The Biological Underpinnings of Bipolar Disorder

TMS has been around since 1985, a much longer time than most people would expect for such innovative neurotechnology. TMS does not have any known side effects and is non-invasive and painless (although at first it can be a bit uncomfortable). Patients remain awake during the procedure and are allowed to engage in any activity that does not involve head rotation. Typical treatment involves five treatments per week, lasting from half an hour to an hour, for four to seven weeks. TMS utilizes a tiny electromagnetic coil instructed by a computer to administer quick bursts of magnetic energy to the left side of the brain’s prefrontal cortex. The prefrontal cortex is involved with decision making and mood regulation, both of which are impaired in bipolar populations. TMS magnetic fields are the same strength as those created by a magnetic resonance imaging (MRI) machine. The magnetic pulses trigger the prefrontal cortex neurons to fire more rapidly and release more neurotransmitters, namely the catecholamines serotonin, dopamine and norepinephrine. TMS can also be used to treat anxiety, lack of appetite, aches and pains and the lack of energy associated with depression. There have now been 30 studies and 10 meta-analyses that have found antidepressant effects of TMS in patients with unipolar depression. In 2008, the U.S. Food and Drug Administration approved TMS for the treatment of unipolar major depression (Kim, Pesiridou & O’Reardon). When one review searched the databases of PubMed, Ovid MEDLINE, and ScienceDirect for reports concerning the TMS use in bipolar disorder, they found ten studies that supported the use of TMS for bipolar disorder (Agarkar, Mahgoub & Young, 2011). TMS treats bipolar depression by stimulating the left prefrontal cortex or inhibiting the right prefrontal cortex (Saba, Rocamora & Kalalou, 2004). However, during mania, there is decreased brain activity on the right side and increased activity on the left side. Stimulating the right side of the prefrontal cortex helps to reduce the effects of mania (Praharaj, Ram & Arora, 2009).

Agarkar, S., Mahgoub, N., & Young, R. C. (2011). Use of transcranial magnetic stimulation in bipolar disorder. The Journal of neuropsychiatry and clinical neurosciences, 23(2), E12-E13.

Kim DR, Pesiridou A, O’Reardon JP. Transcranial magnetic stimulation in the treatment of psychiatric disorders. Curr Psychiatry Reports. 2009;11:447–452.

Praharaj SK, Ram D, Arora M. Efficacy of high-frequency suprathreshold transcranial magnetic stimulation of right prefrontal cortex in bipolar mania: a randomized sham-controlled study. J Affect Disord. 2009;117:146–150.

Saba G, Rocamora J, Kalalou K, et al. Repetitive transcranial magnetic stimulation as an add-on therapy in the treatment of mania: a case series of eight patients. Psychiatr Res. 2004;128:199–202.

Lithium

Lithium has been the gold standard of bipolar medication since the 1950’s. However, lithium only works in approximately one third of patients. The side effects can be severe and include nausea, weight gain, muscle tremors, emotional numbing, weight gain and birth defects for the offspring of pregnant women. Up until recently, scientists and doctors had essentially no idea how lithium worked. A group of scientists mapped the response pathway of lithium using human induced pluripotent stem cells (hiPS), cells taken from bipolar patients and induced to behave like stem cells. A protein called CRMP2, involved in neuron signaling, was found to be inactive in bipolar patients. When lithium was added to a petri dish of hiPS cells, CRMP2 activity returned to normal. These results have been further verified by examining the brain tissue of deceased bipolar patients and finding a reduced amount of CRMP2 (MacDonald, 2017).

