A 72-year-old woman with recurrent manic episodes following thyroidectomy

Vol 9 #4

Soe H. Thein¹, MD

Caroline Giroux², MD

Author information

1.  PGY-2, Psychiatry resident, Department of Psychiatry and Behavioral Sciences, UC Davis Health System, Sacramento, CA, USA
2.  Associate Clinical Professor, Psychiatrist, Department of Psychiatry and Behavioral Sciences, UC Davis Health System, Sacramento, CA, USA

Corresponding author: [email protected]

Abstract

Bipolar disorder is a disease of the young adult, with the peak of onset between the ages of 20 and 29. Late-onset bipolar disorder constitutes approximately 10 percent of bipolar cases and is characterized by the onset of the first manic episode after 50 years of age. There is less familial risk, but higher rates of medical and neurological comorbidities associated with late-onset bipolar disorder, suggesting that secondary manias are common within the subtype. Differentiating late-onset bipolar from secondary mania in the geriatric population can be challenging, given ongoing medical comorbidities. To highlight this point, we present the diagnostic dilemma of a 72-year-old woman with no previous personal or family history of bipolar disorder who developed recurrent mania four years after post-surgical hypothyroidism. A thorough medical workup revealed no evidence of organic insults temporally close to her mania. We hypothesized that her presentation is more consistent with late-onset bipolar disorder, in which her pre-existing genetic vulnerabilities and risk factors for bipolar disorder may be precipitated by her increasing medical comorbidities. We further argued that distinguishing late-onset bipolar disorder from secondary mania may be clinically relevant, as the former may require maintenance therapy to prevent relapse. Therefore, outpatient psychiatry referral is warranted in suspected cases of late-onset bipolar disorder for close monitoring.

Introduction

Bipolar disorder is a chronic mental illness that typically starts in early adulthood. The distribution of age of onset is unimodal, with a peak between the ages of 20 and 29 years (Depp & Jeste, 2004). It is estimated that 90% of the patients experienced their first episode by the age of 50 (Vasudev & Thomas, 2010). Approximately 10% of bipolar disorders had mania after 50 years old and are typically characterized as late-onset (Vasudev & Thomas, 2010). Recent evidence suggests that late-onset bipolar disorder may be distinct from its early-onset counterpart. One main difference appears to be the influence of genetics on the disease expression. Early-onset bipolar disorder is considered to be highly hereditary (Craddock & Jones, 2019). The concordance rates for bipolar disorder in twin studies has been estimated to be as high as 70% (Smoller & Finn, 2003). On the contrary, late-onset bipolar is often associated with less familial risk and a higher rate of medical and neurological comorbidities (Depp & Jeste, 2004; Vasudev & Thomas, 2010). Studies have shown that up to 43% of the patients with late-onset bipolar disorder are found to have concomitant neurological conditions (Benazzi, 2001; Depp & Jeste, 2004; Himmelhoch, Neil, May, Fuchs, & Licata, 1980; Mei-Tal & Meyers, 1985; Shulman, 1999). Given such a high prevalence of comorbidities, there is an ongoing debate about whether late-onset bipolar disorder is distinct from mania due to organic causes (Azorin, Kaladjian, Adida, & Fakra, 2012). Thus, before diagnosing late-onset bipolar disorder, a complete medical workup is critical to rule out reversible secondary causes. However, as medical conditions become more chronic and complex with the aging population, differentiating late-onset bipolar from secondary mania becomes increasingly difficult. To highlight this diagnostic challenge, we present the case of a 72-year-old woman with no previous personal or family psychiatric history who developed recurrent mania four years after post-surgical hypothyroidism following resection for multi-nodular goiter.

The Case

Ms. A was a 72-year-old patient with a past psychiatric history of recurrent unspecified mania and past medical history of post-surgical hypothyroidism, transferred from the Jail Psychiatric Services (JPS) to our emergency department on an involuntary psychiatric hold upon bailout. In late December 2019, the patient bought $500 worth of food from a local restaurant and called the police department to help distribute to the homeless. Upon arrival, the officer found the patient to be talking nonsensically and agitated. Ms. A was charged with assaulting a police officer and resisting arrest and subsequently admitted to the Jail Psychiatric Services (JPS) on an involuntary psychiatric hold.

