Patient Case #1: 27-Year-Old Woman With Bipolar Disorder
- Theresa Cerulli, MD
- Tina Matthews-Hayes, DNP, FNP, PMHNP
Custom Around the Practice Video Series
Experts in psychiatry review the case of a 27-year-old woman who presents for evaluation of a complex depressive disorder.
EP: 1 . Patient Case #1: 27-Year-Old Woman With Bipolar Disorder
Ep: 2 . clinical significance of bipolar disorder, ep: 3 . clinical impressions from patient case #1, ep: 4 . diagnosis of bipolar disorder, ep: 5 . treatment options for bipolar disorder, ep: 6 . patient case #2: 47-year-old man with treatment resistant depression (trd), ep: 7 . patient case #2 continued: novel second-generation antipsychotics, ep: 8 . role of telemedicine in bipolar disorder.
Michael E. Thase, MD : Hello and welcome to this Psychiatric Times™ Around the Practice , “Identification and Management of Bipolar Disorder. ”I’m Michael Thase, professor of psychiatry at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, Pennsylvania.
Joining me today are: Dr Gustavo Alva, the medical director of ATP Clinical Research in Costa Mesa, California; Dr Theresa Cerulli, the medical director of Cerulli and Associates in North Andover, Massachusetts; and Dr Tina Matthew-Hayes, a dual-certified nurse practitioner at Western PA Behavioral Health Resources in West Mifflin, Pennsylvania.
Today we are going to highlight challenges with identifying bipolar disorder, discuss strategies for optimizing treatment, comment on telehealth utilization, and walk through 2 interesting patient cases. We’ll also involve our audience by using several polling questions, and these results will be shared after the program.
Without further ado, welcome and let’s begin. Here’s our first polling question. What percentage of your patients with bipolar disorder have 1 or more co-occurring psychiatric condition? a. 10%, b. 10%-30%, c. 30%-50%, d. 50%-70%, or e. more than 70%.
Now, here’s our second polling question. What percentage of your referred patients with bipolar disorder were initially misdiagnosed? Would you say a. less than 10%, b. 10%-30%, c. 30%-50%, d. more than 50%, up to 70%, or e. greater than 70%.
We’re going to go ahead to patient case No. 1. This is a 27-year-old woman who’s presented for evaluation of a complex depressive syndrome. She has not benefitted from 2 recent trials of antidepressants—sertraline and escitalopram. This is her third lifetime depressive episode. It began back in the fall, and she described the episode as occurring right “out of the blue.” Further discussion revealed, however, that she had talked with several confidantes about her problems and that she realized she had been disappointed and frustrated for being passed over unfairly for a promotion at work. She had also been saddened by the unusually early death of her favorite aunt.
Now, our patient has a past history of ADHD [attention-deficit/hyperactivity disorder], which was recognized when she was in middle school and for which she took methylphenidate for adolescence and much of her young adult life. As she was wrapping up with college, she decided that this medication sometimes disrupted her sleep and gave her an irritable edge, and decided that she might be better off not taking it. Her medical history was unremarkable. She is taking escitalopram at the time of our initial evaluation, and the dose was just reduced by her PCP [primary care physician]from 20 mg to 10 mg because she subjectively thought the medicine might actually be making her worse.
On the day of her first visit, we get a PHQ-9 [9-item Patient Health Questionnaire]. The score is 16, which is in the moderate depression range. She filled out the MDQ [Mood Disorder Questionnaire] and scored a whopping 10, which is not the highest possible score but it is higher than 95% of people who take this inventory.
At the time of our interview, our patient tells us that her No. 1 symptom is her low mood and her ease to tears. In fact, she was tearful during the interview. She also reports that her normal trouble concentrating, attributable to the ADHD, is actually substantially worse. Additionally, in contrast to her usual diet, she has a tendency to overeat and may have gained as much as 5 kg over the last 4 months. She reports an irregular sleep cycle and tends to have periods of hypersomnolence, especially on the weekends, and then days on end where she might sleep only 4 hours a night despite feeling tired.
Upon examination, her mood is positively reactive, and by that I mean she can lift her spirits in conversation, show some preserved sense of humor, and does not appear as severely depressed as she subjectively describes. Furthermore, she would say that in contrast to other times in her life when she’s been depressed, that she’s actually had no loss of libido, and in fact her libido might even be somewhat increased. Over the last month or so, she’s had several uncharacteristic casual hook-ups.
So the differential diagnosis for this patient included major depressive disorder, recurrent unipolar with mixed features, versus bipolar II disorder, with an antecedent history of ADHD. I think the high MDQ score and recurrent threshold level of mixed symptoms within a diagnosable depressive episode certainly increase the chances that this patient’s illness should be thought of on the bipolar spectrum. Of course, this formulation is strengthened by the fact that she has an early age of onset of recurrent depression, that her current episode, despite having mixed features, has reverse vegetative features as well. We also have the observation that antidepressant therapy has seemed to make her condition worse, not better.
Transcript Edited for Clarity
Dr. Thase is a professor of psychiatry at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, Pennsylvania.
Dr. Alva is the medical director of ATP Clinical Research in Costa Mesa, California.
Dr. Cerulli is the medical director of Cerulli and Associates in Andover, Massachusetts.
Dr. Tina Matthew-Hayes is a dual certified nurse practitioner at Western PA Behavioral Health Resources in West Mifflin, Pennsylvania.
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Bipolar Disorder, Case Study Example
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The diagnosis is bipolar 1 disorder because based on DMS-5 criteria, the patient had a mania episode manic due to the rapid cycling and mixed features. The diagnosis is based on the features that Ingram presented of mania being expansive, irritable and elevated. She is tearful, irritable, have insomnia, manic and depressive mood swings (Carvalho et al., 2020). There is a history of the increasing treatment of recurrent major bouts of depression without success. Based on the presentation, Ingram has a rapid, pressured speech and is difficult to interpret due to incoherence. Her behavior of creating a get-rich-quick investment blog which is against the rules of the company. The act proves poor judgment as she could have lost her job. Hence, she is not goal-oriented.
Hyper alertness, insomnia, dysphoria, careless appearance, outfit, and anger are more presentations to qualify for bipolar disorder. Ingram also presents delusions of grandeur as she believes that she can uniquely predict the stock exchange market by herself. She has unconfused and glazed eyes with a classic manic related to bipolar disorder. The husband states that there was a history of at least six episodes in the previous few years, which confirms the rapid cycling (Carvalho et al., 2020). The dismissive attitude and alcoholic father prove the coming up with bipolar disorder as the diagnosis, although it can be confused to unipolar. The symptoms may be directive of depression as it never totally disappears when treated, but most are more specific to bipolar disorder (Warwick et al., 2019).
Question 2: A
Bipolar disorder needs a broad approach in its management involving a multisystem approach depending on the approach, which can be bipolar mania or bipolar depression. For Ingram, this is a manic episode of bipolar disorder. Several pharmacological drugs can be used for this patient, including lithium, Olanzapine, and Valium (Lopez et al., 2018). Lithium, a mood stabilizer, is the first-line drug for this presentation. The drug is prescribed as it controls the highs and lows of bipolar disorder. They manage both depression and mania of bipolar disorder. Valproic acid, Depakote, carbamazepine and lamotrigine can be used in place of lithium (Lopez et al., 2018). Olanzapine is an antipsychotic that can be administered to this patient. The drug has been proven effective in such cases, especially if the patient had been treated for depression before, as in this scenario (Baldessarini et al., 2019). Quetiapine, risperidone, ziprasidone and lurasidone can be used as antipsychotics.
Fluoxetine is a combination of antipsychotics and antidepressants exerting both effects. For bipolar patients like Ingram, the combination of fluoxetine and Olanzapine produce better effects than when prescribed alone. Antianxiety medications are also of great impact to Ingram, bringing the need for Valium benzo diazepam (Baldessarini et al., 2019). The drug improves sleep having in mind the patient experiences insomnia. Based on how the patient presents, the above drugs would effectively manage the symptoms as she is experiencing bipolar mania.
Question 2: B
Decision on medication depends on the presentation of bipolar disorder. If the drugs prescribed fail to work, there is always a chance to change medication. For this case, the above prescription was chosen over other medications due to its effectiveness in bipolar disorder mania (Amodeo et al., 2017). Centrally to bipolar depression, for Ingram, antipsychotics are advised compared to antidepressants. The patient’s presentation does not qualify for any symptom of depression, so fluoxetine should be stopped as it is an antidepressant that will worsen the mania situation (Parker et al., 2017). Unless fluoxetine is combined with Olanzapine, it should be avoided. Bupropion is prescribed for bipolar patients but not for all cases because it is an antidepressant hence good for bipolar depression (Parker et al., 2017). The antidepressants may exacerbate the patient to a manic episode or increase the mixed symptoms.
