Bipolar I Disorder: Pathology and Treatment Considerations

Introduction

Bipolar disorder is a highly complex condition which is less than fully understood but believed to stem from numerous genetic, developmental, and physiologic factors (Sigitova, Fišar, Hroudová, Cikánková, & Raboch, 2017). Bipolar disorder is not a single diagnosis but an umbrella term that encompasses Bipolar I, Bipolar II, cyclothymic disorder and hypomania (Sadock, Sadock, & Ruiz, 2016). This paper will focus on bipolar I disorder. In order to meet the criteria of bipolar I disorder, a patient must demonstrate three or more of the following characteristics: inflated self-esteem or grandiosity, reduced sleep needs, more talkative than usual or pressured speech, flight of ideas or racing thoughts, easily distracted, increased goal-directed activities and excessive participation in high-risk pleasurable activities.

The mood disturbance must be significant enough to impair the person’s ability to function in activities of daily living or be considered harmful to self or others. The episode may not be attributed to any other psychiatric or medical condition (Severus & Bauer, 2013). These characteristics along with the corresponding neural pathways and structural brain changes found in bipolar disorder as well as medical and psychosocial treatment options for the disorder will be explored in this paper.

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Neural Pathways in Bipolar Disorder

The three primary monoamine neurotransmitters (NTs), serotonin, dopamine and norepinephrine, are all believed to be contributors to bipolar disorder, although there are a number of others which may also play a role including brain derived neuortrophic factor (BDNF). The primary NTs are discussed here. Serotonin, believed to be responsible for sleep, energy and eating patterns, is initially synthesized by the precursor tryptophan, an amino acid, and stored in vesicles in the presynaptic neuron. Norepinephrine (NE), responsible for behavior and stress, is synthesized from the precursor amino acid tyrosine and stored the same way in vesicles in the presynaptic neuron (S. M. S. Stahl, 2013). Both NTs are released into the post-synaptic space, trigger the appropriate receptors (5-HT for serotonin and alpha-1 and beta receptors for NE). Both are also concurrently reabsorbed by synapses SERT and NET. As both serotonin and norepinephrine are believed to also be regulated by MAO-A--it breaks both SERT and NET into inactive metabolites--it is hypothesized that increased levels of MAO-A essentially take serotonin and norepinephrine out of circulation, perhaps explaining one of the malfunctions in bipolar disorder (Sigitova et al., 2017). The manifestations of this imbalance are believed to result in an inability of the brain to regulate mood, emotion, sleep, memory and executive processes but the precise mechanisms are unknown (Grande, Berk, Birmaher, & Vieta, 2016). An additional hypothesis proposes that varying levels of dopamine, crucial in emotion and pleasure, also contribute to bipolar disorder due to disruption in dopamine transporters (Sigitova et al., 2017). Dopamine is synthesized by the amino acid tyrosine via the active transport system. Within dopamine containing neurons, tyrosine is converted to dopamine. At the same time, “tyrosine hydroxylase catalyze the addition of a hydroxyl group to the meta position of tyrosine, yielding L-dopa,” (Ayano, 2016, p.2) a precursor to dopamine, norepinephrine and serotonin. Tyrosine not only acts on L-dopa but also other amino acids, including tryptophan, potentially explaining how manipulation of dopamine through medication also impacts serotonin and norepinephrine (Ayano, 2016). Dopamine suppression is implicated in depression (Ayano, 2016), and it is theorized that elevated levels of dopamine have the effect of mania (Ashok et al., 2017) potentially resulting in bipolar disorder.

In terms of structural changes, significant structural brain changes are not found consistently in bipolar disorder (Bootsman et al., 2016)⁠. However there is a theory that “neurotrophic molecules, such as brain-derived neurotrophic factor, have a vital role in signaling pathways of dendritic sprouting and neural plasticity. Dendritic spine loss has been noted in post-mortem brain tissue of patients with bipolar disorder.”(Grande et al., 2016) It is postulated that this loss potentiates the disrupted neural communication pathways but may not demonstrate physical changes on MRI.

Pharmacologic Treatment

Upon confirmation of bipolar I disorder, the first step in treatment is typically pharmacologic as bipolar disorder is typically diagnosed during a period of mania. Depending on the severity of the initial manic episode, hospitalization for stabilization may be determined to be necessary. According to Citrome, quetiapine mono-therapy or lurasidone with lithium or valproate as adjunctive are first line therapy (2014). Efficacy seems to be comparable with both. The exact method of lithium action is unknown, but it is believed to both support serotonin, norepinephrine and dopamine and one study found higher hippocampal volumes in patients with higher lithium volumes. This is believed to be neuroprotective in patients with bipolar disorder.

