CTPSD and Bipolar

Empirical Research Article

Bipolar disorder (BPD) is a complex psychiatric mood disorder that requires extensive research to determine its exact underpinnings including brain structure, genetics, chemical imbalances, and environmental factors such as childhood trauma. This disorder is characterised by elevated and low levels of mood including mania/hypomania and depressive episodes.  Research has sought to identify genetic links, and although there is some evidence of this, no defining genetic markers have been identified.  However, this is currently changing and a shift towards researching other factors such as childhood trauma is gaining momentum in the hope of developing personalised and improved treatment plans that hope to have a greater success rate than traditional pharmacological treatment.

Bipolar disorder refers to a group of affective disorders, depressive and manic or hypomanic, where individuals experience fluctuations in mood and activity levels. This affects sleep, the ability to focus and has the potential to affect relationships and productivity both personally and professionally. Moods are polarized and characterised by recurrent episodes of depression and mania (euphoria, grandiosity and high energy), the severity of the manic episode determines the categorization of bipolar I (BPI) and bipolar II (BPII). Individuals with Bipolar I experience a full or mixed manic episode and may experience one or more depressive episodes.  Bipolar II involves at least one major depressive episode and at least one episode of hypomania, a milder version of mania, for a shorter period of time. When hypomania presents and depressive symptoms do not meet the criteria for depressive episodes it is classified as cyclothymic disorder. Depressive and hypomanic-like symptoms that do not meet diagnostic criteria fall under bipolar disorder not otherwise specified. The prevalence of bipolar has increased from 1% to 5%, largely due to the diagnostic criteria being expanded under the BPD spectrum and now includes less severe forms.  

Diagnostic tools have become more advanced but the different use of criteria and symptom profiles in family, twin and adoption studies can partly explain varying results.   Other psychiatric disorders frequently coexist alongside bipolar. What is to be determined is whether the genetic predispositions underlie the coexisting disorder and their comorbid conditions or not.

One of the greatest challenges in diagnosis are major overlaps with other disorders, which can lead to inaccurate diagnosis. As research expanded, the criteria for diagnosis has changed in an effort to increase accurate diagnosis. However, careful attention needs to be paid to symptomology to ensure that patients are not incorrectly diagnosed. One example is the importance of differentiating between trauma-related emotional dysregulation found in PTSD and bipolar II, with the key differential being an identifiable cause.  High rates of comorbidities, roughly one-third of patients with BPD report a PTSD diagnosis, between the two disorders have been well recorded. This could be due in part to the broadening of the PTSD spectrum to 20 symptoms, moving the focus away from fear responses. Complex PTSD has been categorised as a more severe form of PTSD, with specific symptoms such as problems with mood regulation which can arguably create diagnostic problems when differentiating between the two disorders. Although traumatic stressors can trigger bipolar in those who are genetically predisposed and more vulnerable, research suggests that symptoms could be masked as bipolar II leading to an incorrect and problematic misdiagnosis.  One suggestion for decreasing misdiagnosis in this particular area is taking a comprehensive examination of a patient’s trauma history before diagnosing a patient. 

There have been advances in diagnosis, but the underpinning anatomy, physiology, and pathology of BPD is not within the current scope of existing knowledge. It is a multifaceted disorder resulting from a combination of varying genetic profiles and environmental factors including chronic and traumatic stress.  Although there is evidence that neurotransmitter circuits are involved, there is no distinct deterioration or defectiveness that has been pinpointed as the culprit.

Bipolar disorder type II is especially difficult to diagnose accurately because of the difficulty in differentiation of this disorder from recurrent unipolar depression in depressed patients. Neuroimaging helps to identify the differences, but bipolar I and II are frequently misdiagnosed, because the diagnostic criteria for depressive episodes in the two disorders are identical. This is further compounded by the greater occurrence of depressive rather than hypomanic episodes in bipolar and manic episodes that are not sufficiently intense, thus making it possible to mask as unipolar depression. An integrative approach is  the most promising to identify biological causes to correctly diagnose, classify  and develop personalised and effective treatment plans.