The medications am prescribing for the patient are lithium, Olanzapine and Valium. Lithium or lithium carbonate is the generic name, and the brand names are Eskalith, Lithobid. The drug is classified as a mood stabilizer used for bipolar disorder agents and specifically an antimanic agent. The mechanism of action of lithium is that it works by decreasing abnormal and exaggerated brain activity (Kessing et al., 2018). It does this by decreasing the norepinephrine release and increasing serotonin synthesis, which leads to mood stabilization and lowering of the highs. The dose of lithium is 1800mg daily, taken orally for individuals twelve years and above. A patient taking lithium should expect the following side effects: diarrhea, metallic taste in the mouth, dry lips, sickly feeling, and excessive urination associated with extreme thirst (Kessing et al., 2018). Non-adherence is a common issue in lithium taking which mostly ends in discontinuation of the medication; this depends on the attitude and knowledge of the bipolar disorder patients.
Olanzapine is a generic name that has brand names like Zyprexa and Zyprexa zydis. The drug is an antipsychotic and, specifically, an atypical antipsychotic agent used for manic episodes and schizophrenia (Uguz et al., 2021). The mode of action of Olanzapine is that it works by blocking several neurotransmitter receptors in the brain (Uguz et al., 2021). The goal is to reduce the brain’s activity and bind with histamine H-1, muscarinic, alpha-1 and serotonin type 2 receptors responsible for an active brain. It blocks dopamine from coming to contact with synaptic receptors for potential action. The drug is administered from 10 to 15 milligrams daily orally. Dizziness, depression, weakness, insomnia, restlessness, constipation and unusual behavior are the common side effects of Olanzapine (Uguz et al., 2021). Olanzapine is contraindicated in patients with known hypersensitivity to the drug. It may also elevate diabetes mellitus lead to low white blood count, and cause liver dysfunction. Once the drug is taken, the individual starts to feel more relaxed and calmer, and it is advisable to be taken at night, especially during bedtime, as it has sleepy effects.
Lastly, I would prescribe Valium for the patient. The drug’s generic name is Diazepam, and the brand names are Valium, diastat AcuDial and Diastat. The drug is antianxiety, also called anxiolytic, specifically benzo diazepam (Joseph et al., 2020). It can also act as a skeletal muscle relaxant, a sedative and an anticonvulsant. Valium facilitates the action of gamma-aminobutyric acid, which is a neurotransmitter with an inhibitory effect in the central nervous system, this being its mechanism of action (Joseph et al., 2020). The inhibiting of GABA causes blockage of certain signals in the brain, causing a calming effect hence relieving anxiety, fear, tension, and stress. Diazepam is administered in 2mg, 5mg, and 10 mg orally twice or four times a day. The dose should not exceed 30mg within eight hours. Being an anxiolytic, the common side effects of Valium are dizziness, drowsiness, dry lips, constipation, headache and a feeling of tiredness and weakness (Joseph et al., 2020). Patients with alcohol intoxication, drug abusers, depressed individuals, and patients with myasthenia gravis are contraindicated in taking Diazepam.
Question 4: A
Bipolar disorder can be approached in a non-pharmacological way and be managed as it is chronic and recurrent with often episodes. The disorder involves energy, mood, and activity levels involving extreme highs and extreme lows. Cognitive behavioral therapy, Lifestyle changes, and counseling are some of the non-pharmacological approaches that can be applied for bipolar disorder patients (Amodeo et al., 2017). The interventions will enable the patient to manage their symptoms and improve their life quality overall. In cases of comorbidities, cognitive and behavioral therapy can be applied.
Lifestyle changes can be one of the pharmacological interventions that can be applied to manage bipolar disorder. Sleep is one of the lifestyle aspects. Based on the episode, depressive symptom tends to cause excessive sleep and less sleep for mania episodes. Training the patient to have enough sleep will impact mood changes which will e of positive effect on maintaining the levels of highs and lows (Fornaro et al., 2020). The patient can be educated on sleeping in a comfortable room, going to bed early and regularly, eating fewer meals before sleep and limiting alcohol intake to control their sleep pattern.
Diet is one of the lifestyles considerations that bipolar disorder patients should be enlightened on. A healthy diet reduces the occurrence of mania and depressive attacks. A healthy diet lowers the rate of complications of the diseases and emergency of other chronic and metabolic illnesses like hypertension. Eating disorders are also more likely to occur in this patient, like binge eating, especially in depressive episodes. The need to eat regularly, have a well-balanced diet, and have a meal plan is important to maintain a good lifestyle (Fornaro et al., 2020). Exercise is another lifestyle change that can have a positive effect on the management of the bipolar disorder. Physical activity has proven to affect improving mood in a depressive state. Exercise is believed to activate the body and brain, counteracting the depressive state (Fornaro et al., 2020).
Counseling is important to educate on practicing moderation as the patients are susceptible to addictive behaviors. The addiction mostly involves drugs and alcohol. Lack of moderation and satisfaction tends to drive them to risky behaviors. Counseling on risky behaviors, awareness need for seeking help, and having positive friends can greatly impact the management of the disorder (Bauer et al., 2018). Lastly, cognitive behavioral therapy can effectively treat bipolar disorder, especially if focused on what affects the patients. This involves changing the perception of the patients on how they act and behave. With this, depression and mania can be managed.
Question 4: B
The above non-pharmacological interventions are effective in managing bipolar disorders compared to other interventions. Genetic predisposing may not be tamed, so it can not apply as non-pharmacological management. For other diseases, the genetics can be altered but on this, having a first-degree relative with bipolar predisposes one to acquire it. Lifestyles that expose one to high-stress levels like death and chronic illnesses may not be well controlled to achieve a non-pharmacological intervention (Bauer et al., 2018). A lifestyle-free form drug will be effective compared to others who advise intake of drugs to relieve stress.
To come up with a mental diagnosis, several aspects must be considered and looked into in detail. For this patient, coming up with the diagnosis involved several skills of comprehensive history taking, physical exam, classification of symptoms and a psychological evaluation. On history taking skill, taking a comprehensive history was effective in understanding the occurrence of symptoms, their behaviors and when they occur as different mental problems present differently. History taking was also important to know the duration of the symptoms for the right diagnosis (Bauer et al., 2018).
The second skill was a physical exam. Patients with mental conditions may have difficulty following up for medical treatment. A thorough physical exam will elicit medical conditions present and understand the physical status of the patient. Using the diagnostic and statistical manual mental disorders, the next skill is to group symptoms to diagnose. For this patient, the diagnosis is categorized as a mood disorder and based on the patient presenting complaints. The mood is largely affected by other factors. Although some mental conditions may present in the same way, classification of the symptoms effectively comes up with the right diagnosis (Bauer et al., 2018). The last skill is a psychological evaluation. This diagnosis is the exact brain status, which includes the brain processes, behaviors, patterns, memory, and response. The process involves questioning the individual about their behaviors and activities to come up with a diagnosis.
Treatment skills include assessing the degree of symptoms to know which to start with. For Ingram, the mood was greatly affected by knowing that we give mood stabilizers first. The next skill is the dysfunction caused by the mental illness to determine the management to be provided. Danger assessment is another skill that needs to eliminate the danger as the first approach to managing (Brown, 2019). Several social workers are involved in the achievement of total management of mental illnesses. For Ingram, several social workers can be put on board to assess mental illness, diagnose mental conditions, treat, prevent and control the behavior and emotional states (Brown, 2019). Those involved may include counselors, psychiatrists, spouses, physicians, nurses, and psychologists.
Amodeo, G., Fagiolini, A., Sachs, G., & Erfurth, A. (2017). Older and newer strategies for the pharmacological management of agitation in patients with bipolar disorder or schizophrenia. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders) , 16 (8), 885-890.
Baldessarini, R. J., Tondo, L., & Vázquez, G. H. (2019). Pharmacological treatment of an adult bipolar disorder. Molecular psychiatry , 24 (2), 198-217.
Bauer, M. S., Krawczyk, L., Tuozzo, K., Frigand, C., Holmes, S., Miller, C. J., … & Godleski, L. (2018). Implementing and sustaining team-based telecare for bipolar disorder: lessons learned from a model-guided, mixed-methods analysis. Telemedicine and e-Health , 24 (1), 45-53.
Brown, T. (2019). Social work roles and healthcare settings. Handbook of health social work , 21-37.
Carvalho, A. F., Firth, J., & Vieta, E. (2020). Bipolar disorder. New England Journal of Medicine , 383 (1), 58-66.
Fornaro, M., Carvalho, A. F., Fusco, A., Anastasia, A., Solmi, M., Berk, M., … & de Bartolomeis, A. (2020). The concept and management of acute episodes of treatment-resistant bipolar disorder: A systematic review and exploratory meta-analysis of randomized controlled trials. Journal of affective disorders , 276 , 970-983.