MacDonald, F. (2017, May 13). Finally, Scientists Think They Know How Lithium Treats Bipolar Disorder. Retrieved from https://www.sciencealert.com/finally-scientists-think-they-know-how-lithium-treats-bipolar-disorder

General Antipsychotics

Antipsychotics are used either on their own for mood stabilization or in conjunction with a mood stabilizer. They can serve as sedatives for anxiety, insomnia and agitation and irritability associated with both mania and depression. Olanzapine (Zyprexa), risperidone (Risperdol), quetiapine (Seroquel) and aripiprazole (Abilify) show more promise for treating mania. Only two antipsychotic treatments are approved for treating the depressive part of bipolar disorder: olanzapine in conjunction with fluoxetine (Zoloft) and quetiapine. The brain has a number of dopamine receptors, all labeled D1, D2, D3 and so on. Antipsychotics help relieve psychotic symptoms by reducing the signalling of D2 (Abi-Dargham et al., 2000) and by balancing D1 and D2 receptor pathways (Cazorla et al., 2014).

Abi-Dargham, A. et al. Increased baseline occupancy of D-2 receptors by dopamine in schizophrenia. Proc. Natl. Acad. Sci. USA 97, 8104–8109 (2000).

Cazorla, M. et al. Dopamine D2 receptors regulate the anatomical and functional balance of basal ganglia circuitry. Neuron 81, 153–164 (2014).

Vraylar

Vraylar is not necessarily a common medication for bipolar disorder, but it is worth mentioning because it is the least sedating out of all of the antipsychotics and is associated with the least weight gain. It is used to treat the mania associated with bipolar 1, but the FDA has not approved it yet for depression. It is a dopamine partial agonist and a dopamine regulator, so it can actually make people feel more awake, but Vraylar regulates dopamine at high levels that predispose a bipolar person to mania and keeps them from getting manic. Most antipsychotics work as dopamine antagonists, making the patient feel sleepy. It also acts as a serotonin agonist, helping to further balance mood and behavior (Kunzmann, 2019).

Kunzmann, K. (2019, January 15). Michael Thase, MD: Cariprazine and Current Bipolar Therapies. Retrieved from https://www.mdmag.com/medical-news/michael-thase-md-cariprazine-and-current-bipolar-therapies

Anti-Seizure Drugs

Some drugs originally used to treat epilepsy are now utilized to treat bipolar disorder. These drugs reduce electrical activity in the brain. These drugs include Depakote, Lamotrigine, Tegretol, Gabapentin and Topamax among others. Different anti-seizure medications are more inclined to treat different aspects of bipolar disorder. For example, Depakote and Tegretol are better at treating mania, while Lamotrigine is more effective at treating depression. Anti-seizure drugs, also known as anticonvulsants, work more rapidly than lithium (Purse, 2020).

Purse, M. (2020, February 7). How Can Anticonvulsants Help Treat Mania in Bipolar Disorder? Retrieved from https://www.verywellmind.com/anticonvulsants-for-treatment-of-mania-4006598

In addition to bipolar type 1 and bipolar type 2, bipolar disorder can be further divided into two categories: bipolar disorder with psychosis and bipolar disorder without psychosis. Many genes are currently being studied to determine their role in psychosis, including D-amino acid oxidase, group II metabotropic glutamate receptors, ZNF804A, and catechol-O-methyltransferase (COMT). The neurotransmitter dopamine, when in excess, is believed to be the underlying cause of psychosis. However, this excess in dopamine is found in psychotic patients before they are in a psychotic episode, so dopamine is more of a prerequisite of psychosis than a cause or a result of psychosis. Dopaminergic drugs, like cocaine and amphetamine, can induce psychotic symptoms, especially in schizophrenic and bipolar patients. A common symptom of psychosis is inappropriate attribution of salience to nonsalient stimuli. Alterations in dopamine in the associative striatum likely contribute to this (Winton-Brown, Fusar-Poli, Ungless & Howes, 2014). The associative striatum, the connection between the frontal and parietal associative cortices, is important for goal-directed action and behavioral flexibility. A network model has been proposed that dysfunction in a circuit that includes the associative striatum, prefrontal cortex, and thalamus is a primary trigger of psychosis (Kesby, Eyles, McGrath & Scott, 2018). Auditory hallucinations have been associated with altered connectivity between the hippocampus and the thalamus (Amad et al., 2014). During visual hallucinations, activity between the striatum, thalamus and hippocampus has been found to be increased (Silbersweig et al., 1995). Delusions have been associated with overactivity in the prefrontal cortex (Larivière et al. 2017). People with lesions in the basal ganglia and the caudate nucleus also present with hallucinations and delusions (McMurtray et al., 2014).

