Bipolar II disorder: a state‐of‐the‐art review

Abstract

Bipolar II disorder (BD‐II) is currently identified by both the DSM‐5 and ICD‐11 as a distinct subtype of bipolar disorder, defined by at least one depressive episode and at least one hypomanic episode, with no history of mania. Despite its prevalence and impact, the literature on BD‐II remains relatively sparse. This paper provides a comprehensive overview of the available research and current debate on the disorder, including its diagnostic criteria, clinical presentations, comorbidities, epidemiology, risk factors, and treatment strategies. Patients with BD‐II often present with recurrent depressive episodes, which outnumber hypomanic episodes by a ratio of 39:1. The condition is therefore often misdiagnosed as major depressive disorder and treated with antidepressant monotherapy, which may worsen its prognosis. The recognition of BD‐II is further complicated by the overlap of its symptoms with other disorders, in particular borderline personality disorder. Although BD‐II is often perceived as a less severe form of bipolar disorder, evidence suggests significant functional and cognitive impairment, accompanied by an elevated risk of suicidal behavior, including a rate of completed suicide at least equivalent to that observed in bipolar I disorder (BD‐I). Psychiatric comorbidities, in particular anxiety and substance use disorders, are common. The disorder is associated with a high prevalence of numerous physical comorbidities, with a particularly high risk of comorbid cardiovascular diseases. Various genetic and environmental risk factors have been identified. Inflammation, circadian rhythm dysregulation and mitochondrial dysfunction are being studied as potential pathophysiological mechanisms. Current treatment guidelines, often extrapolated from BD‐I and depression research, may not fully address the unique aspects of BD‐II. Nevertheless, substantial evidence supports the value of some pharmacological treatments – primarily mood stabilizers and atypical antipsychotics – augmented by psychoeducation, cognitive behavioral or interpersonal and social rhythm therapy, and lifestyle interventions. Further research on BD‐II should be a priority, in order to refine diagnostic criteria, identify potentially modifiable risk factors, and develop targeted interventions.

The conceptualization of bipolar disorder (BD) has evolved significantly over time, transitioning from early descriptions of “manic depressive insanity” to a more nuanced understanding of the condition as presenting across a spectrum ¹ . The expression “bipolar disorder” was coined in the 20th century to reflect the biphasic nature of mood dysregulation, oscillating between manic and depressive states. The term “hypomania” was first introduced in the DSM‐III to describe a syndrome similar but less severe than mania ² . The DSM‐III also introduced the concept of “atypical bipolar disorder” to account for individuals who did not fit neatly into the BD or cyclothymic disorder categories, and it was in this context that the term “bipolar II” was first used ² . This framing laid the groundwork for the later conceptualization of bipolar II disorder (BD‐II) as a distinct clinical entity within the mood disorder spectrum ³ , identified as such for the first time in 1994 in the DSM‐IV ⁴ .

Since its introduction, BD‐II has spurred controversy concerning its diagnostic boundaries and clinical utility ⁵ , also as part of the more general debate about the dimensional vs. categorical approach to diagnosis in psychiatry. Indeed, it has been sometimes argued that bipolar disorder may be better conceptualized as just one diagnostic entity with variations in its expression across individuals ⁶ . However, BD‐II is now widely accepted and recognized as a distinct and valid diagnostic category ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ .

Studies have consistently documented that BD‐II is underdiagnosed ¹² , ¹³ . For example, the Jorvi Bipolar Study ¹⁴ screened 1,630 psychiatric outpatients and found that half of the BD‐II cases were previously undiagnosed, with a median delay of almost 8 years from the first episode to diagnosis. Delay in diagnosis can result in progression of illness and provision of inappropriate and potentially iatrogenic treatment. This can compromise the patient's well‐being, impede recovery, and affect quality of life ¹⁵ , ¹⁶ .

Contrary to the perception that BD‐II is a milder form of BD, research indicates that patients often suffer from high depressive burden ¹⁷ , ¹⁸ , ¹⁹ , poor functioning, and poor clinical outcomes ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ . In addition, recent analyses of mortality data indicate that the overall suicide rate and lethality index of suicide attempts in BD‐II are similar to or greater than in bipolar I disorder (BD‐I) ²⁶ , ²⁷ .

Compared to BD‐I, BD‐II is still substantially understudied ²⁸ , ²⁹ . Despite its prevalence and impact, the literature remains relatively sparse, particularly in relation to treatment strategies. This paper aims to provide a comprehensive picture of the available research and current debate on BD‐II, by reviewing its diagnostic criteria, clinical presentations, comorbidities, epidemiology, risk factors, and treatment strategies.

DIAGNOSTIC CRITERIA

BD‐II is identified as a subtype of BD in both the DSM‐5 ³⁰ and ICD‐11 ³¹ , defined by at least one depressive episode and at least one hypomanic episode, with no history of mania. Both systems specify that during the hypomanic episode there is no marked impairment in social or occupational functioning. The DSM‐5 criteria for hypomanic episode also require that the episode is not severe enough to necessitate hospitalization, and that there should not be psychotic features (otherwise the episode should be diagnosed as manic). The ICD‐11 diagnostic requirements similarly specify that mood disturbance in the hypomanic episode “is not accompanied by delusions or hallucinations” ³¹ , while the fact that the hypomanic episode does not “require intensive treatment (e.g., hospitalization)” is mentioned in the section on the differential diagnosis with a manic episode ³¹ .

In both systems, the symptomatic picture of the hypomanic episode is exactly the same as that of the manic episode (although in the ICD‐11 the wording is slightly different in the two descriptions), so that the two episodes differ only in terms of severity. This fact has been subject to some criticism in the past (e.g., “the signs and symptoms of hypomanic episodes as described in DSM‐IV are insufficiently discriminatory from those for mania” ³² ), but possible qualitative differences between manic and hypomanic episodes have not been clarified. It has been sometimes pointed out that increased goal‐directed activity is the key feature of hypomania, even in the absence of a clear mood change ³³ . Moreover, it has been noted that hypomanic episodes are often marked by dysphoria (“mixed hypomania”), reported to be more frequent in some clinical samples than euphoric mood ³⁴ .

