Rethinking Bipolar Disorder Treatment in the Context of Comorbidities
- Anne
- Dec 29, 2025
- 9 min read
Bipolar disorder (BD), formerly known as manic depression, is a chronic mood disorder that causes extreme mood shifts. These mood episodes can be recurring, constant, or occur at irregular intervals. There are two main types of bipolar disorder (I and II), depending on patterns of manic or hypomanic and depressive episodes. People with bipolar type I disorder experience one or more manic episodes with episodes of depression that usually become more common over time. People with bipolar type II disorder have had one or more hypomanic episodes and at least one depressive episode, but with no history of manic episodes. Distinguishing between these subtypes requires a clear understanding of the mood episodes involved. The following definitions, provided by the World Health Organization (2024), outline the primary mood episodes that form the basis for differentiating these subtypes:
Mania is characterized as an abnormally irritable or energetic mood lasting at least one week (or any duration if hospitalization occurs) that causes significant functional impairment and/or psychosis. Three or more of these symptoms must be present during this time: inflated self-esteem or grandiosity, decreased need for sleep, rapid speech, distractibility, increased goal-directed activity, risky behavior, or delusional thinking.
Hypomania is similar to mania, including an elevated mood and increased energy, but it is considered to be less severe and often doesn’t require hospitalization.
Depressive episodes are characterized as a persistent low mood with fatigue, guilt, hopelessness, poor concentration, and are often accompanied by suicidal thoughts. The duration is at least two weeks.
Rapid cycling refers to experiencing four or more mood episode shifts within a 12-month period and is often associated with a more severe and unstable course of illness.
Bipolar disorder can begin at any age, but it is most commonly diagnosed during adolescence or early adulthood (Mayo Clinic, n.d.). Approximately 4.4% of adults in the United States experience bipolar disorder at some point in their lives (Harvard Medical School, 2017). Among those affected, about 82.9% report serious impairment and 17.1% experience moderate impairment (Kessler et al., 2005). Bipolar disorder is progressive and can cause brain changes if untreated, with neurological deficits even during stable/euthymic periods (Maletic & Raison, 2014). This is seen in reduced responsiveness in the dorsal anterior cingulate cortex (dACC), dorsomedial prefrontal cortex (DMPFC), and dorsolateral prefrontal cortex (DLPFC), which impairs decision-making, emotional regulation, and cognitive control. In contrast, the limbic and paralimbic regions, responsible for processing emotions, show increased activity in euthymic bipolar patients.
There are a lot of treatment-related challenges, including polypharmacy and comorbidities, that contribute to issues with recovery and stability. On average, only 51%–70% of individuals with schizophrenia or bipolar disorder take all of their prescribed medications (Velligan et al., 2009). The general treatment guideline starts with non-traditional antidepressants like mood stabilizers or atypical antipsychotics. If those don’t work, treatment can escalate to combinations of meds, and if still ineffective, electroconvulsive therapy (ECT) is considered (Florida Medicaid Mental Health, 2020). Factors such as poor insight, lack of awareness about the illness, distress from specific or general side effects, and the belief that medication is no longer necessary contribute to adherence issues, and comorbidities complicate this. Also, suicide poses a significant risk to those with BD. Research has shown that individuals with a depressive episode as their most recent bipolar episode are more likely to report suicidality, agoraphobia, and social phobia (Munoli et al., 2014). Approximately 25%–50% of BD patients will attempt suicide at least once during their lifetime, and 8%–19% will complete suicide (Munoli et al., 2014).
Understanding bipolar disorder in isolation doesn’t reflect the reality many patients face. Comorbid conditions not only complicate the treatment response, they also contribute to symptom severity, and overall quality of life. There aren’t many controlled studies on treating bipolar disorder when it co-occurs with other conditions, despite the fact that about a third of people with bipolar have at least one comorbidity (Koul & Shetty, 2022). While mood stabilization remains central to bipolar disorder management, addressing co-occurring conditions like anxiety, substance use disorder (SUD), and autism spectrum disorder (ASD) are just as important. The following sections explore how these specific comorbidities interact with bipolar disorder and what that means for treatment approaches.
Anxiety Disorders
Approximately 45% of individuals diagnosed with bipolar disorder will experience a co-occurring anxiety disorder during their lifetime (Lee & Dunner, 2008). The presence of anxiety is associated with longer mood episodes, a higher incidence of suicidality, and poorer day-to-day functioning (Koul & Shetty, 2022). From a neurobiological standpoint, the co-occurrence of anxiety and BD may be linked to dysregulation in brain regions such as the prefrontal cortex, amygdala, and hippocampus, which are involved in emotional regulation, fear processing, and stress response (Medical News Today, 2023).
Selective Serotonin Reuptake Inhibitors (SSRIs) and bupropion are considered lower-risk for inducing manic switches compared to SNRIs or tricyclic antidepressants, but antidepressants should always be used alongside a mood stabilizer in BD. Without a mood stabilizer, they can trigger manic episodes, especially in patients with early-onset BD, rapid cycling, or substance use. For generalized anxiety disorder (GAD) in BD, quetiapine shows mixed results. In cases of comorbid PTSD, treatment should start with mood stabilization, followed by cautious use of second-generation antipsychotics (SGAs) or antidepressants. While risperidone, lamotrigine, and prazosin (for nightmares) are options, there is not much evidence to support their use in this context (Ott, 2018).