Quetiapine and lurasidone both: (a) block serotonin 2A receptors, resulting in enhanced dopamine release improving cognition and (b) act as a partial agonist at the 5HT1A receptor site which may help stabilize mood (S. M. Stahl, 2017). Following stabilization with medication, non-pharmacologic adjunctive therapies should be explored along with clinical follow-up with the patient every 1-2 weeks to ensure stability is indicated. Extensive education to patient, family and close friends is also indicated at this treatment point.

Non-Pharmacologic Treatment Options

In addition to pharmacologic treatment, cognitive behavioral therapy (CBT), social rhythm therapy, or lifestyle therapy should be considered. CBT has been proven effective in impacting the negative-feedback loop of self-talk as well as altering the neural pathways (amygdala and hippocampus) which reinforce and “remember” this new positive pathway. CBT would likely be of benefit in the areas of insomnia, stress reduction, anxiety and interpersonal relationships. It has proven effective in relapse prevention and should be offered to patients under medication management for BD (Shah, Grover, & Rao, 2017).

Electroconvulsive therapy (ECT) has been found to increase gray matter volume as well as hippocampal volume in the brain and is considered a third line treatment option for patients who do not tolerate or achieve good response to medication and psychotherapy alone (Dukart et al., 2014). This treatment would require a support system as the treatment requires multiple trips to the treating office and the patient is not permitted to drive home following treatment.

Finally, one might consider complementary therapies such as omega-3 fatty acids, S-adenosylmethionine (SAM-e), N-acetyl cysteine (NAC), and inositol These supplements have promising results in the treatment of bi-polar disorder with few known or documented side effects. They are active in reducing inflammation, improving catecholamine function and have a role glutathione production--all of which have been implicated in bipolar disorder (Strakowski, 2014).

Other Considerations and Follow-up Care

Patients diagnosed with bipolar disorder require multiple layers of support from both the healthcare team as well as from a social support network. Initial stabilization is essential and requires pharmacologic therapy. In the first week following any type of medication initiation, close follow-up is indicated to evaluate both side effects of medication withdrawal as well as to monitor closely any return of manic symptoms. Consideration of a patient’s insurance coverage as well as his or her ability to maintain follow-up appointments is critical when considering choice of medications as many will require ongoing monitoring of lab values (Grande et al., 2016). In the same way, socioeconomic status will impact alternative treatment options as complementary and alternative therapies such as supplements are rarely paid for by insurance. While insurance is increasingly covering ECT and TMS, there may still be significant economic burden with co-pays. Assessing a patient’s ability to monitor his or her own mood through a tool may be helpful in highlighting any early, subtle changes and is a low-cost monitoring tool. Clinic follow-up every two to three weeks though the initial transition is indicated with further spacing of visits to every three months if stable. If the patient has transportation issues, connecting by phone or video may also be an option. Medicare has, in recent years, relaxed requirements for reimbursement of tele-health services (“Telehealth Insurance Coverage,” n.d.). Annual blood work and full examination is indicated to monitor any metabolic changes as well. As the clinician considers individual or group therapy options, insurance coverage for treatment will play a role as will personal finances. Many will find the co-pays or transportation requirements prohibitive. Most communities of modest size will offer some type of reduced cost or sliding-scale group therapy option. Hospital systems are often a great resource for free or low cost support programs.

Finally, consideration of a patient’s other health conditions should also play a role in determining a care plan. A person with co-existing substance abuse disorder or chronic pain conditions, for example, would require greater support (Miller et al., 2013). Someone with profound physical disabilities will also require a higher level of home and social support as well as assistance with transportation to and from appointments. The care for a patient with the diagnosis of bipolar I disorder is ongoing and complex and will be impacted by the individual’s medical status, socioeconomic background and social support team and is expected to be a lifelong journey.

References

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2. Dukart, J., Regen, F., Kherif, F., Colla, M., Bajbouj, M., Heuser, I., … Draganski, B. (2014). Electroconvulsive therapy-induced brain plasticity determines therapeutic outcome in mood disorders. Proceedings of the National Academy of Sciences, 111(3), 1156–1161. https://doi.org/ 10.1073/pnas.1321399111
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13. Telehealth Insurance Coverage. (n.d.). Retrieved September 19, 2019, from https://www.medicare.gov/coverage/telehealth