In both diagnostic manuals there is a specification that the depressive episode must last for at least two weeks. For the hypomanic episode, the DSM‐5 requires that the symptoms last at least four consecutive days, whereas in the ICD‐11 the requirement is less specific (“at least several days”). The threshold of four days for the diagnosis of hypomanic episode has been debated in the past, and a threshold of two days has been instead proposed ³² . This proposal was supported by the observation that the rate of bipolar family history among bipolar II patients – identified by the two‐day threshold – was similar to that of bipolar I patients and significantly higher than that of patients with major depressive disorder (MDD) ³⁵ . This change in the threshold for the diagnosis of hypomanic episode was indeed considered within the process of development of the DSM‐5, but finally rejected due to concerns about the increased risk of false positives ³⁶ .

Both the DSM‐5 and ICD‐11 specify the minimum number of symptoms in the depressive episode, whereas for the hypomanic episode this specification is only made in the DSM‐5 (at least three symptoms in addition to elevated, expansive or irritable mood, and increased activity or energy), whereas in the ICD‐11 the minimum number of additional symptoms is not made explicit (“several of the following symptoms”).

In the ICD‐11, it is acknowledged that “hypomanic episodes are often difficult to distinguish from normal periods of elevated mood”, and it is underscored that “in order to be considered a hypomanic episode, the symptoms must represent a significant and noticeable change from the individual's typical mood and behavior” ³¹ .

In fact, the issues of the boundary between hypomanic and manic episode, and between hypomanic episode and “normal periods of elevated mood”, remain somewhat in flux. While BD is one of the most stable diagnoses in psychiatry ³⁷ , ³⁸ , ³⁹ , field trials for the DSM‐5 found a concordance rate of 0.40 for a BD‐II diagnosis compared to 0.56 for BD‐I ⁴⁰ . However, the interrater reliability for the diagnosis of BD‐II was still higher than that for MDD (0.28) ⁴⁰ . Moreover, the BD‐II diagnosis reliably separates from that of BD‐I in careful clinical interviews ⁴¹ .

CLINICAL PRESENTATIONS

The accurate identification of BD‐II is crucial for effective management, but this process is complicated by the overlap of symptoms with other disorders. Patients with BD‐II often present with recurrent depressive episodes or symptoms, which outnumber hypomanic episodes or symptoms by a ratio of 39:1 ¹⁷ . However, this ratio may in reality be lower, due to the underestimation or lack of identification of hypomanic episodes or symptoms ⁴² . Indeed, while there is a clear change in functioning that is observable by others during hypomanic episodes, the mood disturbance is by definition not severe enough to cause marked impairment in social or occupational functioning ⁴³ . Further, many patients perceive hypomanic episodes as being pleasant and hence do not seek help during these periods. It is also possible that, in a mixed hypomanic episode, the patient believes that he/she is just irritable in the context of depression, without recognizing the presence of other hypomanic symptoms ¹² .

People with BD‐II typically have their first encounter with the treatment system due to depression, which accounts for over 80% of the time ill ¹⁷ , ⁴⁴ . Therefore, BD‐II is frequently misdiagnosed as MDD and treated with antidepressant monotherapy, which may worsen the prognosis, and potentially increase the risk of suicide attempts ⁴⁵ . The French EPIDEP study reported a BD‐II rate of 40% among patients suffering from a major depressive episode when a DSM‐IV‐based semi‐structured interview was used, which was significantly higher than the 22% rate at initial assessment ⁴⁶ .

A careful screening for history of previous hypomanic episodes must be conducted in all patients presenting with a major depressive episode. Further, since the diagnosis of BD‐II requires careful clinical evaluation to distinguish it also from other conditions, such as borderline personality disorder and attention‐deficit/hyperactivity disorder (ADHD) ⁴⁷ (see below), detecting the episodic nature of hypomania and depression is crucial. Clinicians must assess not only the presence of symptoms, but also their pattern, duration and impact on functioning.

A greater likelihood of mixed states has been found in BD‐II compared to BD‐I ⁴⁸ , with estimates suggesting that up to 40% of individuals with BD‐II experience these states at some point ³⁴ , ⁴⁹ , ⁵⁰ , ⁵¹ . The presence of mixed states is associated with a more severe course of illness, including higher rates of comorbid anxiety and substance use disorders, increased risk of suicidal behavior, more frequent mood episode recurrences and rapid cycling, greater functional impairment, and reduced quality of life ⁵² . Accurate diagnosis and tailored treatment strategies are essential for managing mixed states effectively, which may include a lower threshold for admission ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ .

DIFFERENTIAL DIAGNOSIS

Distinguishing hypomanic episodes from other conditions can be challenging. A key element in diagnosing BD‐II is to establish a history of disordered mood episodes that represent a clear break from previous functioning, in contrast to the more constant symptoms seen in many other psychiatric conditions.

Major depressive disorder

Depressive episodes of BD‐II and MDD both present with symptoms such as depressed mood, lack of interest and motivation, feelings of guilt or low self‐esteem, decreased energy, impaired concentration, changes in appetite, psychomotor agitation or retardation, and suicidal thoughts or behavior. The diagnostic distinction relies on the occurrence of hypomania, which is absent in MDD but present in BD‐II. To avoid missing BD‐II, clinicians should routinely inquire about past episodes of hypomania in patients presenting with depression. Here, obtaining collateral information from family members is essential, as hypomanic symptoms might be more apparent to significant others than to the patient ³³ , ⁵⁷ , ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ .

Several clinical features can increase the suspicion of an underlying bipolar diathesis in patients presenting with depression. These include the presence of multiple discrete episodes, abrupt onset and offset, psychotic symptoms, severe melancholic features, family history of BD, non‐response to antidepressant medication, induction of hypomania by antidepressant medication, early age of onset, and seasonal patterns of mood disturbances ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ . These features have been referred to as the “bipolar signature” ⁶⁹ . BD‐II patients also experience more paranoia, anhedonia and guilt than those with MDD ⁶³ .

The presence of atypical depressive features – i.e., increased appetite, hypersomnia, agitation and heightened interpersonal sensitivity – is more common in BD‐II than MDD ⁷⁰ , ⁷¹ , ⁷² , ⁷³ . Also, patients with BD‐II have significantly more atypical symptoms in depression when compared to those with BD‐I ⁷⁴ . There is an approximately 35% prevalence of psychomotor agitation in BD‐II depressive episodes ⁷⁵ . Seasonal variations in mood, often associated with atypical features ⁷⁶ , are more pronounced in BD‐II, with depressive symptoms observed to peak in winter and hypomanic symptoms in the fall ⁷⁷ , ⁷⁸ . Furthermore, people with BD‐II have been found to be younger and more likely to be educated, compared to those with MDD ⁶³ .