Per records, her initial mental status at the JPS revealed an older woman with significant generalized alopecia. She was wearing a blanket like a toga and a tape-wrapped across her forehead with random letters and numbers written in a black marker. She was irritable. Her thought process was challenging to follow, as she ranted tangential stories of prior careers. There were no suicidal and homicidal ideation or auditory and visual hallucinations. She was subsequently diagnosed with mania and started on psychiatric medications along with Levothyroxine 88 mcg oral dose for her hypothyroidism. She received multiple antipsychotics trials, including Olanzapine Aripiprazole, Haloperidol, and mood stabilizers, such as Lithium and Valproate acid. The patient ultimately responded well to Aripiprazole 20mg PO QAM and Lithium 600mg PO QAM. After 29 days of treatment, she was released from custody on bail. However, given the concerns of ongoing mania, the JPS transferred the patient to our emergency department for further treatment.

In our ED, her mental status exam showed significant improvement compared to the Jail Psychiatric Services intake. She was calm but perseverated on her discharge. Her speech and the thought process were unremarkable. Her mood was euthymic with congruent affect. There were no suicidal, homicidal ideations and no auditory or visual hallucinations. She minimized her recent arrest and reinforced her desire to get discharged. Her insight into mental illness was limited as she denied the involvement of manic episodes in her arrests. Her judgment was also limited due to her reluctance to take medications upon discharge.

History of multiple arrests and hospitalizations

According to her son and a close friend, she started experiencing recurrent manic episodes after her thyroidectomy in 2008. Her first manic episode with psychotic features occurred in 2012. In 2015, she experienced another manic episode. Police found the patient yelling while breaking glasses and dishes in her hotel room. They placed her on an involuntary psychiatric hold for inability to care for herself and subsequently admitted her to the Jail Psychiatric Services. In 2018, the police brought her into the ED from a clinic for disorganized behaviors. At the clinic, she was irritable and yelling out racial slurs with her pants down. She was again placed on an involuntary psychiatric hold.

Despite recurrent manic episodes, she has been resistant to seeing a psychiatrist and taking psychotropic medications. Her primary care physician has offered psychiatry referrals and medications, but the patient refused. She reported seeing a psychologist twice a week in the past. She denied a history of depression, suicide attempts, self-harm behaviors. She further denied emotional, physical, and sexual trauma but endorsed growing up with a mother with depression and alcohol use disorder.

Medical History

Ms. A’s medical history includes obesity, obstructive sleep apnea, a history of benign multi-nodular goiter with surgical resection in 2008, post-surgical hypothyroidism, hyperlipidemia, paroxysmal atrial fibrillation, alpha thalassemia trait, and osteoarthritis of the right knee.

Medications

The patient’s home medications included Levothyroxine 88 mcg daily morning, Simvastatin 10 mg daily at bedtime, Vitamin E 2000 unit once a day.

Social History

The patient currently lives alone in her own house. She was never married but had a son, whom she kept in touch with regularly. She had relatively high psychosocial functioning before her first manic episode in 2012. She finished college and worked as an urban planning consultant until she retired in 2010. She has a fair social support system, consisting of friends and family members. One of her lifelong friends described her as “pleasant” and “friendly.”

Substance Use History

The patient denied a history or active use of tobacco, marijuana, alcohol, or other recreational drugs, including methamphetamine, heroin, or cocaine. Her urine drug screen was consistently negative for all her hospital encounters.

Family History

The patient denied a family history of bipolar disorder or psychotic disorders but endorsed alcohol use disorder and depression in her mother.

Vitals

Blood pressure: 134/64

Pulse: 79

Respiratory Rate: 18

Oxygen Saturation: 100%, at room air

BMI: 36.1

Physical Exam

Generally, the patient appeared as an older woman, not in acute distress. The head and neck exam showed generalized alopecia with a hypopigmented rash with some crusting at the frontal and vertex scalp. The heart exam was a regular rate and rhythm without any murmurs. Lungs were clear to auscultation bilaterally. The abdomen was soft, non-tender to palpation. The patient was alert, and there were no focal neurological deficits. Montreal Cognitive Assessment (MoCA) was 23/ 30, with a deficit in attention and delayed recall.

