Paper Summaries

Martinowich, Keri, et al. “Bipolar Disorder: From Genes to Behavior Pathways.” The Journal of Clinical Investigation, American Society for Clinical Investigation, 1 Apr. 2009, www.jci.org/articles/view/37703.

• Bipolar is classified as a mood disorder that is chronic, and common and is characterized by manic episodes, elevated mood, elevated energy, grandiose thoughts, depression, and in some cases psychosis. These symptoms lead to little functioning which causes lack of productivity. Prognoses for bipolar disorder is poor with chances of relapse and cognitive impairments. Bipolar disorder is a disease that is affected by genetics as well as the environment. When studying bipolar disorder, the monoaminergic neurotransmitter system is looked at; serotonergic, noradrenergic, and dopaminergic systems. Neuroimaging such as fMRIs identified abnormalities in the amygdala, the orbital and medial prefrontal cortex, the anterior cingulate, the medial thalamus, and the basal ganglia. During manic episodes, there is reduced activity in the right prefrontal cortex. The right prefrontal cortex is possibly the cause of poor impulse control, risk-taking, delusions, etc.  

Patino, Luis R, et al. “A Randomized, Double-Blind, Controlled Trial of Lithium versus Quetiapine for the Treatment of Acute Mania in Youth with Early Course Bipolar Disorder.” Journal of Child and Adolescent Psychopharmacology, U.S. National Library of Medicine, Sept. 2021, www.ncbi.nlm.nih.gov/pmc/articles/PMC8568789/.

• This article explains a 6-week experiment that was done comparing the effectiveness and tolerability of lithium and quetiapine treatment for manic episodes in youths who have an early diagnosis of bipolar 1 disorder. Youth that have bipolar 1 disorder tend to experience more significant disability, increased risk of suicide reduced quality of life, and functional impairment. Lithium and quetiapine both showed effectiveness when treating mania in young children in randomized placebo-controlled trials. Quetiapine interacts with dopaminergic and serotonergic receptors. This specific study had participants 10-17 years old with a diagnosis (from the DSM) of bipolar 1 disorder. All of the participants were not allowed to have a previous hospitalization for a manic episode, no psychotropic medication usage a week before starting the trials, etc. Since this study was randomized, some participants were given 100 mg/d of quetiapine or a placebo and 30 mg/d of lithium or a placebo. The study showed that participants receiving the quetiapine achieved improvement than the participants who were receiving lithium.

Chen, Fan. “Study on the Effect Model of Medical Service Rehabilitation Training Combined with Home Care on Symptom Relief of Bipolar Disorder Patients: CNS SPECTRUMS.” Cambridge Core, Cambridge University Press, 9 Mar. 2023, www.cambridge.org/core/journals/cns-spectrums/article/study-on-the-effect-model-of-medical-service-rehabilitation-training-combined-with-home-care-on-symptom-relief-of-bipolar-disorder-patients/2A959AD0E0233564D5C9802485872AE4.

• Bipolar disorders may experience irritability, suicidal ideations, sleeping more, etc. A medical model of medical rehabilitation and family hospitalization was done. This study looked at the effects that medical rehabilitation and family hospitalization had on patients with bipolar disorder. 120 participants were grouped into an experimental group and a control group. Both groups were given medication treatments according to the condition of their bipolar disorder. The experimental group was treated with medical rehabilitation and family hospitalization as well. Hamilton Depression Scale and Bech-Fafaelsdn Manic Scale were taken on both groups before and after the trial. The scores on the HAMD and BRMS for the experimental group were higher significantly than the scores of those in the control group. This medical model shows that patients with bipolar disorder benefit greatly from medical rehabilitation and family hospitalization; these things can effectively relieve symptoms.

Suominen, K., et al. “Gender Differences in Bipolar Disorder Type I and II - Wiley Online Library.” Acta Psychiatrica Scandinavica , 2009, onlinelibrary.wiley.com/doi/10.1111/j.1600-0447.2009.01407.x

• Gender differences in bipolar disorders. Does bipolar disorder have different effects on females than it does on males? Studies show that women are more likely to progress in bipolar disorder more rapidly, and have depressive episodes, bulimia, PTSD, etc. Men typically have manic episodes more often than women do, and some may develop alcoholism. In this study though, 191 patients (in and outpatients) were evaluated. Each participant was given a Mood Disorder Questionnaire. The questionnaire asked each participant from ages 18-59 if they looked for treatment, had been referred to a psychologist, or already received treatment. Results showed that female patients with bipolar disorder showed signs of their first manic episode at a younger age than males did, and also looked for psychiatric treatment before males did. Women patients were more likely to develop eating disorders, phobias, and borderline personality than men were. But men were still more likely to develop substance abuse disorders such as alcoholism, etc. 