Personality and temperament factors may further differentiate BD‐II from MDD. Specifically, patients with BD‐II exhibit higher levels of cyclothymic and hyperthymic temperaments ⁶³ , and are more likely to be sensation seekers ⁷⁹ compared to those with MDD. They may also show higher irritability, anxious worrying, and self‐criticism, and lower social avoidance ⁵⁷ , ⁵⁸ . Studies have found that BD‐II patients have more Cluster B personality disorder diagnoses, ADHD, and substance use issues compared to those with MDD ⁶³ .

Borderline personality disorder

Differentiating BD‐II from borderline personality disorder may pose significant clinical challenges, due to overlapping features such as suicidality, mood symptoms (especially depression), impulsivity, irritability, and risky behaviors. Misdiagnosis can impact treatment outcomes, as patients with borderline personality disorder may be incorrectly treated with biological therapies suited for BD‐II rather than psychological therapies, and vice versa ⁸⁰ .

However, there are distinct differences in the presentation and course between these disorders that can aid in accurate diagnosis and appropriate treatment (see Figure 1). Affective instability, while a core feature of borderline personality disorder, is less common in BD‐II, especially during periods of euthymia ⁸¹ . Also, this instability is often reactive to interpersonal stressors in patients with borderline personality disorder, while affective lability in BD‐II tends to be more autonomous and internally driven ⁸² .

Figure 1.

Comparison of symptoms between bipolar II disorder and borderline personality disorder

People with borderline personality disorder often experience intense fears of abandonment, unstable relationships, chronic feelings of emptiness, and use more maladaptive emotion regulation strategies compared to those with BD‐II ⁸³ . Depressive episodes in the context of BD‐II are more frequently melancholic ⁸⁴ or agitated ⁷⁵ , while depression comorbid with BPD is typically non‐melancholic and reactive to interpersonal life events.

In BD‐II, compared to borderline personality disorder, there is a lower prevalence of trauma history (although this is a risk factor for both conditions ⁸⁵ ), less likelihood of deliberate self‐harm (except in mixed states or depression), more stable relationships, and less sensitivity to criticism ⁸⁶ . The impulsivity in BD‐II is related to hypomanic episodes, while in borderline personality disorder it is mood‐independent. BD‐II responds better to mood stabilizers and atypical antipsychotic drugs, whereas patients with borderline personality disorder benefit more from psychotherapies ⁸⁰ .

Other psychiatric conditions

BD‐I is distinguished from BD‐II by the presence of full manic episodes, with the possible occurrence of psychotic features, which are marked by severe functional impairment and may require hospitalization. Cyclothymia is characterized by a long‐term (at least two years) pattern of numerous periods of hypomanic and depressive symptoms without meeting full criteria for hypomanic or depressive episodes. Anxiety disorders manifest with constant anxiety and worry, without episodic mood changes, and the presence of a variety of physical symptoms, without the mood elevation observed in hypomania. ADHD is marked by a persistent pattern of inattention and hyperactivity usually starting in childhood, without distinct mood episodes. Complex post‐traumatic stress disorder occurs after the exposure to one or more events of a threatening or horrific nature, and is characterized by flashbacks or nightmares, and by heightened emotional responses, such as impulsivity or aggressiveness, but without clear mood episodes. Finally, in substance use disorders, mood changes typically follow substance use rather than occurring independently.

SCREENING

Several tools have been developed to screen for prior manic or hypomanic episodes, and for BD in general. The Mood Disorder Questionnaire (MDQ) is one of the most extensively studied screening tools for BD, with a reported sensitivity of about 60% and a specificity of 85% ⁸⁷ , ⁸⁸ . However, the MDQ has a higher sensitivity for detecting BD‐I than BD‐II ⁸⁹ . Relatedly, it performs poorer in community settings than in clinical cohorts ⁹⁰ .

The Hypomania Checklist (HCL‐32) was designed to capture the more subtle aspects of hypomania ⁹¹ . It has an estimated sensitivity of 80% and a specificity of around 60% in detecting prior hypomanic episodes ⁹² . It can be used in both clinical and community settings, allowing a broader application for screening purposes ⁹³ .

The Rapid Mood Screener (RMS) was developed to screen for BD‐I ⁹⁴ . It queries symptoms of hypomania/mania and depression, with a total of three items allocated to each. In a study aimed to screen for manic symptoms and bipolar I disorder features, when four or more items of the RMS were endorsed, BD‐I was detected with a sensitivity of 0.88, a specificity of 0.80, and positive and negative predictive values of 0.80 and 0.88, respectively ⁹⁴ . The RMS has been subsequently validated in BD‐II ⁹⁵ .

These screening instruments have generally shown better performance in clinical settings rather than in population samples, where there is a more substantial false positive rate. Importantly, these tools are not diagnostic instruments, but merely indicators of the need for closer clinical exploration of potential BD ⁹⁰ , ⁹⁶ .

EPIDEMIOLOGY

The reported prevalence of BD‐II varies significantly across epidemiological studies, likely due to methodological differences. The World Mental Health Survey ⁹⁷ reported an aggregate lifetime prevalence of 0.6% for BD‐I, 0.4% for BD‐II, and 1.4% for subthreshold BD. The data, gathered across 11 countries in the Americas, Europe and Asia, indicated a consistent pattern of prevalence, comorbidity and severity across these diverse regions. However, a systematic review and meta‐analysis including 276,221 individuals ⁹⁸ reported a pooled lifetime prevalence of 1.1% for BD‐I and 1.6% for BD‐II, finding higher lifetime prevalence rates in North Africa and the Middle East.

This disparity likely reflects methodological variability and the lack of gold standard diagnostic criteria for bipolar spectrum disorders, particularly for BD‐II. There is also a significant variance in clinicians’ diagnostic process, particularly when diagnosing BD‐II, as it requires direct information gathering not only from the patient, but also from his/her family and support circle ⁹⁹ .

Furthermore, the fact that BD‐II has been included for the first time only in the 11th revision of the ICD, which has still not been adopted in many countries, has complicated and still complicates the estimation of the global incidence and prevalence of the condition ¹⁰⁰ .