Workup

Her TSH was elevated at 28.44, but free T4 was unremarkable at 0.73. The complete blood count showed chronic microcytic anemia with Hgb of 11.9 g/dL, MCV 73.6 fL, RDW 15.9%. The basic metabolic panel and the hepatic function tests were unremarkable. Other labs, including HIV, syphilis screen, Vitamin B12, folate, were within normal limits. The urine drug screen was negative for substances of abuse, and the plasma ethanol level was negative. Her brain MRI without the contrast showed no evidence of ischemic stroke, hemorrhage, or mass. However, it revealed minimally prominent ventricles and extra-axial CSF spaces, suggesting parenchymal volume loss versus normal pressure hydrocephalus. We deferred lumbar puncture, given low suspicion for meningitis or acute encephalitis due to chronicity and episodic nature of her manic episodes. Upon discharge, the patient received an outpatient workup for her alopecia and hypopigmented scaly rash on the scalp’s frontal and vertex area. The punch biopsy of the area showed discoid lupus erythematosus. The follow-up workup for the systemic lupus erythematosus, anti-nuclear ab, anti-smith ab, anti-SSA ab, anti-SSB ab, dsDNA IgG Ab, Sm/RNP IgG Ab was negative.

Treatment and follow-up

We resumed Aripiprazole 20mg QAM for Ms. A, given her favorable response and tolerability at the JPS, but discontinued Lithium due to her hypothyroidism and age. The patient responded to the medication well and was discharged after two days in the ED. Despite the recent manic episode, Ms. A continued to have limited insight into her decompensation. She was reluctant to take psychotropic medications or follow-up with outpatient psychiatry.

We reached out to the patient’s PCP, who is also within our hospital system, to coordinate continued workup for her mania and psychiatric care referral. With the patient’s consent, we contacted the patient’s son for a family meeting for discharge planning and psychoeducation, focusing on the importance of medication adherence and psychiatric follow-up. Although frustrated with his mother’s recurrent mania, the son was more motivated to be present in her care. The patient’s PCP helped coordinate the outpatient case management service for the patient, ultimately helping her establish a psychiatric appointment.

Discussion

Ms. A had no personal or family psychiatric history and had a relatively high premorbid psychosocial functioning before her recurrent manic episodes. Her psychiatric symptoms appeared to emerge in 2012, four years after her thyroidectomy in 2008. She was around 65 years old at the time of her first documented manic episode. Her case presents a diagnostic challenge in differentiating between late-onset bipolar disorder from mania due to organic causes in an elderly patient, given her ongoing medical comorbidities.

Because late-onset bipolar disorder is relatively rare, we initially focused on ruling out potential secondary causes of mania. The patient’s MRI of the brain without contrast showed parenchymal volume loss and minimally dilated ventricles, raising some concern for the NPH. Although extremely rare, there are cases of NPH causing mania (Kwentus & Hart, 1987; Lee & Chou, 2011). However, the diagnosis of NPH is unlikely in the absence of urinary incontinence, ataxia, or dementia. The patient’s brain imaging finding is likely secondary to age-related brain loss or the increased ventricles-to-brain ratio often found in bipolar patients (Broadhead & Jacoby, 1990; Young, Nambudiri, Jain, De Asis, & Alexopoulos, 1999). The patient’s MoCA score of 23 suggests mild cognitive impairment. Pseudodementia is a well-described presentation of the late-onset bipolar disorder and can help explain the patient’s mild cognitive impairment detected on MoCA (Banga et al., 2013). It would be beneficial to follow the patient’s cognitive status longitudinally to see any improvements upon resolution of her mania and determine if the noted deficits were attributable to her acute mania.

Given her ongoing challenge with maintaining the euthyroid state, we further examined the possibility of acute hypothyroidism-induced mania. Interestingly, our lab work and thorough chart review revealed that Ms. A’s manic episodes could occur with various thyroid function states. For instance, the patient was not in an acute hypothyroid state on her presentation to our ED, as evident by her high TSH and standard free T4. The mismatch between TSH and T4 level may reflect subclinical hypothyroidism state or acute treatment of her hypothyroidism, as TSH typically takes up to 6 weeks to normalize (Chakera, Pearce, & Vaidya, 2012). The patient could have been in an acute hypothyroid state during her manic episode, and recent treatment with levothyroxine in the JPS may have normalized her T4 level. However, during her 2015 manic episode, she was in an acute hypothyroid state, as reflected by her high TSH and low T4. Interestingly, during her ED visit in 2018 for manic, she was euthyroid. Given various thyroid states (including euthyroid) in conjunction with her manic episodes, an acute hypothyroid state does not appear to be necessary to precipitate her manic state.