Joseph, A., Moriceau, S., Sica, V., Anagnostopoulos, G., Pol, J., Martins, I., … & Kroemer, G. (2020). Metabolic and psychiatric effects of acyl-coenzyme A binding protein (ACBP)/diazepam binding inhibitor (DBI). Cell death & disease , 11 (7), 1-10.
Kessing, L. V., Bauer, M., Nolen, W. A., Severus, E., Goodwin, G. M., & Geddes, J. (2018). Effectiveness of maintenance therapy of lithium vs. other mood stabilizers in monotherapy and combinations: a systematic review of observational studies. Bipolar disorders , 20 (5), 419-431.
López-Muñoz, F., Shen, W. W., D’ocon, P., Romero, A., & Álamo, C. (2018). A history of the pharmacological treatment of bipolar disorder. International journal of molecular sciences , 19 (7), 2143.
Parker, G. B., Graham, R. K., & Tavella, G. (2017). Is there consensus across international evidence‐based guidelines for the management of bipolar disorder?. Acta Psychiatrica Scandinavica , 135 (6), 515-526.
Uguz, F., & Kirkas, A. (2021). Olanzapine and quetiapine in preventing a new mood episode in women with bipolar disorder during the postpartum period: a retrospective cohort study. Brazilian Journal of Psychiatry .
Warwick, H., Mansell, W., Porter, C., & Tai, S. (2019). ‘What people diagnosed with bipolar disorder experience as distressing’: a meta-synthesis of qualitative research. Journal of affective disorders , 248 , 108-130.
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CASE STUDY Richard (bipolar disorder, substance use disorder)
Case study details.
Richard is a 62-year-old single man who says that his substance dependence and his bipolar disorder both emerged in his late teens. He says that he started to drink to “feel better” when his episodes of depression made it hard for him to interact with his peers. He also states that alcohol and cocaine are a natural part of his manic episodes. He also notes that coming off the cocaine and binge drinking contribute to low mood, but he has not responded well to referrals to AA and past inpatient stays have led to only temporary abstinence. Yet, Richard is now trying to forge a closer relationship to his adult children, and he says he is especially motivated to get a better handle on both his bipolar disorder and his substance use. He has been more compliant with his mood stabilizing and antidepressant medication, and his psychiatrist would like his dual diagnoses addressed with psychotherapy.
- Alcohol Use
- Elevated Mood
- Impulsivity
- Mania/Hypomania
- Mood Cycles
- Substance Abuse
Diagnoses and Related Treatments
1. bipolar disorder, 2. mixed substance abuse/dependence.
Case Study: Depression and Bipolar Disorder
A 26-year-old graduate student at a rigorous university, Christina was having trouble keeping up with her studies due to a lack of interest, fatigue and feelings of hopelessness – signs of depression and bipolar disorder. Referred by her psychiatrist, she came to the TMS Center of Colorado for an evaluation, desperately hoping for some relief.
Christina had already tried numerous prescription drugs to deal with depression and bipolar disorder, including the prescription drugs Klonopin, Wellbutrin and Vyvanse, along with a three-month course of psychotherapy.
As part of her evaluation, Christina was tested for depression and anxiety. Her Beck Depression Inventory-II ® (BDI) score was 34, which is categorized as severe depression. On the Patient Health Questionnaire-9 ® (PHQ-9) for depression, she scored 16, which is categorized as moderately severe depression. Christina’s Beck Anxiety Inventory ® (BAI) score was a 19, which is just below the cutoff for moderate anxiety. Based on her treatment history and test scores, Christina was recommended for a six-week course of treatment with Brainsway ® deep transcranial magnetic stimulation (dTMS) that was carried out at the TMS Center of Colorado.
Christina received a total of 30 dTMS treatments over seven weeks. After less than two weeks of treatment, her depression and anxiety assessment scores dropped significantly, and she reported feeling “awesome” and waking up without a feeling of “dread.” Within five weeks of starting treatment, Christina’s depression scores indicated a remission of depression, and her anxiety assessment score had dropped to a 3, which is considered negligible. By the end of treatment, her depression scores indicated full remission, and her anxiety levels were greatly decreased.
During the second half of her treatment, Christina often talked about her lack of depression, how productive she had become and how great she was feeling. In her sixth week of treatment, she reported the difference in her mood was like “night and day.” In her final session she reported, “The treatment has made such a difference in my life. [There are] no side effects from medication, and I feel beyond happy.”
Christina is continuing her studies and during treatment was able to secure an internship in her field of study.
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Case Study: Bipolar 1 Disorder
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Bipolar disorder case study
Mood disorders are considered a disease of the XXI century. Nevertheless, psychologists know little about this disease, which makes a case study for bipolar disorder especially relevant today. This mental disorder is characterized by a change of manic and depressive states, mixed states, alternation of euphoria and depression.
Patients with bipolar disorder suffer from more severe mood swings than those with which everybody encounters every day.
Causes of a Bipolar Disorder
Despite numerous studies, scientists have not been able to pinpoint the causes of bipolar disturbance development. For many years, the genetic theory has remained popular, although the principle of inheritance is still not clear. The study of identical twins revealed that if one twin gets bipolar disorder, the second of the twins has a significantly increased chance of getting sick. At the same time, the investigation of the causes of the disease is continuing, because it will allow developing effective methods of prevention and treatment.
There are a lot of bipolar disorder case study examples, the development of which are able to give hope for recovery to thousands of patients around the world. According to modern data, bipolar forms of affective disturbances are more likely to affect men, while monopolar ones are three times more likely to affect women.The structure of the brain can also affect the development of the disease. According to the “ignition hypothesis,” when people genetically predisposed to such a disease experience stress, their threshold of emotional stress is significantly reduced, which causes a spontaneous occurrence of episodes. There is also a theory that abnormal mood swings are associated with the balance of the two neurotransmitters – serotonin and norepinephrine (dopamine disturbances are associated with other psychiatric disorders, psychosis, and schizophrenia).
However, some experts believe that the symptoms of the bipolar spectrum are not an abnormal disturbance of the organism, but only a hypertrophic manifestation of the adaptive function. There is a theory that genes that cause severe affective disorders in certain situations can be useful for survival. The inclination to hide, reduce energy consumption and more sleep, which is characteristic of patients during the depression, may have served as a protective mechanism for human ancestors in difficult times. Weak manifestations of mania could also be an advantage because they give an influx of energy, self-confidence and enhance creativity.Another theory suggests that mania and depression are a kind of mechanism of internal self-regulation, self-defense of a person, which is tormented by fear or great internal contradictions. Deep depression protects and isolates a person from the world, drowning out even the feeling of despair with apathy, and mania allows splashing out latent aggression and coping with fear.
Diagnostic of a Bipolar Disorder
A person suffering from bipolar disturbance can not control his or her mood: at times he or she experiences a powerful energy uplift, which is not always appropriate and which rarely turns out to be productive, and at times he or she suffers from the same causeless decline. In the intervals between phases, patients can feel normal. If this period is prolonged (it can last up to 7 years), the patient sometimes begins to forget that there was an illness in his life.One of the main problems of conducting a case study of bipolar disorder, that the number of phases of this disease and their order is unpredictable. In addition, the disease can manifest only in manic, only in hypo maniacal) or only in depressive phases.
Thus, the results of a case study of bipolar disorder are always very specific, individual and do not allow a researcher to create a complete picture of the development of this disease. Bipolar disorder case study diagnosis is especially difficult at hypo maniacal phase because it is perceived by the patient as a completely innocent flow of energy and an increase in mood. A person feels a spiritual uplift and a belief in one’s abilities. A patient shows a keen interest in a variety of topics; is highly motivated and ready for action. In this period a patient is able to work intensively, without feeling tired, and sleeps less. However, this condition has side effects.
A person becomes too self-confident and may lose the ability to assess the situation sensibly. He easily makes impulsive decisions, takes risks, and makes promises without thinking. Anyway, a person with hypomania is still able to make his activity look more or less normal and does not cause much inconvenience to the society. Analyzing bipolar affective disorder case study, it is possible to conclude that the situation is getting out of control mania stage. A person expresses delusional ideas of greatness or insane projects that one wants to fulfill immediately.
A patient can become irritable or aggressive and make more than strange decisions. The diagnosis depends on the form of this phase. In the presence of manic or mixed (when combined with the symptoms of mania and depressive) episodes “bipolar disorder I” is diagnosed, and if he a patient a history of manifestations of hypomania, it is a “bipolar disorder II.”The second option is considered to be less destructive, although some experts have doubts about this. In either case, the patient will most likely periodically fall into depression.
The most dangerous period from the point of view of suicide is the beginning or end of the depression when the mood has already fallen, and the energy is still enough to take some decisive action.
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[Pediatric bipolar disorder - case report of a bipolar patient with disease onset in childhood and adolescence: implications for diagnosis and therapy]
Affiliations.
- 1 Psychiatrie, Medizinische Universität Graz.