Amad, A. et al. The multimodal connectivity of the hippocampal complex in auditory and visual hallucinations. Mol. Psychiatry 19, 184–191 (2014).

Kesby, J. P., Eyles, D. W., McGrath, J. J., & Scott, J. G. (2018). Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience. Translational psychiatry, 8(1), 1-12.

Larivière, S. et al. Altered functional connectivity in brain networks underlying self-referential processing in delusions of reference in schizophrenia. Psychiatry Res. 263, 32–43 (2017).

Silbersweig, D. A. et al. A functional neuroanatomy of hallucinations in schizophrenia. Nature 378, 176–179 (1995).

McMurtray, A. et al. Acute Psychosis Associated with Subcortical Stroke: Comparison between Basal Ganglia and Mid-Brain Lesions. Case Rep. Neurol. Med. 2014, 428425 (2014).

Winton-Brown, T. T., Fusar-Poli, P., Ungless, M. A. & Howes, O. D. Dopaminergic basis of salience dysregulation in psychosis. Trends Neurosci. 37, 85–94 (2014).

MRI studies have found abnormalities in the brain’s prefrontal cortical areas, striatum (part of the basal ganglia, which initiate movement), and the amygdala (the emotional and fear center of the brain) in the early onset of bipolar disorder. After a number of episodes, manic and depressive, differences have been found in the cerebellar vermis (part of the cerebellum, involved in movement coordination) and lateral ventricles; these areas may be involved in the progression of the disease. Functional MRI (fMRI) studies, which trace oxygenated hemoglobin consumption in the brain, support these results. Bipolar patients may have an inactive prefrontal cortex (involved in decision making and inhibiting impulsive behavior) which may be less effective at inhibiting the limbic system, or the emotional system of the brain, which includes amygdala, anterior striatum and thalamus (Strakowski, Delbello & Adler, 2005). Adolescents with bipolar disorder exhibit smaller volumes of the cerebral cortex and amygdala, but have an enlarged putamen, another part of the basal ganglia (DelBello, Zimmerman, Mills, Getz & Strakowski, 2004).Disruptions in early development, such as in white matter connectivity and prefrontal cortex pruning, leads to decreased connectivity between the prefrontal cortex and the limbic system, especially the amygdala. It is this disconnect that is believed to onset mania (Strakowski et al., 2005). Within the limbic system, the amygdala-anterior paralimbic neural system is believed to be the most crucial to bipolar disorder (Blond, Fredericks & Blumberg, 2012). The right hemisphere of the brain has been implicated in bipolar disorder, supported by the fact that lesions cause manic symptoms and impairments in visuospatial functioning (Bearden, Hoffman & Cannon, 2001). Increased gray matter volume in the hippocampal and parahippocampal gyri may serve as an early marker for bipolar disorder (Laudouceur et al. 2008). The basal ganglia of bipolar patients have been found to be smaller. A higher number of neurons has been found in bipolar patients in the locus coeruleus, a nucleus in the pons of the brainstem that responds physiologically to stress and panic. It is part of the reticular activating system, which is a system that helps us to stay awake by producing norepinephrine and serotonin. Additionally, bipolar brains show deficits in the raphe nuclei, which is the main area of the brain that produces serotonin (Baumann & Bogerts, 2001). 

Baumann, B., & Bogerts, B. (2001). Neuroanatomical studies on bipolar disorder. The British Journal of Psychiatry, 178(S41), s142-s147.

