.

This process is known in biology as homeostasis. Down regulation or up-regulation of receptors is a form of homeostasis that neurons perform to compensate for any change in their availability. Such regulation requires a change in production, which is not immediate, and is perhaps one reason why mood stabilizers and antidepressants have delayed effects. A balance exists among the various chemicals involved in the regulation of signals that affect mood, and therefore bipolar disorder may be viewed partly as a chemical imbalance. Balance is restored through the use of medications that either stabilize nerve cell membranes or block neurotransmitter receptors. Keep in mind that mania is more complicated and less understood than depression and the term chemical imbalance represents an overly simplistic and probably erroneous though heuristically valuable notion.

Scott’s comments:

The first time I became cognitively aware that I might have a psychological condition is as clear to me today as it was eight years ago when it happened. My wife said something to me in our kitchen that “pushed my buttons.” The feeling that came over me was one of intense rage. I could feel the adrenaline coursing through my arteries, and I felt as though there was no way to stop this sensation. I became irate, agitated, and raised my voice. I became belligerent, and couldn’t hold this outburst back. It was at that moment that I realized that I had some sort of chemical imbalance that I couldn’t control using simple “mind over matter” techniques. I was cognitively aware and helpless at the same time. This event was seminal in that I sought psychiatric treatment as a direct result of this episode.


Central nervous system - nerve cells and their support cells in the brain and spinal cord.

Antidepressant - a drug specifically marketed for and capable of relieving the symptoms of clinical depression.

Often used to treat - conditions other than depression.

Mood stabilizer - typically refers to medications for the treatment and prevention of mood swings, such as from depression to mania.

Atypical antipsychotic - a second-generation antipsychotic with a profile of targeted brain receptors that differs from the older antipsychotics, which have fewer neurological side effects and also have mood stabilizing effects.

Anticonvulsant - a drug that controls or prevents seizures.

Anticonvulsants are used in psychiatric practice to treat mania, mood instability, or other mental conditions.

Psychotropic - usually referring to pharmacological agents (medications) that, as a result of their physiological effects on the brain, lead to direct psychological effects.

Catecholamines - a class of neurotransmitters in the brain that include epinephrine, norepinephrine, and dopamine.

Norepinephrine - a neurotransmitter that is involved in the regulation of mood, arousal, and memory.

Serotonin - a neurotransmitter found in the brain and throughout the body. Serotonin is involved in mood regulation, anxiety, pain perception, appetite, sleep, sexual behavior, and impulsive behavior.

Biogenic amines - a group of compounds in the nervous system that participate in the regulation of brain activity, which includes dopamine, serotonin, and norepinephrine.

Homeostasis - the maintenance of relatively stable internal physiological conditions in the body.

Down-regulation - the reduction of receptors in a region of the brain in response to increased neurotransmitter in order to maintain homeostasis.

Up-regulation - the increase of receptors in a region of the brain in response to a reduction of neurotransmitter in order to maintain homeostasis.



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