Neurochemistry of Bipolar Disorder

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>.