BD‐II appears to be more prevalent in females ¹⁰¹ . For example, the Mayo Clinic Biobank, which included 1,465 participants with BD (69% BD‐I and 31% BD‐II), reported that 66.1% of BD‐II patients were female, compared to 58.6% of BD‐I patients ¹⁰² . Similarly, the BipoläR study, which analyzed data from 7,345 individuals registered in the Swedish National Quality Assurance Register for BD, found that females made up 64.9% of BD‐II cases and 57.3% of BD‐I cases ¹⁰³ . This gender disparity in BD‐II prevalence may stem from a combination of biological and psychosocial factors, as well as potential diagnostic biases, since the predominance of depressive symptoms may lead to increased recognition of the disorder in females ¹⁰⁴ .

COURSE

BD‐II often begins with non‐specific symptoms such as anxiety or sleep disturbances, which precede mood swings and full episodes of depression and hypomania (see Figure 2). These symptoms may be accompanied by some degree of functional impairment and distress. Patients typically meet the full diagnostic criteria for BD‐II several years after the initial symptoms appear, emphasizing the need for more attention to the at‐risk and prodromal stages to facilitate early detection and intervention ⁵⁷ , ¹⁰⁵ , ¹⁰⁶ , ¹⁰⁷ , ¹⁰⁸ .

Figure 2.

Representation of a typical clinical course of bipolar II disorder

The onset of BD typically occurs during adolescence and early adulthood, with predominant initial depressive symptoms ¹⁰⁹ . Indeed, a 10‐year follow‐up study of individuals with prepubertal depression found that 33% and 15% later met criteria for BD‐I and BD‐II, respectively ¹¹⁰ . An analysis of large, predominantly European samples indicated an earlier age of onset for individuals with BD‐I compared to BD‐II, although some studies found the opposite ¹⁶ .

The World Mental Health Survey reported a mean age of onset of 18 years for BD‐I, 20 years for BD‐II, and 22 years for subthreshold BD, with the age of onset being inversely correlated with the severity of illness over time ⁹⁷ . There is evidence that the average duration of untreated BD‐II is approximately 10 years ¹⁵ , ¹¹¹ , with BD‐I cases showing a significantly shorter delay of diagnosis than BD‐II cases, especially when comparing male BD‐I patients to female BD‐II patients ¹¹¹ .

A comparative analysis of 25 studies found that patients with MDD, BD‐I and BD‐II were symptomatic 46%, 44% and 43% of the time, respectively, with BD‐II patients experiencing depressive symptoms for 81% of the symptomatic time ¹¹² . Indeed, depression takes the largest toll on quality of life and functioning among individuals with BD‐II ¹¹³ . A naturalistic study found that these patients spent approximately 40% more time in depressive states than those with BD‐I ¹⁹ . Additionally, BD‐II is associated with a higher rate of depressive relapse than BD‐I ¹¹² . Longitudinal studies indicate that recovery from depressive episodes is less common in BD‐II, and that BD‐II patients show greater monthly symptom fluctuation and higher year‐round illness severity compared to BD‐I individuals ¹¹² , ¹¹⁴ . For example, a study involving self‐monitoring over a median of 310 days found that individuals with BD‐II had a lower mean level of mood, and spent more time with depressive symptoms, compared to those with BD‐I ¹⁸ .

Rapid cycling, defined as at least four mood episodes per year, is more prevalent in BD‐II than BD‐I ¹¹⁵ , ¹¹⁶ . This pattern is associated with worse long‐term outcomes, including higher suicide rates ¹¹⁷ . Rapid cycling may occur during a portion of the life course, but is not necessarily an enduring characteristic.

Psychotic features occur in approximately 15% of BD‐II cases, compared to 50% in BD‐I ¹¹⁸ , ¹¹⁹ , though the prevalence is higher in some reports ¹²⁰ . The presence of these features during BD‐II depressive episodes is associated with a greater likelihood of hospitalization and more severe melancholic and catatonic symptoms ¹²¹ . Approximately half (42‐58%) of BD‐II patients have never been hospitalized despite several lifetime episodes, a rate significantly lower than that of BD‐I patients (21‐26%) ²⁵ , ¹²² .

Compared to individuals with BD‐I, those with BD‐II report significantly higher functional impairment, higher burden of illness and poorer health‐related quality of life, even during periods of euthymia ²⁰ . They also experience more residual symptoms, higher rates of antidepressant use and more lifetime personality disorders compared to people with BD‐I ²¹ , ²² , ²⁶ , ¹²² , ¹²³ . These factors raise questions about whether it is the disorder itself, the comorbidities or associated factors that are driving the prognosis ²¹ , ²⁶ .

Individuals with BD‐II report higher rates of family dysfunction, divorce and unemployment compared to those with BD‐I ²³ , ²⁴ , ²⁵ , ²⁶ , ¹²⁴ . Cognitive impairment has been often found in BD‐II ²¹ , ²⁴ , ¹²⁵ , ¹²⁶ , ¹²⁷ . A study reported that approximately half of BD‐II patients had some impairment, with 12% of them being severely and globally impaired ¹²⁸ .

PSYCHIATRIC COMORBIDITIES

Psychiatric comorbidities are the rule in BD‐II and complicate its diagnosis, leading to poorly targeted treatment and contributing to higher morbidity and disability rates. Data from the World Mental Health Survey ⁹⁷ revealed that 83% of individuals with BD‐II have at least one comorbid psychiatric diagnosis, and that more than 50% of them experience three or more psychiatric comorbidities. A systematic review ²⁵ found that people with BD‐II have a 29.5% higher rate of comorbid psychiatric disorders than those with BD‐I. The high prevalence of psychiatric comorbidities in BD‐II stems from its complex clinical presentation and reflects the limitations of current psychiatric classification systems based on overlapping symptoms.

Anxiety disorders are particularly common in people with BD‐II, affecting about 75% of these patients, as estimated by the World Mental Health Survey ⁹⁷ . Similar prevalence rates have been found in other studies ¹²⁹ , ¹³⁰ , ¹³¹ , ¹³² . Specific lifetime prevalence rates include 33% for generalized anxiety disorder and 39% for social anxiety disorder ⁹⁷ . These two comorbidities have been found to be more common among patients with BD‐II than in those with MDD ¹³³ . More overall comorbid anxiety disorders have been reported in BD‐II compared to BD‐I ¹³⁴ , but the relevant evidence remains inconsistent ¹²⁹ . Anxiety symptoms in BD‐II often present as part of the prodrome, preceding mood episodes, and are associated with greater treatment resistance and increased suicidality ¹³⁴ , ¹³⁵ , ¹³⁶ . The frequent co‐occurrence of BD‐II and anxiety disorders suggests possible shared etiological and pathophysiological pathways, and supports the view that they may represent, at least in part of the cases, different aspects of a single disorder rather than separate conditions ⁷⁰ , ¹³⁵ . Genetic studies further reinforce this view, providing data which may indicate a distinct biological subtype of BD‐II with comorbid anxiety ¹³⁷ .