DelBello, M.P, et al. “The Impact of Substance Abuse on the Course of Bipolar Disorder.” Biological Psychiatry, Elsevier, 28 Sept. 2000, www.sciencedirect.com/science/article/pii/S0006322300009008?casa_token=PacKx6XwMRQAAAAA%3A8-W3-CZRV6U6zQoYOZocbHoEAHIstL6GdZdOq_ZUXsG8BRkUuHsnu1xl6Jn20JLGLh7BJ92exgQ.

• During the course of bipolar disorder, substance abuse was fairly common. Research shows that 60% or more of bipolar patients developed some type of substance abuse in their lifetime. Evidence was found that substance abuse was associated with low remission rates during hospitalization and poor response to lithium treatments. Alcohol abuse and cannabis use was observed in this study. This study showed that alcohol abuse was associated with the time patients were experiencing depression, and cannabis use was associated with manic episodes.   

Duffy, Anne, et al. “Early Stages in the Development of Bipolar Disorder.” Journal of Affective Disorders, Elsevier, 21 June 2009, www.sciencedirect.com/science/article/pii/S0165032709002274.

• Genetics plays a big role in the contribution of bipolar disorder, but it is also believed that even though genetics is a big risk factor, a large part of the offspring will not develop bipolar disorder. It is thought that parents who have bipolar disorder are more likely to develop other psychiatric disorders throughout the course of the disorder, and this study aimed to figure out if children who contributed the bipolar disorder gene from the parents are at high risk for developing other psychiatric disorders as well. The children of the parents were assessed for 3 years. The psychological disorders that were most present were anxiety disorders, minor mood disorders, and adjustment disorders (a behavioral or emotional response to a traumatic event). These disorders arose around the age of 16 with depression that was polar (polarity; high or low). Manic, mixed, and depressive episodes did not occur before the children reached puberty. In this study, parents were to complete a SADS-L interview which made sure that their symptoms matched the criteria for the diagnosis of bipolar disorder in the DSM-IV. Offspring of these parents (ages 8-25) were interviewed and assessed by psychiatrists annually or any time a symptom were to arise, and this assessment would happen until they turned 30. Offspring that were of older age had a higher significance of developing major mood, anxiety, sleep, and substance use abusers compared to a control group. The study showed there was an increased risk of mood and non-mood disorders (sleep disorders, anxiety disorders), but not ADHD or OCD.

McAulay , Claire, et al. Early Intervention for Bipolar Disorder in Adolescents: A Psychosocial Perspective, 2017, onlinelibrary.wiley.com/doi/full/10.1111/eip.12474.

• Treating an illness early on in its diagnosis will help outcomes be better for patients. Since the majority of illnesses appear around adolescence, treating the illness early on would be very powerful as the brain matures until 25 years of age. This study looks at treatments such as CBT, psychoeducation, and interventions that can treat early-onset bipolar disorder, which can also help prevent sleep disorders and anxiety.

Stiles , Bradie  M., et al. “Identifying the Complexity of Diagnosing Bipolar Disorder: A Focused ...” Identifying the Complexity of Diagnosing Bipolar Disorder: A Focused Ethnography, 2013, www.tandfonline.com/doi/full/10.1080/01612840.2019.1615584.

• Patients that were assessed positive for bipolar disorder should be started on mood stabilizers or an antipsychotic medication right away. It often occurs that bipolar disorder is misdiagnosed as depressive disorder because patients report more depressive episodes than manic episodes. If correct treatment is not given to someone with bipolar disorder, it may worsen the symptoms. If bipolar disorder is wrongly diagnosed as depressive disorder, which is treated with antidepressants, it can worsen the symptoms of bipolar disorder which increases the risk of suicide attempts, etc.

Tondo , Leonardo, et al. “Lithium Treatment and Risk of Suicidal Behavior in Bipolar Disorder Patients.” The Journal of Clinical Psychiatry, U.S. National Library of Medicine, 1998, pubmed.ncbi.nlm.nih.gov/9721820/.

