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Bipolar Disorder is known to have a range of symptoms and pathologies.( https://onlinelibrary.wiley.com/doi/full/10.1111/j.1399-5618.2007.00484.x ) While the peak age of onset is during the early 20s, approximately 20% of patients showed evidence for bipolar during adolescence ( https://jamanetwork.com/journals/jamapsychiatry/article-abstract/492009 ). As early identification of bipolar disorder and clinical intervention play key roles in improving patient outcomes, the classification of prodromes may serve as a useful tool for clinicians.

Introduction

Prodrome is a term used by mental health professionals to categorize a specific group of signs or symptoms that may precede a mental illness. illness.( https://www.semel.ucla.edu/capps/what-prodrome ) The recognition of prodromes of manic and depressive episodes of bipolar disorder can help to decrease the time in recurrence of such episodes (Goossens, Kupka, Beentjes, & van Achterberg, 2010). Very little research has been conducted in relation to prodromes. A 2010 study examined the order that prodromal symptoms occur for both the manic and depressive episodes of bipolar disorder. The results of the study found that for manic episodes, the most likely change was energy level, followed by sleep and social functioning (Goossens et al., 2010). In depression, mood was most likely to change, followed by energy level, social functioning and sleep (Goossens et al., 2010). The study found that most patients with bipolar disorder are able to recognize their prodromal symptoms better after they have experienced them than when compared to therapeutic interventions. (Goossens et al., 2010). Recognizing prodromes is essential because of their ability to help prevent future manic or depressive episodes.

Mania
Clinical course of children with a depressive spectrum disorder and transient manic symptoms:

Nadkarni and Fristad wanted to assess rates of conversion to bipolar spectrum disorder, and transient manic symptoms (TMS). TMS was classified as manic-like symptoms that do not necessarily reach the duration or frequency/number of symptoms to warrant a diagnosis of BPSD (Bipolar Spectrum Disorder). 165 children (mean age=9.9 years and standard deviation=1.3) with mood disorders were studied. They were classified into groups; DSD (13 children), DSD+TMS (37 children), and BPSD (115 children). All children were assessed using Multi-Family Psychoeducational Psychotherapy, a childrens’ mood disorder treatment utilizing biopsychosocial frameworks and cognitive-behavioral/ family-systems based intervention. After an 18-month follow-up, results showed a significantly higher conversion rate to BPSD for the DSD+TMT group compared to the DSD group alone (40% vs. 12.5%). Conversion was also significantly more frequent in the half of participants that received MF-PEP after a one-year waitlist condition compared to the other half that received immediate treatment (60% vs. 16%). This study made it evident that those who exhibit TMS have a higher risk for eventually developing BPSD. Psychoeducational psychotherapy like the one performed in this study may serve as a protective and efficient treatment. This study also highlights the importance of teaching parents how to detect prodromal manic symptoms that can arise from aggression, irritability, and disruptive behavior.

Pre-depressive vs. pre-manic. The bipolar disorder prodrome revisited: Is there a symptomatic pattern?

Zechel et al assessed the occurrence and course of pre-hypomanic and pre-depressed prodromal symptoms as precursors of BD. This German multi-center study conducted semi-structured interviews for mood swings on 42 outpatients within 8 years of BD (I or II) onset. 40.5% were male with a mean age of 35 and illness onset of 30.5 years. Prior to the first hypomanic episode, 85% reported feeling extremely energetic, 76.2% reported physical agitation, 78.6% reported racing thoughts, 71.4% reported overtalkitiveness, and 71.4% reported low sleep requirement. Preceding pre-depressively, 83% participants reported depressed mood, 78.6% reported physical exhaustion, 81% reported reduced vitality, 76.2% reported tiredness, and 66.7% reported insomnia. Most symptoms emerged during the proximal prodromal phase. Feeling extremely energetic, overtalkitiveness, and racing thoughts lasted significantly longer prior to depression; the pre-depressive prodrome had a longer duration than the pre-manic one, but the two did not significantly differ in severity nor frequency. Early signs of BD-mood swings and interrupted diurnal rhythms-had occurred prior to both episodes. This study underlined the importance of identifying and monitoring not only specific depressive/manic symptoms, but also general symptoms prior to onset of episodes.

Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode

A recent study by Correll et al assessed 52 youths (ages 7-21). This study showed that manic symptoms in youth typically began gradually with slow or rapid deterioration. Patients with diagnosed BD-I or their caregivers (for those under the age of 12) underwent a semistructured interview with the Bipolar Prodrome Symptom Scale-Retrospective (BPSS-R), an assessment developed in order to identify those at clinical high risk for developing mania. The BPSS-R assesses the onset pattern of signs and symptoms before the first major manic and/or depressive episode. These prodromal symptoms were then rated according to severity and frequency. After this, prodromal onset was evaluated with a multiple choice questionnaire. Primarily, prodromes were reported as starting gradually (88.5%) with either slow (59.6%) or rapid deterioration (28.8%).

Differentiation in the Preonset Phases of Schizophrenia and Mood Disorders:

Evidence in Support of a Bipolar Mania Prodrome

Another study conducted by Correll interviewed 52 children and adolescents with bipolar I disorder within 5 years of their first manic episode. Mean age at the time of the first mania episode was 13.4 years, 51.9% were female, 64.7% were white, and 29.4% had a first-degree family member with bipolar disorder. The mean lag between the first manic episode and the interview was 2.8 years. In 61.3% of the patients, the syndromal mood episode consisted of mania, with post-puberty onset in 73.1% of patients. Psychosis occurred in 13 of 20 patients (65%) in whom a major depressive episode preceded mania. Comorbidities included oppositional defiant disorder (53.9%), attention deficit-hyperactivity disorder (32.7%), substance use disorders (23.1%), anxiety-spectrum disorders (19.2%), and learning disorders (7.7%).

While patients with psychotic mania also had a higher prevalence rate of psychosis during a full depressive episode preceding mania (32.2% vs 11.1%), this was not statistically significant (P = .092).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526140/

The proximal prodrome to first episode mania – a new target for early intervention
A literature review conducted by Conus et al found that the most efficacious method to encourage earlier treatment was by identifying impending mania. Furthermore, they reported on a study conducted by Lish in 1994. This study asked 500 participants about their believed onset of symptoms. Of these participants, 33% reported depression/hopelessness at the start of their illness, while 32% reported mania/hyperactivity as the onset of their illness. Furthermore, 18% reported a combination of mania and depression as their first symptoms. The other common first symptoms reported were lack of sleep (24%), functional impairment (24%), mood swings (13%), and delusions/paranoia (9%). Furthermore, a follow up study conducted by Lish revealed  70% of patients reported experiencing manic symptoms prior to diagnosis. Possible manic symptoms included erratic sleeping, heightened mood or elation, racing thoughts and fast speech, increased mental or physical activity, or poor judgment

Depression
A study conducted in 2011 by Alloy and colleagues studied depression as a prodromal symptom for bipolar disorder. They followed 80 children who had been hospitalized for depression without any symptoms of hypomania/mania for 2-4 years. The results of this study found that patients who developed depression prior to age 17 had an increased risk of developing mania or hypomania symptoms later on in life.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192298/

A study conducted by Nadkarni and Fristad (2010) studied the conversion rates to bipolar spectrum disorder from depressive spectrum disorder and transient manic symptoms (Nadkarni & Fristad, 2010). They studied 165 children around 10 years old over an 18 month period. The children were split into a treatment group where they received Multi-Family Psychoeducational Psychotherapy treatment right after their baseline assessment was completed and a control group where they did not receive this treatment until a year after their assessment (Nadkarni & Fristad, 2010). The results found that the group who had to wait for treatment for a year experienced a 60% conversion rate, compared to a 16% conversion rate for the group who received treatment immediately (Nadkarni & Fristad, 2010). It was found that psychoeducational psychotherapy may serve as a protective barrier against risk factors that may result in the conversion of bipolar disorder (Nadkarni & Fristad, 2010).