A large‐scale, cross‐sectional study involving 61,392 adults across 11 countries found that obsessive‐compulsive disorder occurred in 12% of patients with BD‐II ⁹⁷ , suggesting a strong comorbid link that was influenced by familial history of mood disorders ¹³⁸ .

A complex and controversial comorbidity is that with ADHD ¹³⁹ , ¹⁴⁰ , with rates in BD ranging between 5.1% and 47.1% ¹⁴¹ . The symptom similarity between BD and ADHD can complicate the diagnosis and management of both conditions, leading to poorly targeted treatment and potentially contributing to higher morbidity and disability rates ¹⁴² , ¹⁴³ . ADHD in BD‐II is associated with earlier onset of mood symptoms, increased suicidality, and heightened temperamental instability ¹⁴¹ , ¹⁴⁴ . ADHD treatment with stimulants has the potential to adversely affect mood, while untreated ADHD may worsen mood symptoms through significant functional impairments ¹⁴⁴ . Stimulants can effectively treat comorbid ADHD, but should be prescribed alongside adequate mood‐stabilizing treatment and during periods of euthymia, to minimize the risk of treatment‐emergent hypomania or mixed states ¹⁴⁵ , ¹⁴⁶ , ¹⁴⁷ , ¹⁴⁸ .

Borderline personality disorder is the most complex and diagnostically challenging comorbidity associated with BD‐II. Approximately 10% of patients with this condition meet criteria for BD‐II, while 20% of BD‐II patients meet criteria for borderline personality disorder ¹⁴⁹ . Another study reported a 24% lifetime prevalence of borderline personality disorder among individuals with BD‐II ¹⁵⁰ . This results from the high symptomatic overlap between the two conditions, which includes affective instability, impulsivity, mood dysregulation, and heightened suicidality ⁸⁶ . However, despite these similarities, key differences in the patterns of mood and behavior can aid in differential diagnosis, as detailed above (see Figure 1).

According to several studies, approximately 50% of individuals with BD‐II meet the criteria for substance use disorder, with alcohol being the most common substance of abuse ¹⁵¹ , ¹⁵² , ¹⁵³ . BD‐II is associated with a greater risk of alcohol abuse/dependence and benzodiazepine use/abuse ¹⁵⁴ . Chengappa et al ¹⁵⁴ found that 39% of patients with BD‐II are dependent on one or more substances, 17% on two or more, and 11% on three or more. Substance misuse complicates the clinical management of BD‐II by mimicking or triggering mood episodes and amplifying hypomanic impulsivity and depressive symptoms, leading to increased morbidity and compromised treatment adherence ¹⁵⁵ , ¹⁵⁶ , ¹⁵⁷ .

About 14% of patients with BD‐II meet criteria for at least one comorbid lifetime eating disorder ¹⁵⁸ , and the incidence may be as high as 59% in hospitalized BD‐II patients ¹⁵⁹ . Binge eating disorder is particularly common in individuals with BD‐II, and contributes to obesity, metabolic disturbances, and extended depressive episodes, further complicating the course ¹⁶⁰ .

RISK OF SUICIDE

Individuals with BD‐II are at a significantly increased risk of suicide, with approximately 33% of them having a lifetime history of suicide attempts ⁵⁴ . The first year following diagnosis is particularly critical, with a high risk of depressive relapse and suicidal behavior ¹⁶¹ .

A meta‐analysis and systematic review reported that the risk of completed suicide is similar in patients with BD‐II compared to those with BD‐I ²⁷ . Other studies pointed at a higher prevalence of completed suicide in BD‐II ⁵⁵ , ¹¹⁷ , ¹⁶² . A Swedish bipolar registry study reported that the rate of suicide attempts was significantly higher in patients with BD‐II than in those with BD‐I, but no data on completed suicides were provided ²⁶ .

BD‐II patients often experience a longer duration of untreated illness and more frequent comorbid anxiety disorders, which might exacerbate suicidal risk ¹⁶³ , ¹⁶⁴ . Functional impairment, high comorbidity, and a greater tendency to mixed states further contribute to the elevated suicide risk in BD‐II ²⁷ , ⁵⁴ , ⁵⁶ .

PHYSICAL COMORBIDITIES

Physical comorbidities are highly prevalent in individuals with BD‐II, affecting over 90% of them at some point in their lives ¹⁴⁵ , ¹⁶⁵ . They are more frequent than in MDD ⁶³ , especially in patients with a body mass index higher than 35 ¹⁶⁶ . In a study of 1,720 patients with BD ¹⁶⁷ , those with BD‐II exhibited a higher prevalence of gastric ulcer, cardiovascular diseases, Parkinson's disease, and rheumatoid arthritis than those diagnosed with BD‐I.

Primarily due to the elevated risk of physical conditions, life expectancy in BD‐II is reduced by 10 to 20 years compared to the general population ¹⁶⁹ , ¹⁷⁰ , ¹⁷¹ . Cardiovascular diseases are a leading cause of morbidity and premature mortality in patients with BD‐II ¹⁷² . Metabolic disorders – including obesity, type 2 diabetes mellitus, hypertension and dyslipidaemia – are disproportionately common in these patients ¹⁶⁵ , ¹⁷³ , ¹⁷⁴ . Individuals with BD‐II face a threefold increased risk of developing metabolic syndrome compared to the general population ¹⁷⁵ . These metabolic disturbances are linked to more frequent mood episodes, greater depressive symptom severity, and a shorter time to relapse ¹⁷⁶ , ¹⁷⁷ .

Autoimmune diseases frequently co‐occur with BD‐II, amplifying the burden of illness. Over 20% of individuals with BD‐II are affected by autoimmune thyroiditis, with elevated risks also for systemic lupus erythematosus, rheumatoid arthritis, and psoriasis ¹⁷⁸ , ¹⁷⁹ , ¹⁸⁰ . Gastrointestinal disorders, such as irritable bowel syndrome, are also common, with a prevalence of 30% in BD‐II compared to 15% in the general population ¹⁸¹ , ¹⁸² . Chronic pain conditions, including migraine, affect 25% to 35% of BD‐II patients, worsening depressive symptoms and reducing quality of life ¹⁸³ .

