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What Causes Bipolar Disorder In The Brain

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Underlying Mechanism For Cell Loss

The Brain Circuitry of Bipolar Disorder: A View from Brain Scanning Research

Activation of the HPA axis appears to play a critical role in mediatinghippocampal atrophy, as was already discussed. In addition to directly causingneuronal atrophy, stress and glucocorticoids also appear to reduce cellularresilience, thereby making certain neurons more vulnerable to other insults,such as ischemia, hypoglycemia, and excitatory aminoacid toxicity.

Integrated Neurobiology Of Bipolar Disorder

  • 1Department of Neuropsychiatry and Behavioral Sciences, University of South Carolina School of Medicine, Columbia, SC, USA
  • 2Department of Psychiatry, University of Arizona, Tucson, AZ, USA
  • 3Norton School of Family and Consumer Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ, USA

According To The National Alliance On Mental Illness 23 Million People In The United States Suffer From Bipolar Disorder

Every year, 2.9% of the U.S. population is diagnosed with bipolar disorder.1 But what is this condition? Bipolar disorder, or manic depression, is a serious brain disorder that causes extreme shifts in mood, energy, or functioning, and can range from episodes of mania to episodes of depression . These mood swings can range in severity and may last for hours, days, or months. But what causes these mood swings? How does bipolar disorder affect the brain?

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Conflict Of Interest Statement

Dr. Vladimir Maletic has served on advisory boards for Eli Lilly and Company, Lundbeck, Otsuka America Pharmaceuticals, Inc., Pamlab, Pfizer, Sunovion, Teva Pharmaceuticals, and Takeda Pharmaceuticals and as a speaker for Eli Lilly and Company, Lundbeck, Merck, Pamlab, Pfizer, Sunovion, Teva Pharmaceuticals, and Takeda Pharmaceuticals, and has prepared CME materials for NACCME and CME Incite. Dr. Charles Raison has served on advisory boards for Lilly and Pamlab and as a speaker for Pamlab and has prepared CME materials for NACCME and CME Incite.

Changes In Neuroplasticity And Neurotrophin Signaling


The role of BDNF in mood disorders has received more attention than other members of the neurotrophin family. It is involved in neuronal maturation, differentiation and survival, synaptic plasticity, and long-term memory consolidation . Furthermore, compelling preclinical evidence suggests that BDNF plays an important role in regulating the release of serotonin, glutamate, and gamma-aminobutyric acid , as well as in slow-wave sleep modulation . BDNF expression is particularly high in the cerebral cortex and hippocampus .

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Glycogen Synthase Kinase: A Common Target For Mood Stabilizers

Lithium and VPA regulate the activity of a crucial kinase that functionsas an intermediary in numerous intracellular signaling pathways, the enzymeglycogen synthase kinase-3 , suggesting the importance of this enzymein BD research . While lithium inhibits GSK-3 – a constitutively activeand a highly conserved enzyme in evolution – by direct competition with magnesiumfor a binding site, the precise mechanisms by which VPA exerts its actionis still uncertain . Other signals deactivating GSK-3 arise from insulinstimulation, developmental signals, and numerous growth factors . Thus, growth factors may bring about many of their neurotrophic/neuroprotectiveeffects, at least in part, by GSK-3 inhibition. Rapidly increasing evidencesuggests that GSK-3 also plays important roles in regulating neuroplasticityand cellular resilience. GSK-3 phosphorylates – and thereby inactivates -transcription factors and cytoskeletal proteins . Furthermore, changes in GSK-3 mediate MAP-1B phosphorylation, associated with the loss and/or unbundling of stable axonalmicrotubules. Finally, GSK-3β inhibition results in the accumulationof synapsin I, a protein involved in synaptic vesicle docking and release,at growth cone-like areas.

Bipolar Disorder And The New Psychiatry

Psychiatry still relies largely on 19th-Century diagnostic categories. These are based on clusters of symptoms rather than biological markers, and are treated with drugs discovered serendipitously several decades ago. BD typifies this unsatisfactory state of affairs. Although its name has changed , its cardinal features, and how it is assessed and treated have barely altered. An important reason for this stagnation has been the lack of any real traction on its causes and underlying biology, beyond its well-established high heritability . Although there is evidence for altered structural and functional brain connectivity , , , and changes in markers of oxidative stress , mitochondrial function , inflammation , circadian rhythms , and dopamine , it remains difficult to integrate these diverse findings, and to disentangle causative changes from those that are secondary to the disorder and its treatment.