• Suicide risks are more common and are higher in bipolar disorder than in unipolar depression. This study is analyzing the effect of lithium on anti-suicidal behaviors. The hypothesis in this article states that using lithium as a treatment for bipolar disorder would reduce the risk of suicidal behavior and that stopping the use of lithium would increase the risk of suicidal behavior. In the study, 310 bipolar disorder patients were evaluated in a research clinic for twenty years. While these patients were in the research clinic, they received continuing lithium maintenance therapy. This study showed that during the beginning course of the lithium treatment, suicidal behavior was more common, and after the treatment for lithium was discontinued suicidal behavior was more common but only during the first year after stopping the lithium treatment.

Kovacs , Maria, and Myrna Pollock . “Bipolar Disorder and Comorbid Conduct Disorder in Childhood and Adolescence.” Journal of the American Academy of Child & Adolescent Psychiatry, Elsevier, 4 Jan. 2010, www.sciencedirect.com/science/article/pii/S0890856709635693.

• This article is concerned with the relationship between behavior disorders and bipolar disorder in children (adolescents). Some behaviors that were observed were burglary, vandalism, and stealing. 

Calabrese, Joseph  R, and et.al. “A Double-Blind, Placebo-Controlled, Prophylaxis Study of Lamotrigine in Rapid-Cycling Bipolar Disorder  .” J Clin Psychiatry , 2000, www.psychiatrist.com/wp-content/uploads/2021/02/12717_double-blind-placebo-controlled-prophylaxis-study.pdf.

• This trial was double-blind and was done on humans. The patients who were eligible to participate in these trials were men and women who were older than 18 and were diagnosed with bipolar 1 or bipolar 2 as per the DSM-5. Patients required to be in good physical health, had to go for labs, ECGs, physical exams, etc. Patients that were not allowed to participate in this experiment were patients who had a panic disorder, were suicidal, had OCD, social phobia, or an eating disorder within the last year. As stated before, the study was ‘double blind, flexible dose, placebo-controlled, parallel-group designed’. Study was run in a preliminary phase, which is the first phase, and then in a randomized phase, which is the second phase. During the preliminary phase, the patients were typically brought in with euthymia or mood episodes such as mania, hypomania, depression, etc. The patients were started on lamotrigine with a target dosage of 200mg/day; which means in the first two weeks they were given 25mg per day, in the third and fourth week they were given 50mg per day, and in the fifth week they were given 100mg per day. After the fifth week concluded the doses of lamotrigine were adjusted if they needed to be, but the range was from 100mg to 300mg per day. Patients were taken to clinics for screening visits (Mania Rating Scale, medical and psychiatric history, etc). These screening visits were conducted on the first day of the preliminary phase, 14 days after the preliminary phase, and the visits were randomized weekly. If a patient was experiencing mood episodes, other psychotropic mediations were allowed to be used, but only during the first 4 weeks. After 4 to 8 weeks of exposure to lamotrigine, the other psychotropic medications were reduced or diminished because the patient was considered to have meet the criteria for wellness; this criteria was that the patients were given a daily minimum dose of 100mg of lamotrigine with low scores on the tests from the screening visits. During the randomized phase, the patients were assigned a 1:1 ratio treatment with lamotrigine and a placebo in a double-blind fashion. The lamotrigine and the placebo were given in 100mg tablets and were administered once a day. If patients began to experience a change in symptoms, the dosage of the lamotrigine and the placebo (double blind) were increased to the next dose, but the maximum dosage was 500mg. 

McElroy, Susan L., et al. “Axis I Psychiatric Comorbidity and Its Relationship to Historical Illness Variables in 288 Patients with Bipolar Disorder.” American Journal of Psychiatry, 1 Mar. 2001, ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.158.3.420.

• Axis I disorders are disorders like schizophrenia, anxiety, eating, and sleep disorders. It is believed that axis I disorders exist along with bipolar disorder. The methods section in this article takes 288 bipolar disorder patients and gives them "self-rated" questionnaires to diagnose them with axis I co-morbid disorders. 

Tohen, Mauricio, and et.al. “Efficacy of Olanzapine in Combination with Valproate or Lithium in the Treatment of Mania in Patients Partially Nonresponsive to Valproate or Lithium Monotherapy.” Archives of General Psychiatry, U.S. National Library of Medicine, 2002, pubmed.ncbi.nlm.nih.gov/11779284/.