The high prevalence of physical comorbidities in patients with BD‐II exacerbates the illness burden, and is associated with greater treatment resistance and higher hospitalization rates ¹⁶⁵ , ¹⁷⁶ . This underscores the necessity of regular screening for cardiovascular, metabolic, inflammatory, and pain‐related disorders within comprehensive care plans ¹⁶⁷ . Effective management of BD‐II demands a multidisciplinary approach that integrates psychiatric and physical care in both clinical settings and research ¹⁸⁴ , ¹⁸⁵ . Moreover, exploring the bidirectional relationships between BD‐II and physical comorbidities is essential to developing targeted interventions ¹⁸⁶ .

RISK FACTORS AND NEUROBIOLOGY

Trauma is a major risk factor for BD‐II ¹⁸⁷ , with a history of severe childhood abuse being present in about 23% of patients ¹⁸⁸ . This abuse often correlates with an earlier age of onset. Ongoing stress and trauma can further exacerbate or trigger episodes, complicating the course of the disorder ¹⁸⁹ .

Comparative studies show no substantial differences in the prevalence of childhood abuse between BD‐I and BD‐II, indicating that early trauma is a risk factor across the bipolar spectrum ¹⁸⁸ , ¹⁸⁹ . However, offspring of parents with BD‐I experience higher levels of childhood trauma compared to those whose parents have BD‐II, suggesting that the type of parental bipolar disorder might influence the environmental and emotional conditions experienced by children ¹⁹⁰ .

Substance abuse is another risk factor. The use of alcohol and drugs can not only precede the development of bipolar symptoms but also complicate the course of the disorder, leading to poorer clinical outcomes and more complex treatment needs ¹⁹¹ , ¹⁹² , ¹⁹³ , ¹⁹⁴ . Circadian rhythm disruptions, whether due to work, lifestyle, or other disorders, are also linked to a higher incidence of mood disorders, including BD‐II. The misalignment of circadian rhythms can exacerbate or trigger episodes of hypomania and depression ¹⁹⁵ .

Genetic studies suggest that the heritability of BD ranges from 60 to 80%, indicating a strong genetic component ¹⁹⁶ , ¹⁹⁷ , ¹⁹⁸ . Specifically, a 21‐67% range is reported for BD‐II ¹⁹⁹ . Additionally, family studies suggest a higher likelihood of BD‐II among first‐degree relatives of individuals with BD‐II ²⁰⁰ , ²⁰¹ . Genome‐wide association studies (GWAS) have identified genetic distinctions between BD subtypes: in particular, polygenic risk score (PRS) for schizophrenia is higher in BD‐I than BD‐II, while PRS for MDD is higher in BD‐II, suggesting that BD‐II may be more closely related to MDD than BD‐I ²⁰² .

Inflammation has been highlighted as a possible biological factor in the pathogenesis of BD‐II. Studies have identified elevated levels of pro‐inflammatory cytokines such as interleukin‐6 (IL‐6) and tumor necrosis factor‐alpha (TNF‐alpha) in individuals with BD‐II during depressive and hypomanic episodes ²⁰³ . These elevated cytokine levels suggest that inflammation could serve as a biomarker for disease activity and severity, but the evidence for targeted anti‐inflammatory treatments is still inconclusive ²⁰⁴ , ²⁰⁵ , ²⁰⁶ .

BD‐II is increasingly regarded as a disorder of energy regulation. Mitochondrial dysfunction affects cellular energy production, which might lead to the characteristic energy‐related mood disturbances seen in BD‐II ²⁰⁷ , ²⁰⁸ , ²⁰⁹ . Mitochondrial dysfunction may also be responsible for the observed accelerated biological aging and age‐related conditions seen in people with BD, such as autonomic and endothelial dysfunction, increased inflammation, and oxidative stress ²¹⁰ . This line of investigation could lead to the identification of potential biomarkers for BD‐II, as well as novel therapeutic targets ²¹¹ .

TREATMENT

Most evidence concerning treatment comes from studies on BD‐I, with few trials specifically focused on BD‐II. This lack of research specifically targeting BD‐II is partly due to the absence of regulatory incentives, as drugs approved for BD‐I are assumed to be effective for BD‐II, even though this assumption is not always justified.

Acute treatment is based on clinical presentation. Maintenance pharmacotherapy beyond acute episodes, accompanied by psychoeducation, is the main treatment strategy. Pharmacological interventions typically involve a mood stabilizer such as lamotrigine or lithium, an atypical antipsychotic such as quetiapine, or a combination strategy. Due to its recurrent and chronic nature, the treatment of BD‐II for most individuals generally needs to be lifelong. Effective management requires a stable and enduring therapeutic alliance ²¹² , ensuring continuity of care to facilitate treatment adherence and improve outcomes.

Acute treatment of hypomania

Patients experiencing hypomania rarely present for treatment. It is crucial to advise patients on the importance of maintaining mood stabilization as hypomanic episodes often seed subsequent depressive episodes ²⁰ . The goal of treatment of hypomania is to manage the risks associated with impaired judgment and disinhibition, ensuring that patients' behavior and decision‐making are consistent with their usual patterns, allowing them to maintain their normal roles and functions.

There are no large randomized controlled trials (RCTs) that examined the efficacy of pharmacological agents for treatment of hypomania. Clinical experience suggests that all agents that are active in mania are also effective in hypomanic episodes. Treatment guidelines from the Canadian Network for Mood and Anxiety Treatments (CANMAT) and the International Society for Bipolar Disorders (ISBD) ²¹³ , ²¹⁴ recommend withdrawing any potential mania‐inducing medications such as antidepressants, stimulants and corticosteroids, and using mood stabilizers such as lithium, anticonvulsants or atypical antipsychotic agents.

In addition to pharmacotherapy, hypomania may benefit from behavioral interventions. Maintaining healthy daily routines, including a stable sleep‐wake cycle and stress avoidance, is valuable in managing hypomanic episodes.