- 2 Therapiezentrum Justuspark, BVA, Bad Hall.
- PMID: 25383932
- DOI: 10.1055/s-0034-1385271
In recent years, intense controversies have evolved about the existence and exact diagnostic criteria of pediatric bipolar affective disorder. The present study aims to discuss pediatric bipolar affective disorder based on the current literature focussing on the diagnostic prospects. Based on a case study, a process of bipolar disorder developed in childhood is depicted exemplarily. Because of the high comorbidity and overlapping symptoms of paediatric bipolar affective disorder and other psychiatric disorders, the major impact of the differential diagnosis has to be stressed. An early diagnosis and the treatment possibilities are discussed.
© Georg Thieme Verlag KG Stuttgart · New York.
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Functional Imaging Changes in Bipolar Disorder After Psychotherapy or Drug Therapy
An activation likelihood estimation meta-analysis found that both psychotherapies and drug therapies have their own distinct brain effects among patients with bipolar disorder (BD). These findings were published in Psychological Medicine .
Investigators from Anhui Medical University in China searched publication databases from inception through June 2021 for studies of psychotherapy or drug therapy interventions among patients with BD that had functional magnetic resonance imaging (fMRI) data. A total of 21 studies met the inclusion criteria and were considered in this analysis.
The studies evaluated psychotherapy (n=7) or drug therapy (n=12) interventions and fMRIs were conducted during emotional (n=12) or cognitive (n=9) tasks.
Overall, among 527 patients, the interventions associated with 127 increased activation points and 21 decreased activation points. After clustering, there were 10 increased activation clusters and 1 decreased activation cluster. After translating the clusters to brain regions, the increased clusters affected the right anterior cingulate cortex (ACC), bilateral medial frontal gyrus (MeFG), bilateral inferior frontal gyrus (IFG), left amygdala, left lingual gyrus, left angular gyrus, left insula, and right claustrum whereas the right posterior cingulate cortex (PCC) was decreased.
After receiving psychotherapy, the IFG and the superior temporal gyrus (STG) were activated. Drug therapy activated the ACC, MeFG, IFG, amygdala, lingual gyrus, angular gyrus, insula, and claustrum areas and decreased activation in the PCC.
Stratified by tasks performed during fMRI, emotional tasks associated with activation of the ACC and IGF and decreased activation of the PCC whereas the cognitive tasks were associated with activation of the STG and decreased activation of the precuneus and MeFG.
The major limitation of this analysis was the inclusion of only 2 broad categories of interventions.
Study authors concluded, “Different brain regions activated by psychotherapy and drug therapy may be related to distinct therapeutic mechanisms. In addition, the analysis results of emotional tasks and cognitive tasks were inconsistent, which may be due to the different types of tasks assessed. It is suggested that medication may have a bottom-up effect, whereas psychotherapy may have a top-down effect. This meta-analysis may contribute to the clinical differential diagnosis of BD and would be helpful to improve its treatment effect as well as identify more accurate neuroimaging biomarkers for its treatment.”
References:
Luo J, Yi P, Liang M, et al. Distinct brain activity alterations of treatment for bipolar disorders with psychotherapy and drug therapy: activation likelihood estimation meta-analysis. Psychol Med . 2023;1-13. doi:10.1017/S0033291722003889
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clinical case presentation -bipolar disorder. an excellent case of bipolar disorder by dr Asif iqbal .
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- 1. CASE PRESENTATION DR ASIF IQBAL
- 2. HISTORY Pt seen in my psychiatry rotation ,in male ward(khasab hospital) 37 yrs old indian man,with past h/o multiple episodes of depression,last episode was 1 yrs back.never had manic or hypomanic episodes. His wife said his diagnosis was schizophrenia He has 2 wks h/o acute behavioral change . Noted to be overhappy, overconfidant and overactive.But at times noted to be very irritable and verbally aggressive. He works as an electrician.he suddently went to the indian school in khasab and started to give lectures to the students few days ago.
- 3. CONT.. he suddently went to airport in intention to go to india .but he did not book a ticket. He had poor sleep. No h/o confusion or disorientation to time ,place or person. His brother brought medication from india ,3 days ago,has been on olanzapine 7.5 mg HS for past 2 days. Both pt ,his wife and his brother denied smoking cigarette,alcohol intake or drug abuse. He has been in khasab for years.
- 4. General examination Afebrile Pr 72bpm Bp140/90 mmhg Rr 16/min Other systemic examination –normal No neurological focal sign
- 5. Mental state examination Pt was very argumentaive Irritable Talking with an overconfident manner with some grandiosity but no grandiose delusion at time of assesment Not noted to be hallucinating at time of assesment Insight was poor
- 6. Differential diagnosis Bipolar affective disorder Schizophrenia Substance abuse Hyperthyroidism Brain tumor Provisional dx—bipolar affective disorder in manic episode
- 7. Lab inv... CBC,RFT,LFT,came normal RBS 8.4 TFT came normal Planned to do fbs
- 8. Rationale of investigation • CBC-certain anticonvulsant may cause bone marrow suppression. Eg. carbamazepine • Lithium may cause reversible increase in WBC count . • RBS-atypical antipsychotic can cause problem with glucose regulation. • RFT-treatment with lithium can cause renal and electrolyte problem. • TFT-hyperthyroidism ,and sometimes hypothyroidism can cause psychiatric symptoms • LFT-some antipsychotic can cause liver dysfunction • You can do ECG to take as a baseline because some antipsychotic and antidepressant can cause increase QT interval eg. amitriptyline, risperidone ,haloperidol. • You can do urine for drug screed if you suspect drug abuse • You can do EEG if you suspect underlying epilepsy.
- 9. Treatment Initial rx plan was to give haloperidol inj (5 mg im ,max 3 doses in 24 hours)and promethazine inj 25 mg im maximum 3 doses in 24 hours) for agitation sos. Olanzapine increased to 10mg To start sodium valporate as mood stabilizer ,gradually
- 10. What we faced in morning rounds... • Pt said he slept for few hours ,after he has taken olanzapine tab 2 am at night,he went outside the ward to the parking area wanted to go home.brought back by secuirity and received promethazine inj.he slept again at 5 am,he woke at 9 am prior to our morning rounds.since that time noted to be very irritable ,argumentative,and asking to go home .his agitation escalated.staff attempted to administer sos injection but was very difficult due to high level of agitation.MSE:pt was very agitated,standing at bay area of the ward.his agiatation increased when any staff tried to speak with him.he was overfamiliar and socialy disinhibited with other co- patients and attendants,contacted to al masarra hospital regarding transferring pt for admission there and a bed in acute male ward has been booked for the pt.
- 11. Cont.. • Pt abscoded again from the hospital by this time,brought back by police.staff was unable to administer the injections even in the presence of secuirity staff and police officers .pt refused injection and was very aggressive . • Pt's sponsor and pt's brother refused transfer to al masarra hospital despite repeated explanation to them regarding risk of premature discharge and expected negative consequences.also informed them we can't keep the pt in our hospital anymore as he poses great risk to others and our ward is not prepared for such cases.both pt 's brother and sponsor signed LAMA form for refusal to transfer in the presence of PRO and male ward staff nurse .
- 12. • Brother decided to take pt home and book a ticket to india ASAP
- 13. Some home message for antipsychotic • In pregnant women you can use lamotrigine or electroconvulsive therapy. because carbamazepine ,sodium valproate these drugs can cause congenital anomaly. atypical antipsychotics cross placenta but no severe side effect noted, almost all of them pregnancy category C, use them with caution if benefits outweighs risk, preferably consult with psychiatrist for pregnant and breastfeeding patient • In breastfeeding patient you can use olanzapine or quetiapine can be used .haloperidol and risperidone can be used under supervision of psychiatrist only. • For depressive episode in bipolar disorder fluoxetine and olanzapine combination can be used .
- 14. Some home message • For sodium valproate dosages-start with 200 mg tds ,then increase gradually ,effective maintenance dosage between 1000 mg to 1500 mg /day in divided dosage • Antidepressants are not used in bipolar disorder except fluoxetine and olanzapine combination. • Be cautious about use of lithium in bipolar disorder, because of narrow therapeutic window, so need facility of frequent monitoring of serum level. most of the psychiatrist now using other mood stabilizer like sodium valproate. • Treatment option for bipolar disorder is benzodiazepines for acute agitation, antimanic drug like lithium. anticonvulsant /mood stabilizer like sodium valproate and atypical antipsychotics .of course not all together,it varies patient to patient .
- 15. THANK YOU FOR PATIENT HEARING
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- Introduction
- Limitations
- Conclusions
- Article Information
DDD indicates defined daily dose.
a The analyses were repeated after replacing lithium with antipsychotics, valproate and lamotrigine, respectively. The analyses on these drugs were performed in the same way as the analyses on lithium.
HRR indicates hazard rate ratio.