• This study looked at how effective olanzapine was in combination with lithium or valproate. All patients in this study had to be diagnosed with bipolar disorder and have manic or mixed episodes. During study period one, the patients were entered into a 2-7 day “screening and washout period” which all medications other than lithium and valproate were discontinued. Patients who were taking other types of medication were started on either lithium or valproate. Patients were assessed by being given the YMRS (young mania rating scale), and only the patients who were scoring greater than or equal to 16 were given the randomized treatment of either olanzapine of a placebo. During study period two, there was a 6-week double blind phase where levels of lithium and valproate were still being given. Patients were then given a randomized 2:1 ratio to add olanzapine to valproate or lithium or add a placebo to valproate or lithium.

Young, Jared W, et al. “Mice with Reduced DAT Levels Recreate Seasonal-Induced Switching between States in Bipolar Disorder.” Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, U.S. National Library of Medicine, July 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC6006292/.

• In this study mice models were used. This study assessed whether reduced dopamine levels mimicked seasonal induced switches. Whether summer-like states was associated with mania, and winter-like states was associated with depression. Male C57BL/6 J mice were used, male DAT HY (n= ?) and wildtype (n= ?) mice were also used. The training and testing of these mice started when they were 3 months old. The mice were housed with a maximum of 4 per cage, and the chambers they were housed in were climate-controlled photoperiod chambers. There were three types of photoperiods that each chamber was set to; short active photoperiod which was similar to a day/night cycle, a normal-active photoperiod which means lights were on for longer than they were off, and a long-active photoperiod which means lights were on shorter than they were off.

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Young, Jared  W, and et.al. “Increased Risk-Taking Behavior in Dopamine Transporter Knockdown Mice: Further Support for a Mouse Model of Mania.” SageJournals , 2011, journals.sagepub.com/doi/pdf/10.1177/0269881111400646.

• This study used mice models to study risk taking behavior and mania in mice. In this study female DAT KD (knockdown) WT litter mate mice (n=15 per group) were trained using the Iowa Gambling Task (IGT). “The IGT is a type of decision-making task that mimics real life situations by reproducing uncertain conditions based on probabilistic rewards or penalties”. The mice weighed 15-26g. 

Young, Jared  W, and et.al. “Convergent Neural Substrates of Inattention in Bipolar Disorder Patients and Dopamine Transporter-Deficient Mice Using the 5-Choice CPT.” Wiley Online Library , 2019, onlinelibrary.wiley.com/doi/abs/10.1111/bdi.12786.

• This experiment required using 5-choice CPT mice which are mice and a "human attentional task". The task was to respond to a target stimuli while responding to a nontarget stimuli. This was meant to model the neural deficits of bipolar disorder in humans when they have prefrontal cortex lesions or reduced DAT expression. 

Hagihara, Hideo, et al. “Peripheral Blood Metabolome Predicts Mood Change-Related Activity in Mouse Model of Bipolar Disorder - Molecular Brain.” BioMed Central, BioMed Central, 10 Dec. 2019, molecularbrain.biomedcentral.com/articles/10.1186/s13041-019-0527-3.

• This study aimed to identify mood states and biological features associated with mood changes by using an infradian cyclic locomotor activity. This activity revealed that there is a relationship between actual and predicted activity levels. 

Enkhuizen, Jordy van, et al. “Modeling Bipolar Disorder in Mice by Increasing Acetylcholine or Dopamine: Chronic Lithium Treats Most, but Not All Features - Psychopharmacology.” SpringerLink, Springer Berlin Heidelberg, 5 July 2015, link.springer.com/article/10.1007/s00213-015-4000-4.

• The study hypothesized that cholinergic and dopaminergic "pharmacological" manipulations would model depression and mania in the C57BL/6 mice. The mice were given either saline or acetylcholinesterase inhibitor physostigmine and were given the tail suspension test and forced swim test. 

Rosenthal, Sandra J, and Richard McCarty. “Switching Winter and Summer Photoperiods in an Animal Model of Bipolar Disorder.” Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, U.S. National Library of Medicine, Sept. 2019, www.ncbi.nlm.nih.gov/pmc/articles/PMC6785099/.

• Photoperiod chambers have been linked to bipolar disorder and depression in mice. Mice would be placed in a short active photoperiod chamber, a long active photoperiod chamber, and a normal active photoperiod chamber (control). 

Bosse, R., et al. “Valproate Attenuates Hyperactive and Perseverative Behaviors in Mutant Mice with a Dysregulated Dopamine System.” Biological Psychiatry, Elsevier, 7 Feb. 2003, www.sciencedirect.com/science/article/abs/pii/S0006322302014890?casa_token=S40k26U8hroAAAAA%3ApB_ab9Dhfab4UbGDaO9l2TI_3rYMb323p12U_JdHxksdoSDLkDEQDxC6WCHyv-T_YLSPaWGgzlI.