Bearden, C. E., Hoffman, K. M., & Cannon, T. D. (2001). The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. Bipolar disorders, 3(3), 106-150.

Blond, B. N., Fredericks, C. A., & Blumberg, H. P. (2012). Functional neuroanatomy of bipolar disorder: structure, function, and connectivity in an amygdala–anterior paralimbic neural system. Bipolar disorders, 14(4), 340-355.

DelBello, M. P., Zimmerman, M. E., Mills, N. P., Getz, G. E., & Strakowski, S. M. (2004). Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorder. Bipolar disorders, 6(1), 43-52.

Ladouceur, C. D., Almeida, J. R., Birmaher, B., Axelson, D. A., Nau, S., Kalas, C., … & Phillips, M. L. (2008). Subcortical gray matter volume abnormalities in healthy bipolar offspring: potential neuroanatomical risk marker for bipolar disorder?. Journal of the American Academy of Child & Adolescent Psychiatry, 47(5), 532-539.

Strakowski, S. M., Adler, C. M., Almeida, J., Altshuler, L. L., Blumberg, H. P., Chang, K. D., … & Sussman, J. E. (2012). The functional neuroanatomy of bipolar disorder: a consensus model. Bipolar disorders, 14(4), 313-325.

Strakowski, S. M., Delbello, M. P., & Adler, C. M. (2005). The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings. Molecular psychiatry, 10(1), 105-116.

The prevailing hypothesis for the neurochemicals involved in bipolar disorder is the monoamine hypothesis, which suggests that bipolar disorder is caused by an imbalance in the neurotransmitters dopamine, serotonin and norepinephrine. This hypothesis has been supported by the relative success of selective serotonin reuptake inhibitors (SSRI’s) and selective norepinephrine reuptake inhibitors (SNRI’s). Norepinephrine levels are extremely high during mania and extremely low during depression. During mania, dopamine levels in the brain surge, and during depression, they plummet. Bipolar people have a different level of dopamine transporters, and altered availability of this transporter in the striatum, a part of the brain associated with reward, is now considered a biomarker for bipolar disorder (Anand, Barkay, Dzemidzic et al., 2011). Monoamines are not the only neurotransmitters that come into play. Alterations in excitatory amino acid transporters contribute to significantly different levels of glutamate (Rao, Kellom, Reese, Rapoport & Kim, 2012). A balance of excitatory and inhibitory neurotransmitters appears to be central to bipolar disorder. Lithium, the primary treatment for bipolar disorder, elevates levels of the inhibitory neurotransmitter, GABA, which suggests that bipolar disorder might stem from a lack of inhibition. Glutamate, an excitatory neurotransmitter, is found in higher concentrations in the bipolar brain. “Due to the role of glutamate in neurotransmission, brain energy metabolism, astrocyte function, neurotoxicity, neuroplasticity, and learning, the glutamate hypothesis of mood disorders is expected to complement and improve the prevailing monoamine hypothesis,” (Sigitova, Fišar, Hroudová, Cikánková, & Raboch, 2017). The fact that antagonists of glutamate N‐methyl‐D‐aspartate (NMDA) receptor almost immediately creates an antidepressant effect in the bipolar brain supports the glutamate hypothesis (Gerhard, Wohleb & Duman, 2016; Machado‐Vieira, Henter, & Zarate, 2015). Valproate, a common treatment for bipolar disorder, works by lowering levels of glutamate in the brain (Imperial College London, 2008). One other drug that dampens glutamate via the NMDA system is ketamine, a drug FDA-approved for major depressive disorders but is still in trial for bipolar disorder because of its potential to cause mania. Ketamine inhibits the lateral habenula, the “anti-reward system” of the brain. The lateral habenula inhibits the reward system; therefore, ketamine disinhibits the reward system. 

Anand A, Barkay G, Dzemidzic M et al. Striatal dopamine transporter availability in unmedicated bipolar disorder. Bipolar Disord. 2011; 13: 406–413.