The biomedical model, also known as the “disease model” purports that brain disease and biological abnormalities are primarily responsible for mental disorders and has dominated the healthcare system for decades. It is popular because it has important cultural uses, however the focus on the biomedical sometimes results in neglecting a more extensive biopsychosocial approach. Despite years of research scientists have not identified a distinct biological cause, or even a reliable biomarker, for any mental disorder. Despite no biological cause being identified, research to date has shown that decreased serotonin, dopamine and norepinephrine activity is linked to depression, and fluctuations of norepinephrine levels is present in individuals with bipolar. Raised levels of norepinephrine are present during mania, and lowered levels during depressive episodes quoted twice. Lithium, a typical treatment for bipolar, stabilizes serotonin and norepinephrine levels and promotes neurogenesis in the hippocampus of patients as opposed to SSRI’s which provide only short-term treatment for bipolar. Lithium as well as other psychotropic medication works by correcting the neurotransmitter imbalances that are present in mental disorders. On the other side of the coin, recreational drug use can rewire parts of the brain in previously mentally healthy individuals with their addiction leading to bipolar. Despite this research on the presence of chemical imbalances in bipolar disorder, there is little credible evidence that mental disorders are caused by chemical imbalances or that medications work by correcting such imbalances ​​(Deacon, 2013).

To date, bipolar was generally thought to have a significant genetic component but advances in molecular biology and neuropathological research (utilizing post-mortem brain studies) support the idea that brain structure also plays an important role, Individuals with Bipolar exhibit a deficit in the right hippocampus and an increase in basal ganglia activity particularly in the amygdala. When treated with lithium a significantly larger bilateral hippocampus volume has been observed in individuals with bipolar, conversely, reductions or damage to hippocampal volume through cerebral trauma, temporal lobe epilepsy or strokes have the potential to result in “secondary mania” which has the potential to develop into BPD. The increase in basal ganglia activity, primarily in the amygdala which is involved in the processing and regulating responses to emotional stimuli is another key dysfunction in individuals with bipolar. Additionally, when placed under electrochemical stimulation, the amygdala produces manic-like symptoms which further supports the evidence that the amygdala is key to understanding bipolar. On a broader scale, glial reduction, excess signal activity, neuropeptide abnormalities, and monoamine alterations present in bipolar suggest distinct imbalances in neurochemical regulation. Research on the brain structure of individuals with bipolar is limited as it consists of mostly post-mortem studies, with small sample sizes, and in further research is needed of neuroimaging studies to expand our understanding.

The heritable basis for the genetic transmission of bipolar has yielded substantial evidence through family, twins and adoption studies, revealing a strong genetic component for the disorder, although the quest to identify the susceptibility gene and the process in which they interrelate with the environment is ongoing. Studying identical, monozygotic (MZ) and dizygotic (DZ) twins in adoption studies is useful as it helps to separate environmental factors from genetics.  A higher concordance for bipolar disorder in MZ twins than in DZ twins has been recorded, with a 67 % concordance rate in MZ twins compared to 20 % in DZ twins. Challenges arise in determining the specific genetic pattern as this disorder is such a broad-spectrum disorder and thus assuming there is one single genetic pattern is a bold claim. As a disorder with various symptomology and presentation, genetic complexity underlies this disorder. Additionally, because of the challenges in diagnosis due to overlaps with other disorders mentioned above, this creates further difficulties in delineating a single homogenous genetic basis for bipolar as it shares many common risk factor genes with schizophrenia and depression. The genetic component in bipolar is undeniable, however, this may be better understood in terms of risk factors, rather than genetic abnormalities, that interact with the environment with many different genetic and environmental factors resulting in the same disorder.

Low levels of depression and high levels of fish consumption in Japan have been linked.   Some research suggests the decline in fish consumption in Japan is related to a rise in depression. However, the number of such studies is too small.  There is some evidence that reduced levels of omega-3 is linked to depression and an increase in dosage may be most effective for the depressed phase rather than the manic phase of the illness. However, in contrast a Finish study showed that there was no correlation between the dietary intake of Omega-3 fatty acids and depression.

Health plays an important role as major depression is often accompanied by immune dysfunction and increased proinflammatory markers with lower BDNF. This can be due to behavioural changes such as lack of movement and lack of self-care. Social support and low levels of TRP-5-HT, impaired health and vitality, work responsibility and dissatisfaction with the quality of life are significant correlates of depressive symptomatology. 

Childhood trauma (CT) can lead to abnormalities in emotional regulation, impulse control and cognitive functioning that could reduce the ability to cope with environmental risks at a later stage, including cannabis use and stressful life events.  Interferences in biological pathways (including neuroplasticity, inflammation and circadian systems) as a result of CT, increases the risk of BPD. Emerging research has found candidate genes belonging to these pathways that may help moderate the effects. The identification of epigenetic and transcriptomic markers is also being investigated.   It is proposed that it be addressed using psychosocial interventions to design personalised care plans (Aas et al., 2016).  