Acute treatment of depression

The treatment of depression in BD‐II is particularly challenging and often requires a combination of pharmacotherapy and psychotherapy. In a recent meta‐analysis, olanzapine plus fluoxetine, quetiapine, olanzapine, lurasidone, lumateperone, cariprazine, and lamotrigine were found to be more efficacious than placebo in adults with acute bipolar depression across BD‐I and BD‐II ²¹⁵ .

Quetiapine is the only first‐line drug recommended by the CANMAT and ISBD guidelines for the treatment of bipolar II depression ²¹⁴ . This recommendation is supported by pooled data from four placebo‐controlled randomized studies, involving 572 participants, demonstrating that quetiapine monotherapy significantly improves depressive symptoms in BD‐II patients ²¹⁶ .

A recent phase 3, randomized, double‐blind, placebo‐controlled study of patients with bipolar depression and a combined post‐hoc analysis of data from two RCTs ²¹⁷ , ²¹⁸ have shown the superiority of lumateperone over placebo in improving depressive symptoms in both BD‐I and BD‐II patients, suggesting that this agent will gain guideline support for treating depression in BD‐II. However, these results need to be confirmed in other trials, as the sample of BD‐II patients in both studies can be considered small. Lumateperone is the first drug in 15 years that has been approved by the US Food and Drug Administration (FDA) for bipolar depression associated with both BD‐I and BD‐II.

Lamotrigine is also an evidence‐based treatment for BD‐II depression ²¹⁹ . The CANMAT notes that methodological issues have led to an underestimation of its efficacy, with a slow titration to a 200 mg final dose over an 8‐week trial duration, such that participants only had a therapeutic dose for two weeks. In a trial that compared open label lamotrigine monotherapy (N=44) with lithium monotherapy (N=54) in BD‐II depressed patients over a 16 week period, therapeutic doses of lamotrigine resulted in a significant reduction of acute depressive symptoms relative to baseline, with no significant differences in efficacy between lamotrigine and lithium ²²⁰ . Additionally, a double blind RCT evaluating adjunctive lamotrigine treatment with lithium in 124 patients found clinically significant improvement in depressive symptoms in comparison to placebo in a combined group of BD‐II and BD‐I depressed patients ²²¹ .

Lamotrigine's relatively benign tolerability profile is a notable advantage over atypical antipsychotics, particularly given the metabolic side effects associated with the latter treatments in a disorder characterized by risk for cardiovascular disease and in the context of often lifelong therapy ²²² . Moreover, lamotrigine has proven to be effective in women at childbearing age ²²³ and does not carry the serious teratogenicity risks associated with valproate ²²⁴ . However, lamotrigine's prolonged titration regime to start treatment potentially hinders its benefits in acute depression and makes it easier to use for maintenance treatment.

The use of antidepressants in BD‐II remains controversial, due to inadequate and conflicting evidence and the potential risk of treatment‐emergent hypomanic/manic switch ²²⁵ . A systematic review suggests that, while the rates of antidepressant‐associated mood elevations are greater among BD‐II than MDD patients in acute (8.1% vs. 1.5%) and maintenance (16.5% vs. 6.0%) trials, they are lower in BD‐II relative to BD‐I in acute (7.1% vs. 14.2%) and maintenance (13.9% vs. 23.4%) studies ²²⁶ .

Among antidepressants, trial evidence suggests that bupropion is associated with the lowest risk for treatment‐emergent hypomanic/manic switch ²²⁷ . Further, an RCT of BD‐I and BD‐II patients showed that bupropion had similar efficacy as sertraline and venlafaxine ²²⁸ . There is also RCT evidence that sertraline monotherapy is as effective as lithium and lithium+sertraline combination, while venlafaxine demonstrated greater improvement in depressive symptoms compared to lithium in a trial of 129 BD‐II patients ²²⁹ . However, venlafaxine seems to have a greater switch propensity than selective serotonin reuptake inhibitors ²³⁰ .

Based on the above evidence, the CANMAT guidelines ²¹⁴ recommend bupropion, sertraline and venlafaxine as second‐line treatment; and fluoxetine as third‐line treatment for BD‐II depression. Antidepressants are recommended to be used in conjunction with a mood stabilizer ²¹⁴ , ²³¹ .

Lithium, traditionally used as monotherapy or in combination with other pharmacotherapies, has long been a staple in the treatment of BD‐II depression ²³² . However, recent studies have questioned this approach. One study found no significant improvement in depressive symptoms in BD‐I and BD‐II patients treated with lithium at doses ranging from 600 to 1,800 mg/day compared to placebo ²³³ .

A recent small non‐randomized open‐label trial suggested a possible efficacy of psylocibin together with psychotherapy in BD‐II resistant depression ²³⁴ . Moreover, there are some preliminary data from real‐world samples supporting the efficacy of ketamine in the treatment of BD‐II depression ²³⁵ . Nonetheless, the safety of these interventions, especially in the long‐term, is still to be determined.

Overall, the acute treatment of BD‐II depression requires a careful balance of pharmacotherapy, lifestyle interventions and psychotherapy, with a focus on individualized treatment plans to manage symptoms effectively and minimize the risk of relapse and treatment‐emergent complications.

Maintenance pharmacotherapy

The majority of individuals with BD require maintenance treatment to prevent subsequent episodes, reduce residual symptoms, and restore functioning and quality of life ²³⁶ . There is a notable paucity of evidence specifically addressing this subject in BD‐II. The clearest guidance has been provided by CAMMAT ²¹⁴ , suggesting that quetiapine (Level 1), lithium and lamotrigine (Level 2) monotherapies exhibit the strongest evidence as first‐line agents for maintenance treatment of BD‐II.

Lithium is recognized for its efficacy in long‐term management. It must be noted, however, that most lithium studies did not report findings separately for BD‐I and BD‐II. In a systematic review and network meta‐analysis examining the comparative effectiveness of medications in maintenance therapy, lithium was indicated as the primary option when prescribing a relapse‐prevention medication for patients with BD ²³⁷ , ²³⁸ . Lithium reduced time in hypomania/mania by 61%, and time in depression by 53%, in the entire sample, with a lower proportion of time with mood symptoms for BD‐II than for BD‐I ²³⁹ .

Patients with BD‐I and BD‐II have a significantly longer time to relapse into any mood episode and depression with quetiapine relative to placebo ²⁴⁰ . Quetiapine is as effective as lithium when added to treatment as usual for patients with either BD‐I or BD‐II, with BD‐II patients responding better ²⁴¹ . There are no data for other antipsychotic agents in BD‐II, although aripiprazole ²⁴² and asenapine ²⁴³ have evidence for maintenance therapy of BD‐I and are recommended for long‐term treatment of this condition.