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Bipolar Disorder Affects Brain Regions Controlling Inhibition Emotion

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Analysis of a large sample indicated widespread bilateral patterns of reduced cortical thickness in adolescents and adults with bipolar disorder.

is known to be highly heritable with individual risk depending partially on genetics. However, the underlying neurobiological mechanism of the disorder remains unclear. The prognosis for individuals with is mixed: currently approved medications are ineffective for many patients,Derrek Hibar, PhD, of the University of Southern California, Marina del Rey, and colleagues wrote.

To better understand pathophysiology of bipolar disorder, researchers assessed cortical gray matter thickness and surface area measures from brain MRI scans of 1,837 individuals with bipolar disorder and 2,582 healthy controls.

Participants with bipolar disorder exhibited thinner cortical gray matter in frontal, temporal and parietal regions of both brain hemispheres.

Bipolar disorder had the largest effect on left pars opercularis, left fusiform gyrus and left rostral middle frontal cortex.

When accounting for age at the time of MRI, longer illness duration was associated with reduced cortical thickness in frontal, medial parietal, and occipital regions.

A history of psychosis was associated with reduced cortical surface area, but mood state at time of scan was not.

Prefrontal Cortical Abnormalities In Bipolar Disorder

What is Bipolar Disorder?

Prefrontal cortical abnormalities are a common finding in bipolar disorder. Imaging studies have reported functional and structural changes in the vmPFC of adolescents and young adult bipolar patients relative to healthy controls . Dysfunction of vmPFC activity may be common to mood disorders and independent of mood state because it has been described in both unipolar and bipolar depression as well as in the context of elevated mood . The vmPFC has rich reciprocal connections with limbic formations and the hypothalamus. Together with the ACC and amygdala, the vmPFC may belong to an integrative network involved in processing emotionally relevant information, which coordinates autonomic and endocrine responses and influences behavior . Aberrant vmPFC activity in the context of bipolar illness may therefore be reflected in compromised ability to adapt to changes in emotional and social circumstances. Manic patients tend to be excessively preoccupied by hedonic interests, whereas depressed individuals demonstrate impaired emotional and endocrine homeostasis. Furthermore, endocrine disturbances are also a common feature of elevated mood states . The vmPFC is also a source of feedback regulation to monoaminergic brainstem nuclei, so its malfunction may be reflected in altered neurotransmission .

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What Happens In The Brain To Cause Bipolar Disorder

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Integration Of Neurobiological Findings

As we noted at the beginning of this review, from a neurobiological perspective, there is no such thing as bipolar disorder. Rather, it is almost certainly the case that there are many somewhat similar, but subtly different, pathological conditions that produce a final common pathway disease state that we currently diagnose as bipolarity. This heterogeneity reflected in the lack of synergy between our current diagnostic schema and our rapidly advancing scientific understanding of the condition puts a hard limit on all attempts to articulate an integrated perspective on bipolar disorder. Also posing a challenge to the integrative enterprise is the fact that nothing could be further from a static condition than bipolar disorder. Whereas, most psychiatric conditions vacillate within a single register between symptom exacerbation and various degrees of recovery, those attempting to fully understand bipolar disorder must contend with the fact that exacerbations come in two distinct flavors manias and depressions and that often these exacerbations can take any of a nearly infinite number of combinations of these two mood disturbances.

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What Does The Research Say

A 2017 found that people may experience changes in the working memory processes of update and recall both during and between episodes of bipolar disorder. This can make it hard for people to function in work or study.

A study published in 2007 found that some people who experience psychosis in bipolar disorder may have difficulty with executive functioning. This can affect their ability to plan or carry out tasks.

Other researchers have described impairment in executive functioning as a core dysfunction that some people may experience when they are between high and low phases.