Childhood trauma is one of the possible pathogenetic factors and is strongly linked to bipolar. Sexual and emotional abuse in particular, are linked to suicide attempts.  It can induce early onset and accelerate the process (Larsson et al., 2013). Sexual abuse was more prevalent in BD 1 and emotional neglect was more frequent in BD II. This could also be attributed to varying sensitivities to childhood trauma in BP1 and BP I when discussing the severity on the continuum. Emotional neglect has been found to be the single most significant factor in this study, sexual abuse was found to be the least reported abuse by BP patients.  (Watson et al 2013).  Physical neglect was also linked to the severity of the mood episodes and psychotic features.  Childhood maltreatment is more prevalent in less developed countries,  and dependent on culture and socio-economic issues.  Lower education levels often lead to a poor standard of living with a higher risk of maltreatment resulting in an increased risk of mental health disorders.

There is no doubt that bipolar is a complex disorder, not only with regard to its symptomatology but also with regard to discovering the underlying causes. Due to twin studies and other genetic research, it is clear there is a strong heritable basis, however, due to the intricacies of both biological, social and environmental factors the causes and links are unclear. One of the initial challenges faced is the broad spectrum of bipolar, with distinctions between bipolar I, bipolar II and cyclothymic within the disorder as well as overlaps in symptoms between depression, PTSD and complex PTSD. These challenges in diagnoses are mirrored in difficulties to identify causes, however with genetic studies as well as studies on trauma a clearer image is emerging. Ultimately it is unlikely that a distinct cause will ever be identified due to challenges that begin with diagnosis and delineating symptoms and continue into the depths of genetic research, however, the more that is understood, the better equipped both medical professionals and those who support those with bipolar will become. What is known is that bipolar results from a complex interplay of biology, heritability, and environment and none can be understood or addressed in isolation.  


Aas, M., Henry, C., Andreassen, O. A., Bellivier, F., Melle, I., & Etain, B. (2016). The role of childhood trauma in bipolar disorders. Springer Science and Business Media LLC. doi:10.1186/s40345-015-0042-0

Baranyi, A., Amouzadeh-Ghadikolai, O., von Lewinski, D., Breitenecker, R. J., Rothenhäusler, H., Robier, C., . . . Meinitzer, A. (2017). Revisiting the tryptophan-serotonin deficiency and the inflammatory hypotheses of major depression in a biopsychosocial approach.  (San Francisco, CA) (5) e3968. doi:10.7717/peerj.3968

Bearden, C. E., Thompson, P. M., Brambilla, P., Sassi, R. B., Mallinger, A. G., Soares, J. C., . . . Glan, D. C. (2008). Three-dimensional mapping of hippocampal anatomy in unmedicated and lithium-treated patients with bipolar disorder. Neuropsychopharmacology (New York) 33(6), 1229-1238. doi:10.1038/sj.npp.1301507

Cakir, S., Tasdelen Durak, R., Ozyildirim, I., Ince, E., & Sar, V. (2016). Childhood trauma and treatment outcome in bipolar disorder. Journal of Trauma & Dissociation 17(4), 397-409. doi:10.1080/15299732.2015.1132489

Caligiuri, M. P., Brown, G. G., Meloy, M. J., Eberson, S. C., Kindermann, S. S., Frank, L. R., . . . Lohr, J. B. (2003a). An fMRI study of affective state and medication on cortical and subcortical brain regions during motor performance in bipolar disorder. Psychiatry Research: Neuroimaging, 123(3), 171-182.

Carmassi, C., Bertelloni, C. A., Cordone, A., Cappelli, A., Massimetti, E., Del; Oste, V., & Dell & Osso, L. (2020). Exploring mood symptoms overlap in PTSD diagnosis: ICD-11 and DSM-5 criteria compared in a sample of subjects with bipolar disorder. Journal of Affective Disorders (276) 205-211. doi:10.1016/j.jad.2020.06.056

Craddock, N., & Jones, I. (1999). Genetics of bipolar disorder. Journal of Medical Genetics 36(8), 585-46. doi:10.1136/jmg.36.8.585

Deacon, B. J. (2013). The biomedical model of mental disorder: A critical analysis of its validity, utility, and effects on psychotherapy research. Clinical Psychology Review, 33(7), 846-861. doi:10.1016/j.cpr.2012.09.007

Drevets, W. C. (2000). Neuroimaging studies of mood disorders. Biological Psychiatry 48(8), 813-829. doi:10.1016/S0006-3223(00)01020-9

Etain, B., Henry, C., Bellivier, F., Mathieu, F., & Leboyer, M. (2008). Beyond genetics: Childhood affective trauma in bipolar disorder. Bipolar Disorders, 10(8), 867-876.