Gerhard DM, Wohleb ES, Duman RS. Emerging treatment mechanisms for depression: Focus on glutamate and synaptic plasticity. Drug Discov. Today 2016; 21: 454–464.

Grady, S. E., Marsh, T. A., Tenhouse, A., & Klein, K. (2017). Ketamine for the treatment of major depressive disorder and bipolar depression: a review of the literature. Mental Health Clinician, 7(1), 16-23.

Imperial College London. “Chemical Signature Of Manic Depression Discovered.” ScienceDaily. ScienceDaily, 10 February 2008. <www.sciencedaily.com/releases/2008/02/080205123833.htm>.

Fifty percent of patients with bipolar disorder have a family history. In families known as multiplex families, the majority of members display the phenotype of the disorder across generations. Twin studies show that the concordance for bipolar illness is between 40 percent and 80 percent in monozygotic twins and is only 10 to 20 percent in dizygotic twins, which suggests a genetic component to the disorder. No Mendelian pattern has been discovered yet, but statistical analyses have computed patterns of polygenic inheritance.

Bipolar disorder occurs in a high incidence in the Old Order Amish community. This community is descended from a small number of immigrants who settled in Lancaster, Pennsylvania before 1750. The  community kept excellent genealogical, disease, and death records. This allowed researchers to study the chromosomes of hundreds of affected individuals and identify the specific gene (a missense variant of KCNH7) responsible for bipolar disorder in the Old Order Amish (Egeland, 1988). However, more than one gene may be  responsible for a disorder and epigenetic factors may make it difficult to ascertain the specific function of each gene. In fact, subsequent research indicated that multiple genes contribute to risk for bipolar disorder in the Old Order Amish (Georgi et al., 2014). Moreover, in the general population, bipolar disorder has been shown to be affected by multiple genes (polygenic) and affected by environmental factors (Serretti & Mandelli, 2008).

Genomewide association analysis, which identifies susceptibility genes for complex disorders, has begun to implicate specific genes for bipolar disorder, namely DGKH, CACNA1C, and ANK3. Since bipolar disorder is polygenic, large samples are necessary to find the modest effect loci that are factors in bipolar disorder (Barnett & Smoller, 2009).

Barnett, J. H., & Smoller, J. W. (2009). The genetics of bipolar disorder. Neuroscience, 164(1), 331-343.

Egeland, J. (1988). A Genetic Study of Manic-depressive Disorder among the Old Order Amish of Pennsylvania. Pharmacopsychiatry, 21(02), 74–75. doi: 10.1055/s-2007-1014651 

Georgi, B., Craig, D., Kember, R. L., Liu, W., Lindquist, I., Nasser, S., … Bućan, M. (2014). Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate. PLoS Genetics, 10(3). doi: 10.1371/journal.pgen.1004229

Serretti, A. & Mandelli, L. (2008) The genetics of bipolar disorder: genome ‘hot regions,’ genes, new potential candidates and future directions. Mol Psychiatry 13, 742–771 doi:10.1038/mp.2008.29