Overall, while it is tempting to develop a pharmacological treatment algorithm for BD‐II, there is a paucity of robust evidence from clinical trials specifically involving BD‐II patients. Clinicians utilize a range of anecdotal and off‐label treatments which could be effective but with limited research evidence, highlighting a substantive unmet evidence need.

Psychotherapies

Guidelines emphasize the importance of psychological interventions for the maintenance treatment of BD‐II ²⁴⁴ . Combining pharmacotherapy with psychotherapy can significantly improve treatment outcomes, reduce the risk of relapse, and enhance overall patient well‐being ²⁴⁴ . Various psychotherapy modalities offer specific benefits, addressing different aspects of the disorder ²³⁶ .

Cognitive behavioral therapy (CBT) focuses on identifying and modifying negative thought patterns and behaviors that contribute to mood episodes. It helps patients develop and enhance coping strategies and problem‐solving skills ²⁴⁵ .

Family‐focused therapy (FFT) involves the patient's family in the treatment process. It aims to improve family communication, reduce relational stress, and create a more supportive home environment. It educates family members about BD‐II and teaches them how to recognize and respond to mood episodes, thereby enhancing the overall support system for the patient ²⁴⁶ , ²⁴⁷ .

Interpersonal and social rhythm therapy (IPSRT) – the only psychotherapy assessed in a randomized controlled trial in a sample consisting of only BD‐II patients ²⁴⁸ – targets disruptions in daily routines and social rhythms that can trigger mood episodes ²⁴⁹ , ²⁵⁰ . It helps patients establish and maintain regular daily routines, including sleep‐wake cycle, and improves interpersonal relationships.

A network meta‐analysis of 39 randomized clinical trials involving 3,863 participants demonstrated that manualized psychotherapy – such as CBT, FFT and IPSRT – in combination with pharmacotherapy is more effective in reducing recurrences compared to pharmacotherapy alone ²⁴⁸ .

Psychoeducation

Psychoeducation is a valuable tool for effective treatment of BD‐II, aiming to enhance patient and caregiver understanding of the nature of the condition, treatment options, and management strategies ²⁵¹ , ²⁵² . It helps patients and their families to identify early signs of mood episodes, understand the necessity of medication adherence, and manage lifestyle factors that can influence the course of the disorder ²⁵³ . In so doing, it empowers patients to take an active role in their treatment.

Lifestyle interventions

Lifestyle interventions play a significant role in managing BD‐II. These interventions benefit both mental and physical health, contributing to overall well‐being and improved health outcomes ²⁵⁴ . Maintaining a regular sleep‐wake cycle and managing stress through mindfulness, exercise, and relaxation techniques can help stabilize mood and enhance emotional resilience ²⁵⁵ . Dietary considerations, such as maintaining a balanced diet, may also contribute to better health outcomes ²⁵⁶ . The ketogenic diet is an area of interest, although only pilot trial data are available ²⁵⁷ , ²⁵⁸ .

Given the higher prevalence of physical health issues in individuals with BD‐II, regular monitoring of activity levels, blood pressure, weight changes, cholesterol and glucose levels is crucial.

CONCLUSIONS

BD‐II is a distinct condition within the bipolar spectrum, characterized by recurrent depressive and hypomanic episodes without the presence of mania. Despite its high prevalence and impact, it remains underdiagnosed ¹² , ¹³ , which often leads to prolonged periods of untreated illness, mis‐management, and poor clinical outcomes, underscoring the need for improved awareness and tailored treatment approaches ¹⁵ , ¹⁶ . Depression is the primary clinical burden in BD‐II, with individuals spending over 80% of their symptomatic time in depressive states ¹⁷ , ²⁰ , leading to significant functional impairment and a suicide risk comparable to BD‐I ⁵⁴ , ⁵⁵ .

Currently, treatment guidelines for BD‐II are largely extrapolated from studies on BD‐I and MDD, limiting the validity and specificity of therapeutic recommendations. Maintenance pharmacotherapy beyond the treatment of acute episodes, in conjunction with psychoeducation, constitutes the primary therapeutic strategy ²¹⁴ , ²³² , ²⁵¹ . The chronic and recurrent nature of BD‐II typically requires ongoing management throughout the patient's lifetime, necessitating a stable therapeutic alliance to enhance treatment adherence and improve clinical outcomes ²¹² . Mood stabilizers such as lamotrigine, lithium, and atypical antipsychotics – particularly quetiapine – have demonstrated efficacy in managing bipolar depression and preventing relapse ²¹³ , ²¹⁴ .

The role of antidepressants in BD‐II remains controversial, due to concerns over treatment‐emergent hypomania and mixed states ²³¹ . Evidence suggests that the risk of hypomanic switching is lower in BD‐II compared to BD‐I, and antidepressants may have a place in the treatment of BD‐II when combined with mood stabilizers ²²⁶ , ²²⁸ . Nevertheless, the lack of robust, BD‐II‐specific clinical trials requires further research to determine the safety and efficacy of antidepressants in this population.

The high prevalence of psychiatric and physical comorbidities in BD‐II significantly complicates its clinical management ¹⁴⁵ . Common psychiatric comorbidities include anxiety disorders, substance use disorders, and borderline personality disorder, all of which contribute to greater symptom severity and pose unique treatment challenges ⁹⁷ , ¹⁶⁵ . Physical conditions, such as obesity, metabolic syndrome and cardiovascular diseases, are highly prevalent ¹⁴⁵ , ¹⁶⁵ . Cardiovascular diseases are the leading cause of reduced life expectancy in individuals with BD‐II ¹⁶⁸ . These comorbidities exacerbate the symptomatic burden of the disorder, and highlight the critical need for an integrated, multidisciplinary approach to care ¹⁶⁷ .

Future research must adopt a systemic approach that integrates fields such as endocrinology, immunology, metabolic regulation, and neuroscience to unravel the complex pathophysiology of BD‐II. This systems‐level framework is essential for identifying biomarkers that bridge symptomatic and biological profiles, enabling the development of clinical phenotypes to guide targeted treatments and inform personalized care strategies ²⁰⁵ .

By addressing the unique challenges posed by BD‐II through targeted research and refined clinical practices, we can advance care and improve outcomes for this often‐overlooked population.