Faraone, S. V., & Tsuang, M. T. (2003b). Heterogeneity and the genetics of bipolar disorder

Hakkarainen, R., Timo, M. B. J., Haukka, Jarmo, Demetrius, & Jouko. (2004). Brief report: is low dietary intake of omega-3 fatty acids associated with depression?

Hamazaki, K. (2019). Role of omega-3 polyunsaturated fatty acids in mental Health-Studies from Japan. Journal of Oleo Science, 68(6), 511-515. doi:10.5650/jos.ess19008

Haske, M. G. (2013). Cardiology for anesthesiologists (international anesthesiology clinics 50, number 2, spring 2012). Anesthesiology (Philadelphia), 118(6), 1486-1487. doi:10.1097/ALN.0b013e31828ce645

Janiri, D., Sani, G., Danese, E., Simonetti, A., Ambrosi, E., Angeletti, G., . . . Spalletta, G. (2014). Childhood traumatic experiences of patients with bipolar disorder type I and type II. Journal of Affective Disorders, 175, 92-97. doi:10.1016/j.jad.2014.12.055

Kiesler, D. J. (2000). Beyond the disease model of mental disorders.

Larsson, S., Aas, M., Klungsøyr, O., Agartz, I., Mork, E., Steen, N. E., . . . Melle, I. (2013). Patterns of childhood adverse events are associated with clinical characteristics of bipolar disorder. BMC Psychiatry, 13(1), 1-9.

MacQueen, G. M., Hajek, T., & Alda, M. (2005). The phenotypes of bipolar disorder: Relevance for genetic investigations. Molecular Psychiatry, 10(9), 811-826. doi:10.1038/sj.mp.4001701

Martinowich, K., Schloesser, R. J., & Manji, H. K. (2009). Bipolar disorder: From genes to behavior pathways. The Journal of Clinical Investigation, 119(4), 726-736. doi:10.1172/JCI37703

Mathews, C. A., & Reus, V. I. (2003). Genetic linkage in bipolar disorder. CNS Spectrums, 8(12), 891-904. doi:10.1017/S1092852900028686

Moskvina, V., Craddock, N., Holmans, P., Nikolov, I., Pahwa, J. S., Green, E., Donovan, M. C. (2009). Gene-wide analyses of genome-wide association data sets: Evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk. Molecular Psychiatry, 14(3), 252-260. doi:10.1038/mp.2008.133

Muneer, A. (2016). Bipolar disorder: Role of inflammation and the development of disease biomarkers. Psychiatry Investigation, 13(1), 18-33. doi:10.4306/pi.2016.13.1.18

Phelps, J., Angst, J., Katzow, J., & Sadler, J. (2008). Validity and utility of bipolar spectrum models. Bipolar Disorders, 10(2), 179-193. doi:10.1111/j.1399-5618.2007.00562.x

Phillips, M. L., & Kupfer, D. J. (2013a). Bipolar disorder diagnosis: Challenges and future directions. Elsevier BV. doi:10.1016/s0140-6736(13)60989-7

Quaid, K. A., Aschen, S. R., Smiley, C. L., & Nurnberger, J. I. (2001). Perceived genetic risks for bipolar disorder in a patient population: An exploratory study.  Journal of Genetic Counselling (10)1.

Shih, R. A., Belmonte, P. L., & Zandi, P. P. (2004). A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders. International Review of Psychiatry (Abingdon, England), 16(4), 260-283. doi:10.1080/09540260400014401

Vawter, M. P., Freed, W. J., & Kleinman, J. E. (2000). MODELS OF DISEASE: neuropathology of bipolar disorder. Biol Psychiatry (48) 486-504.

Viola, T. W., Salum, G. A., Kluwe-Schiavon, B., Sanvicente-Vieira, B., Levandowski, M. L., & Grassi-Oliveira, R. (2015a). The influence of geographical and economic factors in estimates of childhood abuse and neglect using the childhood trauma questionnaire: A worldwide meta-regression analysis. Child Abuse and Neglect, 51, 1-11. doi:10.1016/j.chiabu.2015.11.019

Watson, S., Gallagher, P., Dougall, D., Porter, R., Moncrieff, J., Ferrier, I. N., & Young, A. H.     (2014). Childhood trauma in bipolar disorder. Australian & New Zealand Journal of Psychiatry48(6), 564-570.