• DAT knockdown mice are used in this experiment. DAT knockdown mice are mice that have a dysregulated dopamine system. These mice were given valproate to regulate hyperactivity in mice, and the results showed that the valproate helped lessen hyperactivity in the DAT knockdown mice. 

Young , Jared  W, and et.al. “The Mania-like Exploratory Profile in Genetic Dopamine Transporter Mouse Models Is Diminished in a Familiar Environment and Reinstated by Subthreshold Psychostimulant Administration.” Pharmacology, Biochemistry, and Behavior, U.S. National Library of Medicine, 2010, pubmed.ncbi.nlm.nih.gov/20363246/.

• This study uses DAT knockdown mice because this species of mice tends to display manic behaviors. The mice were dosed with a pharmaceutical called GBR 12909. Additionally to being given this drug, the mice were given the behavioral pattern monitor test. 

Valvassori, Samira  S, and et.al. “Lithium Modulates the Production of Peripheral and Cerebral Cytokines in an Animal Model of Mania Induced by Dextroamphetamine.” Wiley Online Library , 2015, onlinelibrary.wiley.com/doi/abs/10.1111/bdi.12299.

• This study hypothesizes that bipolar disorder is related to immune system alterations and inflammation. Lithium is often used to treat lithium. This study looks at the effects of lithium on behavior (mania, etc.) and the effects it has on inflammation in the body. 

Nester, E J, and et.al. “Chronic Antidepressant Administration Decreases the Expression of Tyrosine Hydroxylase in the Rat Locus Coeruleus.” PNAS, 1990, www.pnas.org/doi/full/10.1073/pnas.87.19.7522.

• As the title of this article suggests, it is hypothesized that the chronic use of antidepressants can decrease the expression of tyrosine hydroxylase; TH converts the amino acid tyrosine to the neurotransmitter dopamine. 

Knapen , S.E, and M. van de Werken . “The Duration of Light Treatment and Therapy Outcome in Seasonal Affective Disorder.” Journal of Affective Disorders, Elsevier, 1 June 2014, www.sciencedirect.com/science/article/pii/S0165032714003292#:~:text=Discussion,people%20with%20seasonal%20affective%20disorder.

• This study looks at seasonal affective disorder, which is essentially symptoms of major depression that are correlated with seasonal changes. Seasonal depression of often treated with light therapy. This study aims to look at light therapy treatments and their affectivenss after one and two weeks, whether females or males respond differently to the light therapy treatments, etc. 

Leclercq, Bastien, et al. “Photoperiod Integration in C3H Rd1 Mice.” Journal of Pineal Research, U.S. National Library of Medicine, 2021, pubmed.ncbi.nlm.nih.gov/33326640/.

• The superchiasmastic nucleus (SCN) is responsible for circadian rhythm in mice. The SCN encodes photoperiodic variations when melatonin is being secreted. Levels of melatonin are increased nocturnal levels in the winter and decreased nocturnal levels in the summer. Locomotor activity and melatonin secretion are looked at in this study. The mice are exposed to either long active photoperiods or short active photoperiods. 

Nishino, Seiji, and Emmanuel Mignot . “Dopamine Reuptake Inhibitor.” Dopamine Reuptake Inhibitor - an Overview | ScienceDirect Topics, 2011, www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/dopamine-reuptake-inhibitor#:~:text=Bupropion%20is%20unique%20among%20antidepressants,it%20is%20most%20commonly%20prescribed.&text=Another%20unique%20feature%20of%20bupropion%20is%20its%20lack%20of%20serotonergic%20effects.

• Explains the antidepressant I am using in the methods section of my paper. 

Costa-Nunes, João P, et al. “Animal Models of Depression and Drug Delivery with Food as an Effective Dosing Method: Evidences from Studies with Celecoxib and Dicholine Succinate.” BioMed Research International, U.S. National Library of Medicine, 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4433645/.

• Used dosages of antidepressants that were similar to this article in my methods. 

Kapur , Shitij, et al. “Antipsychotic Dosing in Preclinical Models Is Often Unrepresentative of the Clinical Condition: A Suggested Solution Based on in Vivo Occupancy.” The Journal of Pharmacology and Experimental Therapeutics, U.S. National Library of Medicine, 2020, pubmed.ncbi.nlm.nih.gov/12606608/.

• Used dosages of antipsychotics that were simular to this article in my methods.