People with bipolar disorder who experience psychosis are

The changes that occur with bipolar disorder may affect a persons memory, but some of the treatments for the condition can also have an impact.

What Are The Signs And Symptoms

An Overview of the Causes of Bipolar Disorder

A person with bipolar disorder will go through episodes of mania and at other times experience episodes of depression . These aren’t the normal periods of happiness and sadness that everyone experiences from time to time. Instead, the episodes are intense or severe mood swings, like a pendulum that keeps arcing higher and higher.

Symptoms of mania include:

  • anger, worry, and anxiety
  • thoughts of death or suicide

In adults, episodes of mania or depression usually last for weeks or months, although they can be shorter in length. In children and adolescents, though, these episodes can be much shorter, and a kid or teen can even go back and forth between mania and depression throughout the day.

Episodes of mania or depression may happen irregularly and follow an unpredictable pattern or they may be linked, with a manic episode always following a period of depression, or vice versa. Sometimes episodes have a seasonal pattern. Mania in the spring, for example, may be followed by depression in the winter.

Between episodes, someone with bipolar disorder usually returns to normal functioning. For some people, though, there is little or no “break period” between their cycles. These mood swing cycles can change slowly or rapidly, with rapid cycling between mania and depression being much more common in women, children, and adolescents.


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Pathohistologic Findings Associated With Bipolar Disorder

Pathohistologic research has uncovered significant cell pathology associated with bipolar disorder. It appears that all three of the glial cell families may be affected, linking the pathogenesis of the condition to abnormalities in astroglia, oligodendroglia, and microglia . Postmortem studies of bipolar patients have noted a reduction in both glial cell numbers and density . Glial alterations have been reported in the subgenual ACC, dorsolateral PFC, orbitofrontal cortex, and the amygdala of unmedicated bipolar patients . Interestingly, one study found evidence that treatment with lithium or valproate may mitigate some of the glial loss . Furthermore, a significant 29% reduction in oligodendroglia numerical density in the dorsolateral PFC white matter was detected in bipolar patients compared with controls . Evidence of diminished myelin staining in the dorsolateral PFC and reductions of S100B immune-positive oligodendrocytes in the hippocampus of bipolar subjects further extend these findings . Indeed, convergent imaging, histologic and imaging evidence indicates that oligodendroglial deficits may be the key CNS cellular abnormality in bipolar disorder .

Several studies have examined changes in monoaminergic nuclei that may affect mood regulation. Patients with bipolar disorder appear to have a higher number of noradrenergic neurons in the locus ceruleus as well as subtle structural deficits of serotonergic neurons in the dorsal raphe .

How Do Doctors Treat It

Although there’s no cure for bipolar disorder, treatment can help stabilize moods and help the person manage and control symptoms. Like other teens with long-lasting medical conditions , teens with bipolar disorder need to work closely with their doctors and other medical professionals to treat it.

This team of medical professionals, together with the teen and family, develop what is called a treatment plan. Teens with bipolar disorder will probably receive medication, such as a mood stabilizer, from a psychiatrist or other medical doctor. A psychologist or other type of counselor will provide counseling or psychotherapy for the teen and his or her family. Doctors will watch the symptoms closely and offer additional treatment advice if necessary.

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Treatment For Psychotic Disorders

The stigma surrounding psychotic disorders has changed greatly over the years. Patients went from no treatment available, to rather questionable treatment methods, to old-school medications with notable side effects.

Weve come a long way in terms of research, therapy and medication. Psychiatrists now use a combination of both science-based methods and emotional approaches . Having a sense of understanding and respect for those living with these conditions has also made recovery a real possibility for them.

You cant prevent a psychotic disorder, especially if its genetic, but you can avoid possible triggers.

Just like any physical condition, working out, eating well and limiting your substance use can play a positive role in improving your mental health.

If you or a loved ones brain does experience psychosis, you should treat it like any other part of the body and get help. With the right medication, therapy and support from your Valleywise Health community, you or your friends and family members can feel confident in getting back to a more normal life.

Chemical Imbalance In The Brain

Causes of Bipolar Disease

Bipolar disorder is widely believed to be the result of chemical imbalances in the brain.