Anxiety
A study conducted by Duffy et al (2013) found that offspring of parents with bipolar disorder, high risk offspring, often have an anxiety disorder according to a longitudinal study of repeated clinical assessments. The prevalence of anxiety disorders occurred more often and earlier in the high risk group than the control group.

https://www.sciencedirect.com/science/article/pii/S0165032713002942

Du et al (2017) investigated the relationship between anxiety disorders and bipolar disorder using both retrospective analysis for participants diagnosed with bipolar disorder (BD) (n=48) and participants diagnosed with an anxiety disorder (AD) completed surveys 3, 6, 12, and 18 months after initial data collection to follow whether the anxiety disorder would develop into bipolar disorder. The AD group was divided further into groups depending on the use of mood stabilizers. 14 of the 186 participants with AD had BD by the end of the study.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655950/

Kinley et al. (2011) found that panic attacks are a possible indicator of future psychopathology. The study was investigating the question of whether panic attacks predict the onset of Axis I disorders. Axis I disorders include substance abuse and dependence, major depression, dysthymia, mania, hypomania, panic disorder with or without agoraphobia, agoraphobia without panic, social phobia, phobia, generalized anxiety disorder. In-person interviews were conducted with a sample of 43,093 participants (81% response rate) composed of 18-24 year olds over the years 2001-2002.

https://onlinelibrary.wiley.com/doi/full/10.1002/da.20809

Merikangas et al (2012) aimed to investigate the prevalence and correlates of bipolar disorder on an international scale and describe its impact, comorbidity, and service utilization in the WHO World Mental Health Survey initiative. Cross-sectional in-person household surveys were used to measure the responses of 61,392 adults across 11 countries in the Americas, Europe, and Asia. The study found

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486639/

Zoltán et al (2010)

https://journals.lww.com/co-psychiatry/Fulltext/2010/01000/Outcome_from_mild_traumatic_brain_injury.4.aspx#pdf-link

Aggression/Irritability
DeckersbachT,PerlisRH,FrankleWG,GraySM,GrandinL,DoughertyDD,Nieren- berg AA, Sachs GS. Presence of irritability during depressive episodes in bipolar disorder. CNS Spectr. 2004;9(3):227-231.

Deckersbach et al (2004) was interested in studying the frequency of irritability in patients  with bipolar I disorder during an exclusively major depressive episode, according to the DSM-IV. 34 patients exhibiting exclusively major depressive episodes were tested using the Clinical Monitoring Form (CMF). Their results indicated that abnormal irritability can be distinct in bipolar I disorder and can occur outside of mania or mixed states.

Read the full study: https://www.cambridge.org/core/journals/cns-spectrums/article/presence-of-irritability-during-depressive-episodes-in-bipolar-disorder/319D0529B61DB8A4815218686D6A6E26

Faedda GL, Baldessarini RJ, Glovinsky IP, Austin NB. Pediatric bipolar disorder: phenomenology and course of illness. Bipolar Disord 2004: 6: 305–313. a Blackwell Munksgaard, 2004

Faedda et al. (2004) study was focused on the distinct features present in childhood bipolar disorder. While the study wasn’t exclusively focused on the irritability prodrome, it mentioned some interesting findings in regards to it. Moodiness, as they defined it as consisting of irritability and or temper tantrums, occur significantly more in girls, whereas aggression and anxiety are more present in boys.

Read the full study:

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1399-5618.2004.00128.x

Homish, Gregory G., et al. "Predictors of later bipolar disorder in patients with subthreshold symptoms." Journal of affective disorders 144.1-2 (2013): 129-133.

Homish et al (2013) conducted a study examining non-institutionalized, civilian subjects who exhibited elation and or irritability, but not lifelong mania or hypomania. These same subjects were examined again three years later. They found that  elation/irritability could be an indication of bipolar disorder, especially when coupled with difficulty concentrating, racing thoughts, or hyperactivity.