This website is written by Taylor Bak. Many studies have supported that depression causes cognitive impairment (Beats, Sahakian & Levy, 1996; Porter, Bourke & Gallagher, 2007). These impairments include deficits in short-term memory, verbal and visual recognition memory, spatial recognition memory, and both immediate and delayed memory recall (Murphy, & Sahakian, 2001) Clinically depressed patients perform worse on tests of executive function, including the Wisconsin Card Sorting Task (WCST) and the Tower of London test of planning ability. These tests both assess the functioning of the prefrontal cortex, an area crucial for decision making. Research has shown significant differences between people with bipolar depression and unipolar depression. Bipolar patients receive lower scores on tests of learning and verbal fluency (Wolfe, Granholm, Butters, Saunders, & Janowsky, 1987). Although it is generally recognized that mania causes functional cognitive impairments, few studies have addressed it. It is difficult to give neuropsychological tests to patients who are acutely manic. One study administered tests of attention, visuospatial function and memory to manic patients and found that half exhibited moderate to severe cognitive impairment (Taylor & Abrams, 1986). Manic patients display impaired serial list learning, and patients who have more severe mania have a worse deficit (Henry, Weingartner & Murphy, 1971). Serial list learning requires subjects to learn a list of words in order and repeat them. The authors refer to this as a “reversible learning disorder” that occurs only during mania. Additionally, manic patients are impaired on tests of pattern and spatial recognition memory and delayed visual recognition. People with bipolar disorder, like those with depression, have diminished executive functioning skills due to reduced activity in the prefrontal cortex. Bipolar patients exhibit this dysfunction even while in the euthymic, or non-manic and non-depressive state of remission, although to a lesser degree. Many neuropsychological studies have been conducted to distinguish mania from psychosis induced by schizophrenia, since the two are often confused. Manic and schizophrenic people tend to do similarly on tests of selective attention, perceptual span (which measures the region of effective vision during eye fixations while reading), and shifting attention set, which is a measure of cognitive flexibility, the ability to think about two concepts at once or shift between mental concepts smoothly. Andreasen & Powers (1974) found that overinclusive thinking, the inability to confine thoughts within the boundaries of one given topic, is more common in manic episodes than in schizophrenic episodes. Patients with schizophrenia perform more poorly than patients with bipolar disorder on tests of psychomotor speed, attention, and memory. Additionally, within-subject studies have been conducted to determine the neuropsychological differences between mania and depression. Bulbena & Berrios (1993) utilized a neuropsychological battery of tests of attention, memory, visuospatial functioning and choice reaction time. Patients performed worse than controls, but at the same level during manic and depressive states. Another study found no significant differences in intelligence (measured by the Wechsler Adult Intelligence Scale) or in tests of reading, line orientation and facial recognition (Goldberg et al., 1993). Patients in a manic state differ from patients in depressive states in that their pattern and spatial recognition memory are more impaired.

Andreasen, N. J. C., & Powers, P. S. (1974). Overinclusive thinking in mania and schizophrenia. The British Journal of Psychiatry, 125(588), 452-456.

Beats, B. C., Sahakian, B. J., & Levy, R. (1996). Cognitive performance in tests sensitive to frontal lobe dysfunction in the elderly depressed. Psychological medicine, 26(3), 591-603.

Bulbena, A., & Berrios, G. E. (1993). Cognitive function in the affective disorders: a prospective study. Psychopathology, 26(1), 6-12.

Goldberg, T. E., Gold, J. M., Greenberg, R., Griffin, S., Schulz, S. C., Pickar, D., … & Weinberger, D. R. (1993). Contrasts between patients with affective disorders and patients with schizophrenia on a neuropsychological test battery. The American Journal of Psychiatry.

Henry, G. M., Weingartner, H., & Murphy, D. L. (1971). Idiosyncratic patterns of learning and word association during mania. American Journal of Psychiatry, 128(5), 564-574.

Porter, R. J., Bourke, C., & Gallagher, P. (2007). Neuropsychological impairment in major depression: its nature, origin and clinical significance. Australian & New Zealand Journal of Psychiatry, 41(2), 115-128.

Murphy, F. C., & Sahakian, B. J. (2001). Neuropsychology of bipolar disorder. The British Journal of Psychiatry, 178(S41), s120-s127.

Taylor, M. A., & Abrams, R. (1986) Cognitive dysfunction in mania. Comprehensive Psychiatry. 27. 186-191.

Wolfe, J., Granholm, E., Butters, N., Saunders, E., & Janowsky, D. (1987). Verbal memory deficits associated with major affective disorders: a comparison of unipolar and bipolar patients. Journal of Affective Disorders, 13(1), 83-92.