Substance Use Disorder (SUD)
Substance use disorder (SUD) is highly prevalent in individuals with bipolar disorder, with around 42% experiencing drug dependence/abuse over their lifetime (McElroy et al., 2001). BD has the second-highest rate of SUD among all psychiatric disorders, with the highest rate being associated with antisocial personality disorder (Regier et al., 1990). There is an increased risk of developing SUD in males with BD compared to females with BD (Hunt, Malhi, Cleary, Lai, & Sitharthan, 2016). Lifetime prevalence rates show that 33% of individuals with BD report alcohol abuse and 16% report marijuana use (McElroy et al., 2001). A meta-analysis found that, after alcohol, cannabis was the most frequently used substance among individuals with BD (20%), followed by other drug use such as cocaine and amphetamines at 17% (Hunt, Malhi, Cleary, Lai, & Sitharthan, 2016).
Substance abuse is generally harmful for people with BD because it can disrupt neurotransmitter function and worsen mood instability. However, emerging research suggests cannabis might play a therapeutic role in certain contexts. The endocannabinoid system, which helps regulate emotional processes, could be a potential target for symptom management. Specifically, CB2 receptor activation and CB1 receptor antagonism have been proposed as mechanisms that might help reduce irritability and promote relaxation (Arjmand et al., 2019). Also, several genetic studies have identified CB1 receptor gene variants that may increase susceptibility to bipolar disorder (Monteleone et al., 2010).
Autism Spectrum Disorder (ASD)
It’s hard to determine the true rate of comorbidity between autism and bipolar disorder, largely because pediatric bipolar disorder is often underdiagnosed (Frazier, Doyle, Chiu, & Coyle, 2002). There is also a lack of an agreed-upon definition of bipolar disorder in children, making early diagnosis (which is crucial for intervention services and prevention of SUD) inconsistent and difficult (Raja & Azzoni, 2008). Manic symptoms also tend to emerge later in development, which means bipolar disorder might not be recognized until adolescence or adulthood. Diagnostic criteria often rely heavily on self-awareness and the accurate recall of mood states, which can pose challenges particularly for those with autism who may struggle with emotional self-awareness and difficulty interpreting or expressing their feelings clearly. This makes both diagnosis and comorbidity tracking more complicated and less reliable.
Genetic studies on the comorbidity between bipolar disorder and autism are important for understanding how they influence each other. Research shows that autistic children with a family history of bipolar disorder tend to show more violent behavior, agitation, and mood swings that cycle, along with obsessive traits and issues with sleep and appetite (DeLong, 1994). While traits like savant-like abilities are often seen as positive, these kids also experience developmental regression, which researchers still don’t fully understand. Many people attribute these behaviors to autism alone, but it’s possible that undiagnosed bipolar disorder in these children is also playing a role. Looking at this in a broader context is key, because understanding these complexities could lead to better outcomes for these children as they grow into adulthood.
Looking Forward
Future approaches to treating bipolar disorder must reflect its clinical complexity and the high prevalence of psychiatric comorbidities. Research continues to support the efficacy of lithium in reducing suicidal behavior (Latalova, Kamaradova, & Prasko, 2014), and emerging evidence suggests that lithium and valproate are effective not only for mood stabilization but also in reducing substance use among cannabis users. Additionally, the neuroprotective agent citicoline may help reduce cocaine consumption in individuals with bipolar disorder (Preuss, Schaefer, Born, & Grunze, 2021). These pharmacological developments offer promising avenues for improving clinical outcomes, particularly in cases complicated by substance use disorders.
However, these medical advances must be part of a broader, integrated treatment strategy. Accurate recognition of co-occurring psychiatric diagnoses is critical for formulating a comprehensive and effective care plan. This dual identification allows clinicians to develop targeted interventions and realistic therapeutic goals that address the full complexity of a patient's condition. Without such diagnostic clarity, treatment efforts risk being fragmented, leading to suboptimal outcomes, higher relapse rates, and reduced long-term functioning.
As we rethink the treatment of bipolar disorder, it becomes clear that a siloed, symptom-focused approach is insufficient. Comorbidities such as anxiety disorders, substance use disorder, and autism spectrum disorder are not peripheral, but rather they are central to how bipolar disorder presents, progresses, and responds to treatment. These overlapping conditions complicate diagnosis, challenge medication adherence, and introduce unique neurobiological variables that must be addressed through a coordinated approach (Koul & Shetty, 2022; Raja & Azzoni, 2008).
Moving forward, neuroscience must play a central role in identifying shared mechanisms, refining diagnostic criteria, and developing new treatment pathways. Understanding how these comorbidities interact at the neurobiological level, such as through dysregulation in the prefrontal cortex, amygdala, and hippocampus, will be essential to designing interventions that are not just clinically effective but transformative. Only by embracing this complexity can we shift from managing symptoms to truly improving the lives of those affected by bipolar disorder and its many comorbidities.
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