Another hypothesis is that rather than a cross-sectional thyroid hormone level, the degree of hormonal fluctuation is responsible for her mania, especially given the patient’s ongoing TSH fluctuations. The central nervous system is particularly sensitive to changes in thyroid hormones (Bauer, Heinz, & Whybrow, 2002).There are cases where acute alterations in thyroid function causing mania (Brownlie, Rae, Walshe, & Wells, 2000; Iga, Taniguchi, & Ohmori, 2005; Irwin, Ellis, & Delahunt, 1997). Ms. A similarly has had recurrent fluctuating TSH levels, despite a trial of multiple thyroid formulations, including Cytomel, Armour, and Synthroid. Further workup was done to rule out possible organic causes of thyroid level fluctuations. The outpatient endocrinology workup for malabsorption, including Celiac disease, was unremarkable (Gliadin IgA negative, Gliadin IgG negative, Tissue Transglut IgA negative, Tissue Transglut negative). Thyroid autoimmune workup, with antibodies to thyroid peroxidase antibody (TPO) and thyroid-stimulating immunoglobulins (TSI), was negative. Ultimately, we do not see any overt pathologies that explain the patient’s fluctuations in thyroid levels, except a possibility of non-consistent medication adherence. Per her PCP, the patient may have ongoing challenge with taking her thyroid medication regimen as prescribed.

A definitive diagnosis of mania secondary to fluctuations in thyroid hormones would require following the patient over an extended period of medication adherence to see if the stable thyroid function is noticed along with the absence of recurrence of psychiatric symptoms. Given the lack of such longitudinal data, we were unable to identify definitive organic insults temporally close to Ms. A’s manic episodes. Thus, Ms. A’s case poses a diagnostic dilemma between late-onset bipolar disorder and secondary mania. Do we characterize her illness as the former, given no relationship between mania and acute perturbations? Is the secondary mania a better diagnosis as it captures the involvement of her medical conditions? We felt that neither diagnosis appears to sufficiently capture the totality of Ms. A’s narrative and complexity of the pathogenesis of the bipolar disorder in expression of her mania.

Recent advancements in neuroscience revealed that development of bipolar disorder involves multiple interconnected processes, such as genetics, neurodevelopmental course, neurotransmitter signal transduction, and systemic inflammation (Sigitova, Fišar, Hroudová, Cikánková, & Raboch, 2017). Given such intricacy, it is reasonable that multiple pathophysiological processes can converge on the final common pathway responsible for the clinical expression of mania (Krauthammer & Klerman, 1978). Thus, rather than being a direct consequence of an organic process, late-onset bipolar disorder may be conceptualized as an expression of pre-existing genetic vulnerabilities and risk factors, coincidentally precipitated by multiple triggers, such as increasing chronic medical conditions or psychosocial stressors (Azorin et al., 2012). Ms. A has genetic susceptibility as evident by depression in a first-degree relative, and bipolar risk factors, such as adverse childhood experience and obesity (Etain, Henry, Bellivier, Mathieu, & Leboyer, 2008; Zhao, Okusaga, Quevedo, Soares, & Teixeira, 2016). We hypothesized that her fluctuating thyroid state may have exacerbated her suboptimal medical and neurological reserve and ultimately expressed the pre-existing vulnerabilities into late-onset bipolar disorder. In other words, Ms. A’s attenuated genetic and predisposing factors, which may otherwise remain dormant, appear to have been expressed subsequently to an accumulation of sufficient precipitants.

The phenomenology of late-onset bipolar disorder, where the first manic episode distantly following a significant stressor, has previously described. DeKay and Matuszak have reported a 68-year-old woman with no previous personal or family history of bipolar disorder who developed recurrent mania six-weeks after the course of her chemotherapy treatment for non-small cell lung cancer (Dekay & Matuszak, 2011). Even after remission of her lung cancer, she continued to experience mania and ultimately required maintenance antipsychotic treatment. Similar to ours, there were no acute insults closely associated with each manic episode, except that a significant medical event occurred temporally distant to the onset of first mania. The added stress from lung cancer and its chemotherapy could have exacerbated the pre-existing medical and psychiatric susceptibility enough to express their late-onset bipolar disorder. The model also explains why she continues to experience recurrent manic episodes even after remission from lung cancer and discontinuation of chemotherapy – a clinical course unlikely in a secondary mania.