The cumulative dose was calculated based on the period from the index date through the 5 years following. Patients were then followed up from the date 5 years after the index date until osteoporosis, death, or January 1, 2019, whichever came first. The incidence rates of osteoporosis were compared between patients who received treatment (corresponding to the cumulative doses outlined in the figure) and patients who did not, stratified by cumulative dose. The hazard rate ratios (HRR) were adjusted for age, sex, Charlson Comorbidity Index, use of systemic corticosteroids, use of sedative medication, and any eating disorder diagnosis. The P values for the log-rank tests of dose-response associations were as follows: lithium, P < .001; antipsychotics, P = .13; valproate, P = .13; and lamotrigine, P = .30. DDD indicates defined daily dose; HR, hazard ratio.
eMethods. Description of sensitivity analyses
eTable 1. Definition of variables
eTable 2. Baseline characteristics of the cohort
eTable 3. Association between bipolar disorder and osteoporosis stratified by incident/prevalent bipolar disorder status
eTable 4. Association between bipolar disorder and osteoporotic fractures
eTable 5. Association between bipolar disorder and osteoporosis stratified by sex
eTable 6. Association between treatments of bipolar disorder and osteoporosis stratified by incident/prevalent bipolar disorder status
eTable 7. Association between treatments of bipolar disorder and osteoporotic fractures
eTable 8. Association between treatments of bipolar disorder and osteoporosis stratified by sex
eFigure 1. Log-log survival functions (time to osteoporosis) confirming proportional hazards
eFigure 2. Venn diagram showing the overlap between lithium treatment and other treatments
eFigure 3. Venn diagram showing the overlap between antipsychotic treatment and other treatments
eFigure 4. Venn diagram showing the overlap between lamotrigine treatment and other treatments
eFigure 5. Venn diagram showing the overlap between valproate treatment and other treatments
eFigure 6. Association between the duration of lithium, antipsychotic, valproate and lamotrigine treatment of bipolar disorder and the risk of osteoporosis stratified by sex
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Köhler-Forsberg O, Rohde C, Nierenberg AA, Østergaard SD. Association of Lithium Treatment With the Risk of Osteoporosis in Patients With Bipolar Disorder. JAMA Psychiatry. 2022;79(5):454–463. doi:10.1001/jamapsychiatry.2022.0337
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Association of Lithium Treatment With the Risk of Osteoporosis in Patients With Bipolar Disorder
- 1 Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark
- 2 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- 3 Department of Affective Disorders, Aarhus University Hospital - Psychiatry, Aarhus, Denmark
- 4 Dauten Family Center for Bipolar Treatment Innovation, Massachusetts General Hospital, Boston
- 5 Harvard Medical School, Boston, Massachusetts
Question Is lithium treatment for bipolar disorder associated with a decrease in risk of osteoporosis?
Findings This cohort study of 22 912 patients with bipolar disorder and 114 560 reference individuals from the general population in Denmark who were followed up for a total of 1 213 695 person-years found that bipolar disorder was associated with an increase in risk of osteoporosis and that treatment with lithium was associated with a decrease in risk of osteoporosis in a cumulative dose-response–like manner. Conversely, treatment with antipsychotics, valproate, and lamotrigine was not associated with a reduction in risk of osteoporosis.
Meaning Lithium treatment was associated with a reduction in risk of osteoporosis; these findings warrant further investigation.
Importance Osteoporosis, a systemic skeletal disorder associated with substantial morbidity and mortality, may be particularly common among individuals with bipolar disorder. Lithium, a first-line mood-stabilizing treatment for bipolar disorder, may have bone-protecting properties.
Objective To evaluate if treatment with lithium is associated with a decrease in risk of osteoporosis among patients with bipolar disorder.
Design, Setting, and Participants This retrospective cohort study included 22 912 adults from the Danish Psychiatric Central Research Register who received an initial diagnosis of bipolar disorder in the period from January 1, 1996, to January 1, 2019. For each patient with bipolar disorder, 5 age- and sex-matched individuals were randomly selected from the general population as reference individuals. Individuals with bipolar disorder prior to January 1, 1996, those with a diagnosis of schizophrenia or schizoaffective disorder prior to being diagnosed with bipolar disorder, and those with osteoporosis prior to the index date were excluded. Of the 114 560 reference individuals included, 300 were diagnosed with bipolar disorder during follow-up and were censored from the reference group from the date of diagnosis forward. For patients with bipolar disorder, treatment periods with lithium, antipsychotics, valproate, and lamotrigine were identified. Analyses were performed between January 2021 and January 2022.
Exposures Bipolar disorder and treatment with lithium, antipsychotics, valproate, and lamotrigine.
Main Outcomes and Measures The primary outcome was osteoporosis, identified via hospital diagnoses and prescribed medications. First, incidence of osteoporosis was compared between patients with bipolar disorder and reference individuals (earliest start of follow-up at age 40 years) using Cox regression. Subsequently, incidence of osteoporosis for patients receiving treatment with lithium, antipsychotics, valproate, and lamotrigine, respectively, was compared with that of patients who were not treated with these medications.
Results A total of 22 912 patients with bipolar disorder (median [IQR] age, 50.4 [41.2-61.0] years; 12 967 [56.6%] women) and 114 560 reference individuals (median [IQR] age, 50.4 [41.2-61.0] years; 64 835 [56.6%] women) were followed up for 1 213 695 person-years (median [IQR], 7.68 [3.72-13.24] years). The incidence of osteoporosis per 1000 person-years was 8.70 (95% CI, 8.28-9.14) among patients and 7.90 (95% CI, 7.73-8.07) among reference individuals, resulting in a hazard rate ratio (HRR) of 1.14 (95% CI, 1.08-1.20). Among patients with bipolar disorder, 8750 (38.2%) received lithium, 16 864 (73.6%) received an antipsychotic, 3853 (16.8%) received valproate, and 7588 (33.1%) received lamotrigine (not mutually exclusive). Patients with bipolar disorder treated with lithium had a decrease in risk of osteoporosis (HRR, 0.62; 95% CI, 0.53-0.72) compared with patients not receiving lithium. Treatment with antipsychotics, valproate, and lamotrigine was not associated with reduced risk of osteoporosis.
Conclusions and Relevance In this study, bipolar disorder was associated with an increase in risk of osteoporosis, and lithium treatment was associated with a decrease in risk of osteoporosis. These findings suggest that bone health should be a priority in the clinical management of bipolar disorder and that the potential bone-protective properties of lithium should be subjected to further study, both in the context of bipolar disorder and in osteoporosis.
Osteoporosis is a common chronic systemic skeletal disorder associated with substantial morbidity and mortality. 1 , 2 While advanced age and female sex are the main characteristics associated with risk of osteoporosis at the population level, there are several additional risk factors at the individual level. 1 , 2 Recent evidence suggests that bipolar disorder may be such a risk factor. 3 - 5
Bipolar disorder is a severe mental illness characterized by recurrent manic, hypomanic, depressive, and mixed episodes, which affects 1% to 2% of the population worldwide. 6 , 7 While manic and hypomanic episodes are defining for the disorder, it is the depressive episodes that account for the main burden of illness, 8 - 10 and depression is considered to be an important risk factor for poor bone health and osteoporosis, possibly mediated by lifestyle factors, such as poor diet and lack of physical activity or exercise. 11 , 12 Accordingly, a recent meta-analysis 3 suggested that individuals with bipolar disorder are at elevated risk of fractures. Two small cross-sectional studies have found lower bone mineral density among 61 drug-naive newly diagnosed patients with bipolar disorder compared with healthy control individuals 4 and a high prevalence of osteopenia (50%) and osteoporosis (12.5%) among 16 elderly inpatients with bipolar disorder, respectively. 5 However, there is a lack of adequately powered longitudinal studies on the associations among bipolar disorder, its pharmacological treatment, and osteoporosis.
A wide range of medications may affect the risk of osteoporosis. 1 , 13 Lithium, a cornerstone in the pharmacological treatment of bipolar disorder since the 1950s 14 , 15 that remains widely used, 6 , 16 is of interest in this regard. While some small observational studies have indicated that treatment with lithium is associated with reduced risk of fractures, others point to negative or neutral effects of lithium on bone mass density. 17 - 22 That lithium could potentially have a beneficial effect on bone structure is supported mechanistically by animal studies demonstrating that lithium stimulates bone formation through activation of β-catenin via inhibition of glycogen synthase kinase-3β. 20 , 21 If lithium also stimulates bone formation to a substantial degree in humans, it may protect individuals with bipolar disorder receiving lithium treatment against development of osteoporosis. However, we are not aware of any longitudinal studies having addressed this possibility. A potential explanation for this gap in the literature is that such studies require data from a period in which treatment for bipolar disorder is ongoing and the risk of osteoporosis is present. As treatment for bipolar disorder is often initiated in young adulthood while osteoporosis is a disease predominantly affecting elderly individuals, 1 , 2 such data are rare.