Read the full study:

https://www.sciencedirect.com/science/article/pii/S0165032712004697

Mammen OK, Pilkonis PA, Chengappa KN, Kupfer DJ. Anger attacks in bipolar depression: predictors and response to citalopram added to mood stabilizers. J Clin Psychiatry. 2004;65(5):627-633.

Read the full study: https://www.psychiatrist.com/jcp/article/pages/2004/v65n05/v65n0506.aspx

Psychosis
Conroy et al. (2019) states that CBT (cognitive behavioral therapy) is recommended over pharmacological treatments as of late because of safety and efficacy concerns. Regardless, early intervention is critical to prevent the transition to psychosis or at least alleviate the debilitating symptoms and discomfort that psychosis inflicts on daily living. Prevention methods include avoiding drugs of abuse, treating comorbid symptoms (anxiety, depression), and in some cases refraining from taking antipsychotic medication until/unless severe or threatening changes and symptoms occur. Early detection maximizes the efficacy of these methods. Nelson et al (2009) conducted a study that assessed patients from early psychosis treatment centers. They were administered omega-3-FA in addition to up to 20 sessions of CBCM (cognitive-behavioral case management) or placebo with CBCM. Despite only 11% of the sample having a transition rate and no difference between rates of experimental and control groups, significant symptom and functional improvement was observed.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196741/

For perspective, psychosis occurs in 53-97%  of adults with bipolar disorder, and 60-80% in youth. However, there is a surprising deficit in information about assessments of a potential bipolar disorder prodrome in studies of subjects who are at clinical high risk for schizophrenia. In order to further understand bipolar prodromes and its association with psychosis, an important distinction needs to be made. there is a phenotypic overlap between the bipolar prodrome and schizophrenia prodrome. For example, an article by Correll et al. (2007) found that subsyndromal unusual ideas were significantly more associated with of the schizophrenia prodrome, while obsessions/compulsions, suicidality, difficulty thinking, communicating clearly, depressed mood, decreased concentration/memory, fatigue/lack of energy, constant mood fluctuations, and physical agitation were more likely to be associated with the mania prodrome.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526140/

Cyclothymia
A study conducted in 2005, studied the pre-bipolar symptoms of bipolar and hypothesized that juvenile depression is pre-bipolar. The study obtained completed data from 80 depressed children. Children were assessed using a cyclothymic-hypersensitive treatment (CHT) scale, among many other types of assessments that they also were given. 43% of the 80 children patients were diagnosed with bipolar disorder. The diagnosis of bipolar disorder was more common in those patients who had a cyclothymic temperament. This also followed along other symptoms such as rapid mood shifts, aggressiveness, psychotic symptoms, or suicidality. The conclusion of this study found that CHT precedes bipolar transformation. Cyclothymic symptoms are more easily detectable in children then when compared to adults.

https://www.sciencedirect.com/science/article/pii/S0165032703002544

Sleep Disturbance
A study conducted in 2011, studied disturbed sleep and the involvement with early recognition of bipolar disorder. Three different studies were conducted. The first study was a prospective study that followed the offspring of parents with bipolar disorder. They looked at sleep disturbances, current psychopathology, and criteria for bipolar disorder. A link in a cohort of patients at an average age of 16.5 years old was found between sleep disturbances and later onset of bipolar disorder.

The second study was a prospective study that looked at patients with a diagnosis for sleep disturbance or insomnia. They looked at sleep, current psychopathology, and criteria for bipolar and depression in children. The results of the study found that insomnia correlates with later depressive episodes.

The third study was a retrospective study on patients with bipolar disorder and examined their psychopathology and sleep prior to their first affective episode. They gathered information from 58 patients diagnosed with Bipolar Disorder Type I. Results found that 26% of the patients had decreased sleep prior to their first hospitalization, and the disturbed sleep symptom did not occur until after age 13. Sleep disturbance is the 4th most common symptoms of bipolar disorder after depression, irritability, and decreased energy. 24% of patients reported lack of sleep as their first sign of the disease of bipolar disorder. It was found that prodromal symptoms occur 9-12 years before the diagnosis of the disorder. https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1399-5618.2011.00917.x