The formulation of late-onset bipolar disorder as the product of the interaction of heterogeneous factors, an entity distinct from secondary manias, may be clinically relevant. First, the fact that the patient does not have a family history of bipolar disorder should not lower the suspicion for the diagnosis of late-onset bipolar, especially in the absence of identifiable secondary mania. The presence of even unipolar depression in first-degree relatives appears to serve as the subthreshold genetic vulnerability that can manifest as late-onset mania when triggered by various factors (Azorin et al., 2012). Second, unlike secondary manias, which often remit altogether after fixing reversible causes, late-onset bipolar disorder may require maintenance treatment (National Institute for Health and Care Excellence, 2020; Shulman et al., 2019). Recurrent risk of bipolar disorder remains constant beyond 70 years of age (Angst, Gamma, Sellaro, Lavori, & Zhang, 2003). Multiple studies have further suggested that without treatment, approximately 20% of geriatric patients may experience recurrence of mood episodes within one-year period (Al Jurdi et al., 2008; Oostervink, Boomsma, & Nolen, 2009). Given a sizable risk of relapse in late-onset bipolar disorder, outpatient psychiatry referral is warranted for close monitoring in suspected cases.

In Ms. A’s case, where the time and resources are limited by expiration of her involuntary psychiatric hold and the ED setting, outpatient psychiatry referral is even more paramount for continued evaluation and care. Thus, after ruling out common secondary causes, we focused on care coordination with her PCP emphasizing the need for maintenance therapy, linkage with community resources and psychoeducation on diagnosis and the importance of psychiatric follow-up to minimize the risk of relapse. Upon discharge, Ms. A was ultimately able to establish psychiatric care with assistance from outpatient case management service coordinated by her PCP. She remains in remission on Aripiprazole monotherapy, as of writing this paper.

References

Al Jurdi, R. K., Marangell, L. B., Petersen, N. J., Martinez, M., Gyulai, L., & Sajatovic, M. (2008). Prescription patterns of psychotropic medications in elderly compared with younger participants who achieved a “recovered” status in the systematic treatment enhancement program for bipolar disorder. American Journal of Geriatric Psychiatry. https://doi.org/10.1097/JGP.0b013e318187135f

Angst, J., Gamma, A., Sellaro, R., Lavori, P. W., & Zhang, H. (2003). Recurrence of bipolar disorders and major depression: A life-long perspective. European Archives of Psychiatry and Clinical Neuroscience. https://doi.org/10.1007/s00406-003-0437-2

Azorin, J. M., Kaladjian, A., Adida, M., & Fakra, E. (2012). Late-onset Bipolar Illness: The Geriatric Bipolar Type VI. CNS Neuroscience and Therapeutics. https://doi.org/10.1111/j.1755-5949.2011.00255.x

Banga, A., Gyurmey, T., Matuskey, D., Connor, D. F., Kaplan, R. F., & Steffens, D. C. (2013). Late-life onset bipolar disorder presenting as a case of pseudo-dementia: A case discussion and review of literature. Yale Journal of Biology and Medicine.

Bauer, M., Heinz, A., & Whybrow, P. C. (2002). Thyroid hormones, serotonin and mood: Of synergy and significance in the adult brain. Molecular Psychiatry. https://doi.org/10.1038/sj.mp.4000963

Benazzi, F. (2001). Bipolar II depression in late life: Prevalence and clinical features in 525 depressed outpatients. Journal of Affective Disorders. https://doi.org/10.1016/S0165-0327(99)00038-5

Broadhead, J., & Jacoby, R. (1990). Mania in old age: A First Prospective Study. International Journal of Geriatric Psychiatry. https://doi.org/10.1002/gps.930050403

Brownlie, B. E. W., Rae, A. M., Walshe, J. W. B., & Wells, J. E. (2000). Psychoses associated with thyrotoxicosis – “thyrotoxic psychosis.” A report of 18 cases, with statistical analysis of incidence. European Journal of Endocrinology. https://doi.org/10.1530/eje.0.1420438

Chakera, A. J., Pearce, S. H. S., & Vaidya, B. (2012). Treatment for primary hypothyroidism: Current approaches and future possibilities. Drug Design, Development and Therapy. https://doi.org/10.2147/DDDT.S12894

Craddock, N., & Jones, I. (2019). Genetics of bipolar disorder. In Bipolar Disorder: The Science of Mental Health. https://doi.org/10.4324/9781315054308-4