To clarify associations among bipolar disorder, its pharmacological treatment, and the risk of osteoporosis—and the potentially protective effect of lithium on the risk of developing osteoporosis in particular — we designed a nationwide longitudinal register-based study addressing the following sequential research questions. Is the risk of osteoporosis elevated among individuals with bipolar disorder compared with age- and sex-matched individuals from the general population? Among patients with bipolar disorder, is treatment with lithium associated with a decrease in risk of developing osteoporosis?
This study was based on data from nationwide Danish registers. Every legal resident in Denmark receives a unique personal registration number, either at birth or when becoming a legal resident on immigration. The unique personal registration number enables data linkage across registers at the level of the individual. 23 In the present study, we used the following registers: the Danish Civil Registration System, which contains information on vital status 23 ; the Danish Psychiatric Central Research Register and the Danish National Patient Register, which contain information on all inpatient contacts to Danish hospitals since 1994 as well as all outpatient and emergency department contacts since 1995, including diagnoses registered in accordance with the International Classification of Diseases, Tenth Revision ( ICD-10 ) 24 - 26 ; and the Danish National Prescription Registry, which contains information on all prescriptions redeemed at Danish pharmacies since 1995, registered in accordance with the Anatomical Therapeutic Chemical (ATC) coding system managed by the World Health Organization. 27 , 28
The use of deidentified register data for the purpose of this study was approved by Statistics Denmark and the Danish Health Data Authority. No further ethical approval is required for register-based research in Denmark. The project is registered with the Danish Data Protection Agency.
Our first aim was to compare the incidence of osteoporosis among individuals with bipolar disorder with that among reference individuals from the general population. We used the Danish Psychiatric Central Research Register to identify all individuals with bipolar disorder (at the time of their first ICD-10 diagnosis of bipolar disorder) in the period from January 1, 1996, to January 1, 2019. Individuals registered with a diagnosis of bipolar disorder prior to January 1, 1996, as well as individuals registered with a diagnosis of schizophrenia or schizoaffective disorder prior to being diagnosed with bipolar disorder were excluded ( ICD-10 codes are presented in eTable 1 in the Supplement ). We defined the index date as either the date of incident bipolar disorder (for those having received the incident bipolar disorder diagnosis on or after their 40th birthday) or the 40th birthday (for those having received the incident bipolar disorder diagnosis before their fortieth birthday). This was done to focus on a period in which the risk of osteoporosis was present. 1 Via the Danish National Patient Register and the Danish National Prescription Registry, we excluded individuals that had a hospital contact leading to a diagnosis of osteoporosis or redeemed a prescription for a medication used in the treatment of osteoporosis prior to the index date ( ICD-10 and ATC-codes used to operationalize osteoporosis are presented in eTable 1 in the Supplement ). For each individual with bipolar disorder, we used the Danish Civil Registration System to match 5 randomly selected reference individuals from the entire Danish population on index date, birth year, and sex. Reference individuals were without bipolar disorder, schizophrenia, schizoaffective disorder, and osteoporosis up until the index date (defined as for the individuals with bipolar disorder). Of 114 560 reference individuals, 300 were diagnosed with bipolar disorder during follow-up, resulting in them being censored from the reference groups on the date of the diagnosis and followed up as patients with bipolar disorder from that date.
To investigate how treatment with lithium, as well as other drugs with mood-stabilizing properties, is associated with the risk of developing osteoporosis, we focused on the patients with bipolar disorder described above and identified all prescriptions for lithium, any antipsychotic, valproate, and lamotrigine they had redeemed after the index date (ATC codes are presented in eTable 1 in the Supplement ), as antipsychotics, lamotrigine, and valproate are also routinely used in the treatment of bipolar disorder. 6
Osteoporosis was defined either by a diagnosis of osteoporosis following an inpatient or outpatient hospital contact with osteoporosis with pathological fracture, osteoporosis without pathological fracture or osteoporosis in other disease or by redemption of a prescription for a medication used in the treatment of osteoporosis (eTable 1 in the Supplement ). Thereby, we aimed to cover all diagnosed and treated cases of osteoporosis in Denmark, from less severe (ie, redeemed prescriptions, including those from all general practitioners in Denmark) to more severe (ie, requiring hospital contact).
We followed up the individuals with bipolar disorder from the index date and the age- and sex-matched reference individuals from the general population from the matched date until death, January 1, 2019, or development of osteoporosis (or date of bipolar disorder diagnosis for the reference individuals), whichever came first. We estimated incidence rates of osteoporosis per 1000 person-years of follow-up and used Cox proportional hazard regression to compare the incidence rates of osteoporosis between individuals with bipolar disorder and the matched reference individuals. For an illustration of this analysis, see Figure 1 A. We also plotted cumulative incidence proportions (Aalen-Johansen curves) for osteoporosis. To understand (post hoc) whether our finding of an increased cumulative incidence proportion for osteoporosis among the reference individuals compared with the patients with bipolar disorders in the late stages of follow-up was likely because of healthy survivor bias (substantial mortality among those with bipolar disorder resulting in selective survival of healthy individuals with a beneficial prognosis with regard to risk of developing osteoporosis), we repeated the Cox proportional hazard regression described above using death as outcome. Furthermore, we conducted 2 sensitivity analyses stratifying on incident and prevalent bipolar disorder and restricting the outcome to osteoporosis with pathological fracture ( ICD-10 code M80) (eMethods in the Supplement ).
We compared the incidence rate of osteoporosis between patients with bipolar disorder that redeemed a lithium prescription and patients with bipolar disorder that did not redeem a lithium prescription using Cox proportional hazards regression. To avoid survival bias, patients that initiated lithium treatment were considered unexposed from the index date until they redeemed the first lithium prescription. Thereby, we accounted for the fact that the time to initiation of lithium treatment represents unexposed survival time, which could lead to immortal time bias if not treated correctly. We used 2 different models to assess the effect of lithium on the risk of osteoporosis. The first model took treatment duration into account and followed up the patients with bipolar disorder from the date of the first redeemed lithium prescription after the index date until lithium discontinuation (defined as 6 months after the last redeemed lithium prescription), osteoporosis, death, or January 1, 2019, whichever came first. The second model used an intention-to-treat approach in which patients with bipolar disorder were followed up from the date of the first redeemed lithium prescription until osteoporosis, death, or January 1, 2019, whichever came first ( Figure 1 B).
Because use of corticosteroids, presence of chronic somatic diseases, and low weight are known to negatively affect bone health and sedative medications increase the risk of fractures, which may lead to detection of osteoporosis, 1 , 2 we included the following covariates in the Cox regression: redemption of at least 1 prescription for a systemic corticosteroid and redemption of at least 1 prescription for a sedative medication (ie, benzodiazepines or hypnotics), 27 the Charlson Comorbidity Index that covers 19 chronic diseases, 29 and any eating disorder diagnosis (yes or no). 24 Here, the redeemed prescriptions stemmed from the year leading up to the index date, while the diagnostic codes stemmed from in- and outpatient contacts at Danish hospitals in the two years leading up to the index date (see the specific ICD-10 and ATC codes in eTable 1 in the Supplement ). The association between lithium treatment and osteoporosis was quantified by the unadjusted hazard rate ratio (HRR), a partly adjusted HRR (adjusted for age and sex), and a fully adjusted HRR (adjusted for age, sex, Charlson Comorbidity Index, use of corticosteroids and sedative medication, and eating disorder). As there are substantial sex differences in the incidence of osteoporosis, 1 , 2 we repeated the analyses after stratifying by sex. Sensitivity analyses stratifying on incident and prevalent bipolar disorder and restricting the outcome to osteoporosis with pathological fracture ( ICD-10 code M80) are described in the eMethods in the Supplement .
Subsequently, we estimated whether lithium affected the risk of osteoporosis in a dose-response–like manner. For this analysis, we identified all patients with bipolar disorder with an index date in the period from January 1, 1996, to January 1, 2010. In the period from the index date and 5 years forward, the cumulative dose of lithium was calculated using the following formula: dose × number of pills per package / defined daily dose (DDD). 28 Patients who died or developed osteoporosis in this 5-year period were excluded. The remaining patients were followed up until osteoporosis, death, or January 1, 2019, whichever came first. The incidence rate of osteoporosis among patients with bipolar disorder receiving lithium treatment was then compared with that of patients with bipolar disorder who did not receive lithium treatment in the period from the index date and 5 years forward. This comparison was made using Cox proportional hazards regression adjusted for age, sex, Charlson Comorbidity Index, use of corticosteroids and sedative medication, and eating disorder, stratified according to the cumulative dose (≤100 DDDs, >100-365 DDDs, >365-730 DDDs, >730-1460 DDDs, and >1460 DDDs). The potential cumulative dose-response association was assessed using the log-rank test ( Figure 1 C). These analyses were repeated after stratifying by sex.