The chemicals responsible for controlling the brain’s functions are called neurotransmitters, and include noradrenaline, serotonin and dopamine.

There’s some evidence that if there’s an imbalance in the levels of 1 or more neurotransmitters, a person may develop some symptoms of bipolar disorder.

For example, there’s evidence that episodes of mania may occur when levels of noradrenaline are too high, and episodes of depression may be the result of noradrenaline levels becoming too low.

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Cognitive Effects Of Bipolar Medications

Studies examining cognitive function and neural systems in bipolar disorder are typically confounded by medication status. It is common for patients in research studies to be maintained on mood-stabilizing medications, and many studies also include subgroups of patients receiving neuroleptics, antidepressants and sedatives. These medications may act directly to influence cognitive function in either a beneficial or detrimental manner. A number of studies have investigated the effects of lithium medication on cognition, . These studies have employed a variety of designs, cither comparing bipolar patients on and off lithium medication, comparing lithium-treated euthymic patients against, controls, or studying the effects of lithium versus placebo in healthy volunteers.- These studies have shown reliable effects on psychomotor speed, consistent, with frequent complaints of mental slowing from patients. There is also some evidence for impaired learning and memory function, but higher-level executive function and attention appear to be spared, and there is no evidence for cumulative effects of long-term treatment. A number of the neuropsychological studies in euthymic bipolar patients have also performed post-hoc analyses to examine potential confounding effects of lithium treatment- and have generally found patients receiving lithium to perform similarly to those not receiving lithium.

Reduced Gray Matter In The Brain

First, lets talk about how bipolar disorder affects gray brain matter. The central nervous system is made up of two different kinds of tissue: gray matter and white matter. The gray matter in the brain enables us to control movement, memory, and emotions. It mainly serves to process information in the brain. Structures, like axons, carry signals generated by our sensory organs and include touch, smell, sight, hearing, and taste. The gray matter sends signals to nerve cells in the central nervous system where nerve synapses, which are spaces between neurons, produce a response.

One study led by the USC Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine of USC: ENIGMA on bipolar disorder brain function showed thinning gray matter in the brains of patients with bipolar disorder. The greatest of these deficiencies were found specifically in the frontal and temporal regions of the brain. Additionally, some patients with bipolar disorder in the study also showed greater discrepancies in gray brain matter.2 When your brain matter decreases, you may experience symptoms like:

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Bipolar Psychosis And The Brain

It’s impossible to separate the physical brain from the neurochemicals in the brain, but there are actually structural differences in the brain of people who experience psychosis. There can be a chronic shut down of the frontal lobes and there is a particular part of the limbic system called the where the dopamine system is especially hyperactive. Antipsychotic medications work by blocking dopamine in this area. The limbic system, the emotional part of the brain, is also central to the causes and ultimately treatment of bipolar psychosis. Brain research into this area is vital as new medications and other treatments are based on new research. In other words, if we do find out exactly where psychosis resides in the brain and specifically what chemicals are affected, medications can be much more targeted.

APA ReferenceFast, J. . What Causes Psychosis? Psychosis and the Brain, HealthyPlace. Retrieved on 2021, October 16 from

Living With Bipolar Disorder

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Teens normally face ups and downs with school, family, work, and friends. Dealing with bipolar disorder at the same time is a very difficult challenge. One 16-year-old reader who was diagnosed with bipolar disorder at 14 wrote to us about the experience:

“I had mood swings that were the worst anyone could have ever seen. My poor parents thought I hated them, but really I was sick and didn’t even realize it. But now I am on medications for my disorder and I live a pretty normal life. My family and friends support me, and they, along with my therapist, have helped me get to the point where I am today. I just want other teens to know that even though it is hard at times to be bipolar, things will get better.”

If you’ve been diagnosed with bipolar disorder, taking your medications as prescribed, reporting any changes in how you feel or function, and participating in therapy will be key to living a successful life. In addition to treatment, making a few lifestyle changes, such as reducing stress, eating well, and getting enough sleep and exercise can help someone who is living with the condition. And many teens find it helps to join a support network such as a local support group for people with bipolar disorder.

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