Dekay, J. W., & Matuszak, J. (2011). A 68-year-old woman with lung cancer and late-onset bipolar disorder. Psychiatric Annals. https://doi.org/10.3928/00485713-20110425-04

Depp, C. A., & Jeste, D. V. (2004). Bipolar disorder in older adults: A critical review. Bipolar Disorders. https://doi.org/10.1111/j.1399-5618.2004.00139.x

Etain, B., Henry, C., Bellivier, F., Mathieu, F., & Leboyer, M. (2008). Beyond genetics: Childhood affective trauma in bipolar disorder. Bipolar Disorders. https://doi.org/10.1111/j.1399-5618.2008.00635.x

Himmelhoch, J. M., Neil, J. F., May, S. J., Fuchs, C. Z., & Licata, S. M. (1980). Age, dementia, dyskinesias, and lithium response. American Journal of Psychiatry. https://doi.org/10.1176/ajp.137.8.941

Iga, J. I., Taniguchi, T., & Ohmori, T. (2005). Mood swing from severe depression to mania following acute alteration of thyroid status [1]. General Hospital Psychiatry. https://doi.org/10.1016/j.genhosppsych.2005.05.008

Irwin, R., Ellis, P. M., & Delahunt, J. (1997). Psychosis following acute alteration of thyroid status. Australian and New Zealand Journal of Psychiatry. https://doi.org/10.3109/00048679709062692

Krauthammer, C., & Klerman, G. L. (1978). Secondary Mania: Manic Syndromes Associated with Antecedent Physical Illness or Drugs. Archives of General Psychiatry. https://doi.org/10.1001/archpsyc.1978.01770350059005

Kwentus, J. A., & Hart, R. P. (1987). Normal pressure hydrocephalus presenting as mania. Journal of Nervous and Mental Disease. https://doi.org/10.1097/00005053-198708000-00010

Lee, C. Y., & Chou, Y. H. (2011). Aripiprazole in treating a manic episode associated with hydrocephalus: A case report. Primary Care Companion to the Journal of Clinical Psychiatry. https://doi.org/10.4088/PCC.10l01018yel

Mei-Tal, V., & Meyers, B. S. (1985). Empirical study on an inpatient psychogeriatric unit: Diagnostic complexities. International Journal of Psychiatry in Medicine. https://doi.org/10.2190/apug-89n0-x5f6-6032

National Institute for Health and Care Excellence. (2020). Bipolar disorder: assessment and management. Australian Family Physician.

Oostervink, F., Boomsma, M. M., & Nolen, W. A. (2009). Bipolar disorder in the elderly; different effects of age and of age of onset. Journal of Affective Disorders. https://doi.org/10.1016/j.jad.2008.11.012

Shulman, K. I. (1999). Bipolar disorder in old age. Canadian Family Physician. https://doi.org/10.1007/0-306-47521-9_8

Shulman, K. I., Almeida, O. P., Herrmann, N., Schaffer, A., Strejilevich, S. A., Paternoster, C., … Sajatovic, M. (2019). Delphi survey of maintenance lithium treatment in older adults with bipolar disorder: An ISBD task force report. Bipolar Disorders. https://doi.org/10.1111/bdi.12714

Sigitova, E., Fišar, Z., Hroudová, J., Cikánková, T., & Raboch, J. (2017). Biological hypotheses and biomarkers of bipolar disorder. Psychiatry and Clinical Neurosciences. https://doi.org/10.1111/pcn.12476

Smoller, J. W., & Finn, C. T. (2003). Family, Twin, and Adoption Studies of Bipolar Disorder. American Journal of Medical Genetics – Seminars in Medical Genetics. https://doi.org/10.1002/ajmg.c.20013

Vasudev, A., & Thomas, A. (2010). “Bipolar disorder” in the elderly: What’s in a name? Maturitas. https://doi.org/10.1016/j.maturitas.2010.02.013

Young, R. C., Nambudiri, D. E., Jain, H., De Asis, J. M., & Alexopoulos, G. S. (1999). Brain computed tomography in geriatric manic disorder. Biological Psychiatry. https://doi.org/10.1016/S0006-3223(98)00201-7

Zhao, Z., Okusaga, O. O., Quevedo, J., Soares, J. C., & Teixeira, A. L. (2016). The potential association between obesity and bipolar disorder: A meta-analysis. Journal of Affective Disorders. https://doi.org/10.1016/j.jad.2016.05.059