Finally, all analyses regarding the effect of lithium were repeated while replacing lithium (as exposure) with antipsychotics, valproate, and lamotrigine, respectively (ATC codes in eTable 1 in the Supplement ). The lithium, antipsychotics, valproate, and lamotrigine groups were not mutually exclusive, as patients with bipolar disorder are often treated with 2 or more of these drugs concomitantly. 6
For all Cox proportional hazards regression analyses, the proportional hazards assumption was confirmed by comparing the log-log survival functions (eFigure 1 in the Supplement ). The analyses were conducted using Stata version 15 (StataCorp) via remote access to servers at Statistics Denmark. Tests were 2-sided and significance was set at P < .05.
We identified 22 912 individuals with incident bipolar disorder diagnosed in the period from January 1, 1996, to January 1, 2019 (median [IQR] age, 50.4 [41.2-61.0] years; 12 967 [56.6%] women), and 114 560 reference individuals (median [IQR] age, 50.4 [41.2-61.0] years; 64 835 [56.6%] women). Rates of comorbidities and medication use were higher among patients with bipolar disorder compared with reference individuals. See Table 1 for characteristics of patients and reference individuals and eTable 2 in the Supplement for sex-stratified characteristics.
During the 1 213 695 person-years of follow-up (median [IQR] follow-up per person, 7.68 [3.72-13.24] years), 1585 of the patients with bipolar disorder and 8146 of the reference individuals developed osteoporosis according to the operationalization used in this study, corresponding to incidence rates of 8.70 (95% CI, 8.28-9.14) and 7.90 (95% CI, 7.73-8.07) per 1000 person-years, respectively, and an HRR of 1.14 (95% CI, 1.08-1.20). The analyses stratifying the cohort on incident and prevalent bipolar disorder yielded similar results (eTable 3 in the Supplement ). The same was the case for the analysis using osteoporosis with pathological fracture as outcome (eTable 4 in the Supplement ).
Figure 2 A shows that the elevated incidence of osteoporosis among patients with bipolar disorder was particularly pronounced during the first approximately 15 years of follow-up, while the incidence was higher among reference individuals from approximately 16 years of follow-up and onwards. This finding is to be interpreted alongside the results of the post hoc analysis with death as outcome ( Figure 2 B), suggesting that the substantially increased mortality rate among patients with bipolar disorder may explain the osteoporosis incidence pattern (healthy survivor bias). Specifically, patients with bipolar disorder who remained alive more than 16 years after the initiation of follow-up represent a selected group (eg, healthy lifestyle) with a lower risk of osteoporosis compared with reference individuals that remained alive at this late stage of follow-up.
The results of the sex-stratified comparison of the incidence rate of osteoporosis among patients with bipolar disorder and reference individuals are available in eTable 5 in the Supplement . While the incidence rate was lower among male individuals, the association between bipolar disorder and osteoporosis was particularly pronounced among male individuals (HRR, 1.42; 95% CI, 1.26-1.60) compared with female individuals (HRR, 1.07; 95% CI, 1.01-1.13).
Among patients with bipolar disorder, 8750 (38.2%) received lithium, 16 864 (73.6%) received an antipsychotic, 3853 (16.8%) received valproate, and 7588 (33.1%) received lamotrigine (not mutually exclusive). Characteristics of the patients with bipolar disorder receiving lithium, antipsychotics, valproate, and lamotrigine are shown in Table 1 . The treatment overlaps are visualized in eFigures 2, 3, 4, and 5 in the Supplement .
Table 2 lists the results of the analyses investigating the association between lithium treatment of bipolar disorder and osteoporosis. Lithium treatment (compared with no lithium treatment) was associated with a substantial and statistically significant decrease in risk of osteoporosis. This decrease in risk was found both in the model taking treatment duration into account (HRR, 0.62; 95% CI, 0.53-0.72) and in the intention-to-treat model (HRR, 0.78; 95% CI, 0.71-0.87). Treatment with antipsychotics, valproate, and lamotrigine showed no material or statistically significant association with the risk of osteoporosis in the adjusted models. The analyses stratifying the cohort on incident and prevalent bipolar disorder yielded similar results (eTable 6 in the Supplement ), as did the analyses using osteoporosis with pathological fracture as outcome (eTable 7 in the Supplement ) and the sex-stratified analyses (eTable 8 in the Supplement ).
The results of the cumulative dose-response association analyses of lithium, antipsychotics, valproate, and lamotrigine are shown in Figure 3 . Here, only lithium treatment corresponding to more than 2 years was associated with a statistically significant decrease in risk of osteoporosis. The higher the cumulative lithium dose, the greater the decrease in risk of osteoporosis (log-rank test P < .001). The sex-stratified analyses yielded similar results (eFigure 6 in the Supplement ).
In this nationwide study of 22 912 patients with bipolar disorder and 114 560 age- and sex-matched reference individuals followed up for 1 213 695 person-years, bipolar disorder was associated with an increase in risk of osteoporosis. This finding is consistent with prior reports of increase in risk of fractures, 3 low bone mineral density, and osteopenia 5 among patients with bipolar disorder. Furthermore, in this study, the association between bipolar disorder and osteoporosis was substantially more pronounced among men than among women. While the data available for the present study do not allow for exploration of this apparent effect modification by sex, it should be addressed in future studies.
We also found that treatment with lithium — unlike treatment with antipsychotics, valproate, and lamotrigine — was associated with a decrease in risk of osteoporosis. This resonates well with prior studies having suggested a potentially bone-protective effect of lithium, 17 , 18 likely mediated by its activation of β-catenin via inhibition of glycogen synthase kinase-3β. 20 , 21 In this regard, a recent whole-exome sequencing study identified AKAP11 (the gene encoding A-kinase anchoring protein 11) as associated with risk of bipolar disorder. 30 At the protein level, AKAP11 interacts with glycogen synthase kinase-3β. 31 Hence, the findings of this study are also plausible from a mechanistic perspective.
There are 2 main implications of the results of this study. First, the finding of elevated risk of osteoporosis in bipolar disorder adds to a growing body of evidence suggesting that bone health should be a priority in the clinical management of bipolar disorder. 3 , 12 Specifically, guiding patients toward a lifestyle supporting bone health (no smoking, reduced alcohol consumption, healthy diet, and exercising) and monitoring bone density via dual-energy x-ray absorptiometry scans among those with additional risk factors seems warranted. Second, as new treatment modalities for osteoporosis are sorely needed, 1 , 2 the potential bone protective effect of lithium should be subjected to further study. In this context, the results of an ongoing randomized clinical trial investigating whether lithium increases bone healing in patients with long bone fractures 32 will be of great interest.
There are limitations to this study. First, quantitative measures of bone health (eg, bone mineral density) were not available to us. However, by defining osteoporosis via hospital discharge diagnoses and prescribed medications, the study outcome should have clinical validity. Second, data on diagnoses assigned prior to the ICD-10 being adopted in Denmark (January 1, 1994) were not available for this study. Hence, the cohort of patients with bipolar disorder is not incident in the strict sense. However, we did ensure that patients were at least 2-year incident, as those registered with a diagnosis of bipolar disorder in the period from January 1, 1994, to December 31, 1995, were not included in the cohort. Third, it cannot be excluded from consideration that there is a healthy user bias associated with lithium treatment owing to the associated blood-testing regimen. On the other hand, as lithium is often used for prevention of manic episodes, patients treated with lithium may be more severely ill compared with those treated with antipsychotics, valproate, and lamotrigine, which would counter a healthy user bias. Fourth, data on pharmacological treatment during inpatient hospital stays are not available in the Danish registers, and this may have affected the calculations of treatment duration. Fifth, data on redemption of prescriptions from Danish pharmacies prior to 1995 are not available via the Danish National Prescription Registry. We therefore have no information on pharmacological treatment from that period. As such, exposure to pharmacological treatment prior to the inception of the Danish National Prescription Registry (eg, those considered as not taking lithium or other mood-stabilizers in the present study may in fact have a history of use [ie, misclassification]) is likely to have added noise in the detection of any true signals, like the apparent association between lithium and decrease in risk of osteoporosis. Sixth, there was a large overlap between the treatment cohorts (eFigures 2, 3, 4, and 5 in the Supplement ), which likely also complicates signal detection because of potential interactions between the mood-stabilizing drugs, which may affect the risk of osteoporosis. Yet lithium stood out as the only treatment associated with a substantial and statistically significant decrease in risk of osteoporosis. Seventh, there is a risk of detection bias because bipolar disorder is associated with unintentional injuries 33 , 34 that may increase the likelihood of pathologic fractures due to osteoporosis and their detection. Eighth, information on diet, exercise, alcohol consumption, and smoking, which—from a mediation perspective—is important in the context of osteoporosis, is not available in the Danish registers.
The results of this study suggest that individuals with bipolar disorder were at elevated risk of developing osteoporosis and that lithium treatment was associated with a reduction in this risk. These findings suggest that bone health should be a priority in the clinical management of bipolar disorder and that the potential bone-protective properties of lithium should be subjected to further study, both in the context of bipolar disorder and in osteoporosis.
Accepted for Publication: January 27, 2022.
Published Online: March 30, 2022. doi: 10.1001/jamapsychiatry.2022.0337
Corresponding Author: Søren Dinesen Østergaard, MD, PhD, Department of Affective Disorders, Aarhus University Hospital - Psychiatry, Palle Juul-Jensens Boulevard 175, 8200 Aarhus N, Denmark ( [email protected] ).
Author Contributions: Drs Köhler-Forsberg and Rohde had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design : All authors.
Acquisition, analysis, or interpretation of data : Köhler-Forsberg, Rohde, Østergaard.
Drafting of the manuscript : Köhler-Forsberg, Østergaard.
Critical revision of the manuscript for important intellectual content : Rohde, Nierenberg.
Statistical analysis : Köhler-Forsberg, Rohde.
Supervision : Nierenberg, Østergaard.
Conflict of Interest Disclosures: Dr Köhler-Forsberg reports honoraria for lectures for Lundbeck. Dr Rohde received the 2020 Lundbeck Foundation Talent Prize. Dr Nierenberg is a consultant for Abbott Laboratories, Alkermes, American Psychiatric Association, Appliance Computing Inc, Mindsite, Basliea, BrainCells Inc, Brandeis University, Bristol Myers Squibb, Clintara, Corcept, Dey Pharmaceuticals, Dainippon Sumitomo (now Sunovion), Eli Lilly, EpiQ, Mylan, Forest, Genaissance, Genentech, GlaxoSmithKline, Hoffman LaRoche, Infomedic, Intra-Cellular Therapies, Lundbeck, Janssen Pharmaceutica, Jazz Pharmaceuticals, Medavante, Merck, Methylation Sciences, Naurex, NeuroRx, Novartis, Otsuka, PamLabs, Parexel, Pfizer, PGx Health, Ridge Diagnostics Shire, Schering-Plough, Somerset, Sunovion, Takeda Pharmaceuticals, Targacept, and Teva; consulted through the Massachusetts General Hospital Clinical Trials Network and Institute for AstraZeneca, BrainCells Inc, Dainippon Sumitomo/Sepracor, Johnson and Johnson, Labopharm, Merck, Methylation Science, Novartis, PGx Health, Shire, Schering-Plough, Targacept and Takeda/Lundbeck Pharmaceuticals; receives grant or research support from American Foundation for Suicide Prevention, Agency for Healthcare Research and Quality, Brain and Behavior Research Foundation, Bristol-Myers Squibb, Cederroth, Cephalon, Cyberonics, Elan, Eli Lilly, Forest, GlaxoSmithKline, Janssen Pharmaceutica, Intra-Cellular Therapies, Lichtwer Pharma, Marriott Foundation, Mylan, National Institute of Mental Health, PamLabs, Patient-Centered Outcomes Research Institute, Pfizer, Shire, Stanley Foundation, Takeda, and Wyeth-Ayerst; honoraria include Belvoir Publishing, University of Texas Southwestern Dallas, Brandeis University, Bristol-Myers Squibb, Hillside Hospital, American Drug Utilization Review, American Society for Clinical Psychopharmacology, Baystate Medical Center, Columbia University, Controlled Risk Insurance Company, Dartmouth Medical School, Health New England, Harold Grinspoon Charitable Foundation, Imedex, Israel Society for Biological Psychiatry, Johns Hopkins University, MJ Consulting, New York State, Medscape, MBL Communications Inc, Massachusetts General Hospital Psychiatry Academy, National Association of Continuing Education, Physicians Postgraduate Press, State University of New York Buffalo, University of Wisconsin, University of Pisa, University of Michigan, University of Miami, University of Wisconsin at Madison, World Congress of Brain Behavior and Emotion, American Professional Society of ADHD and Related Disorders, International Society for Bipolar Disorder, SciMed, Slack Publishing, Wolters Kluwer Publishing, the American Society for Clinical Psychopharmacology (formerly NCDEU), Rush Medical College, Yale University School of Medicine, National Nuclear Data Center, Nova Southeastern University, National Alliance on Mental Illness, Institute of Medicine, Continued Medical Education Institute, and the International Society for CNS Clinical Trials and Methodology; is currently or was formerly on the advisory boards of Appliance Computing Inc, BrainCells Inc, Eli Lilly, Genentech, Johnson and Johnson, Takeda/Lundbeck, Targacept, and InfoMedic; owns stock options in Appliance Computing Inc, BrainCells Inc, and Medavante; has copyrights to the Clinical Positive Affect Scale and the Massachusetts General Hospital Structured Clinical Interview for the Montgomery Asberg Depression Scale exclusively licensed to the Massachusetts General Hospital Clinical Trials Network and Institute. Dr Østergaard received the 2020 Lundbeck Foundation Young Investigator Prize and owns units of mutual funds with stock tickers DKIGI and WEKAFKI, as well as units of exchange traded funds with stock tickers TRET, 2B76, EXH2, QDVE, QDVH, USPY, SADM, and BATE. No other disclosures were reported.
Funding/Support: Dr Rohde is supported by the Danish Diabetes Academy, funded by the Novo Nordisk Foundation (NNF17SA0031406) and the Lundbeck Foundation (R358-2020-2342). Dr Nierenberg is supported by grants from the Patient-Centered Outcomes Research Institute (PaCR-2017C2-8169, XPPRN-1512-33786, XPPRN-1512-33786), the Thomas P. Hackett, MD Endowed Chair in Psychiatry at MGH, and the Dauten Family Center for Bipolar Treatment Innovation. Dr Østergaard is supported by grants from the Novo Nordisk Foundation (NNF20SA0062874), the Lundbeck Foundation (R358-2020-2341 and R344-2020-1073), the Danish Cancer Society (R283-A16461), the Central Denmark Region Fund for Strengthening of Health Science (1-36-72-4-20), the Danish Agency for Digitisation Investment Fund for New Technologies (2020-6720), and Independent Research Fund Denmark (7016-00048B).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank Helene Bøtker, BS, Aarhus University, for her contribution to the literature search. She was not compensated for her contributions.
Additional information: The data used for this study cannot be shared according to Danish Law. Access to the data can be obtained by application to Statistics Denmark and the Danish Health Data Authority.
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Immune cell ratios are higher in bipolar affective than unipolar depressive disorder and modulated by mood episode: a retrospective, cross-sectional study.
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Koureta, A.; Asimakopoulos, L.O.; Bozikas, V.P.; Agorastos, A. Immune Cell Ratios are Higher in Bipolar Affective than Unipolar Depressive Disorder and Modulated by Mood Episode: A Retrospective, Cross-Sectional Study. Brain Sci. 2023 , 13 , 448. https://doi.org/10.3390/brainsci13030448
Koureta A, Asimakopoulos LO, Bozikas VP, Agorastos A. Immune Cell Ratios are Higher in Bipolar Affective than Unipolar Depressive Disorder and Modulated by Mood Episode: A Retrospective, Cross-Sectional Study. Brain Sciences . 2023; 13(3):448. https://doi.org/10.3390/brainsci13030448
Koureta, Anastasia, Lampros O. Asimakopoulos, Vasilios P. Bozikas, and Agorastos Agorastos. 2023. "Immune Cell Ratios are Higher in Bipolar Affective than Unipolar Depressive Disorder and Modulated by Mood Episode: A Retrospective, Cross-Sectional Study" Brain Sciences 13, no. 3: 448. https://doi.org/10.3390/brainsci13030448
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A total of 21 studies met the inclusion criteria and were considered in this analysis. The studies evaluated psychotherapy (n=7) or drug therapy (n=12) interventions and fMRIs were conducted ...
clinical case presentation -bipolar disorder. 1. CASE PRESENTATION DR ASIF IQBAL. 2. HISTORY Pt seen in my psychiatry rotation ,in male ward (khasab hospital) 37 yrs old indian man,with past h/o multiple episodes of depression,last episode was 1 yrs back.never had manic or hypomanic episodes. His wife said his diagnosis was schizophrenia He has ...
Two small cross-sectional studies have found lower bone mineral density among 61 drug-naive newly diagnosed patients with bipolar disorder compared with healthy control individuals 4 and a high prevalence of osteopenia (50%) and osteoporosis (12.5%) among 16 elderly inpatients with bipolar disorder, respectively. 5 However, there is a lack of ...
Immune dysregulation is implicated in the pathophysiology of both bipolar and major depressive disorder, while immune cell ratios (IRCs) have recently been proposed as clinically applicable immune biomarkers. We investigated IRCs differences in affective disorders and their association with current mood episodes and clinical features. This retrospective cohort study analyzed neutrophil&ndash ...