BIPOLAR DISORDER

IMPORTANT DEFINITIONS

DEFINE » Rapid Cycling: A severe course specifier for bipolar disorder, defined by the occurrence of four or more distinct mood episodes within a 12-month period. Considered a form of treatment-resistant bipolar disorder, frequently associated with high morbidity, increased suicide risk and greater prevalence in women

DEFINE » Behavioural Inhibition (BIS): Regulates behavioural inhibition, avoidance in potential threats, punishment and non-rewards. Higher trait BIS scores are linked to depressive moods, negative affect, and anxiety. Low BIS sensitivity is linked to lack of inhibition, which can increase manic symptoms, whereas high BIS is linked to the shutdown of behavioural approach

DEFINE » Behavioural Activation (BAS): Regulates approach behaviours, sensitivity to reward, and goal-directed actions via dopaminergic pathways. Individuals with bipolar disorder often have overly sensitive BAS, causing them to response excessively to reward-related cues, leading to mania. High BAS correlates with euphoria, excessive energy, reduced need for sleep, impulsivity, and goal-striving behaviour.

DEFINE » Trans-diagnostic: focuses on the shared mechanisms, symptoms or neurobiological factors across different mental disorders rather than on specific categories. This perspective addresses high comorbidity rates by targeting underlying processes like emotional dysregulation, cognitive biases, and avoidance, which are common symptoms to conditions like anxiety and depression.

DEFINE » Ion channelopathy: A diverse group of diseases caused by the dysfunction of ion channels- pore-forming proteins that control the flow of ions (such as sodium, potassium, calcium and chloride) across cell membranes.

DEFINE » Intracellular Signaling Cascades: Play a crucial role in the pathophysiology of psychiatric disorders. Acts as the bridge between extracellular neurotransmitter signals and nuclear gene expression. These pathways are often dysregulated in Bipolar Disorder and Major Depressive Disorder, leading to impaired neuroplasticity, reduced synaptic connectivity, and neuronal atrophy in key brain regions such as the hippocampus and prefrontal cortex

BIPOLAR DISORDER

A condition where individuals suffer from alternating depressed and elevated moods (mania). Though the depressed mood is self-explanatory, mania is characterized by abnormally energized or irritable affect, reduced sleep, and high levels of impulsivity. The degree of mania can be less extreme (hypomania) and this level of severity is generally what separated Bipolar I and Bipolar II. 

    CRITERION A: Criteria have been met for at least one manic episode. The manic episode may have been preceded by     and may be followed by hypomanic or major depressive episodes.

    CRITERION B: The occurrence of the manic and major depressive episode(s) is not better explained     by schizoaffective disorder, schizophreniform disorder, delusional disorder, or other specified or     unspecified schizophrenia spectrum and other psychotic disorder. 

NOTE: Major depressive episodes are common in Bipolar I disorder but are not required for the diagnosis. Hypomanic episodes are common in Bipolar I disorder but are not required for the diagnosis. 

MANIC EPISODE

    CRITERION A: A distinct period of abnormality and persistently elevated expansive or irritable mood, and abnormally and     persistently increased goal directed activity or energy lasting at least one week and present most of the day, nearly every     day. 

    CRITERION B: During the period of mood disturbance and increased energy or activity, three or more of the following     symptoms are present to a significant degree and represent a noticeable change from usual behaviour

  • Inflated self-esteem and grandiosity

  • Decreased need for sleep

  • More talkative and a pressure of speech

  • Racing thoughts and flight of ideas

  • Distractibility

  • Increase in goal directed activity or psychomotor agitation (purposeless activity)

  • Excessive risk-taking behaviour (spending, sex, foolish / impulsive investments)

    CRITERION C: The disturbance is sufficiently severe to cause marked impairment in functioning or necessitate     hospitalization to prevent risk to self or others, or there are psychotic features\

    CRITERION D: Constitute exclusions based on substance use/drug side effects, or the presence of psychotic features in     the absence of prominent mood symptoms

HYPOMANIC EPISODE

    CRITERION A: A distinct period of abnormality and persistently elevated expansive or irritable mood, and abnormally and     persistently increased goal directed activity or energy lasting at least one week and present most of the day, nearly every     day. 

    CRITERION B: During the period of mood disturbance and increased energy or activity, three or more of the following     symptoms are present to a significant degree and represent a noticeable change from usual behaviour

  • Inflated self-esteem and grandiosity

  • Decreased need for sleep

  • More talkative and a pressure of speech

  • Racing thoughts and flight of ideas

  • Distractibility

  • Increase in goal directed activity or psychomotor agitation (purposeless activity)

  • Excessive risk-taking behaviour (spending, sex, foolish / impulsive investments)

    CRITERION C: The episode is associated with an unequivocal change in functioning that is uncharacteristic of the     person when non-symptomatic

    CRITERION D: The disturbance on mood and change in functioning is observable by others

    CRITERION E-G: Exclusion based on major impairment, psychotic features, substance use or medication

NOTE: Differences between Hypomanic and manic episodes exist in their severity, duration and functionality. Manic episodes last one week, cause severe impairment, often include psychotic features and may require hospitalization. Hypomanic episodes last at least four days, are milder, and do not cause significant dysfunction nor psychotic features

RISK FACTORS

(Palmier-Clause et al, 2016)

  • Bipolar risk was strongly associated with childhood abuse and neglect. Emotional abuse 4x as likely to occur in those with bipolar disorder versus controls 

  • Higher rates of Childhood Maltreatment (CMT) for bipolar disorder compared to major depressive disorder, but comparable to schizophrenia

(Horton et al, 2005)

  • Suicide risk in those with bipolar disorder best predicted by prior suicide attempts and sense of hopelessness (like MDD) 

  • For non-fatal suicidal behaviour, best predictors were family history of suicide, early bipolar onset, MDD, rapid cycling, comorbidity and substance abuse

(Rowland et al, 2018) 

  • The catalysts for bipolar disorder are understudied. There is a combination of genetic factors, current life stress, substance abuse that may contribute 

  • Evidence from MZ twin studies suggests a concordance of 40-70%. Similarly, the lifetime risk of bipolar disorder in first-degree relatives is 5-10% higher than the general population (Craddock et al, 1999) 

  • Recent twin studies show 70-80% heritability with one bipolar parent and a tenfold risk over the normal population (Craddock & Skylar, 2013) 

(Fajutrao et al, 2009) 

  • Between 21-54% of bipolar sufferers attempt suicide, much higher than MDD 

  • In Europe, between 60-70% of those with bipolar were unemployed and received disability payments 

  • In the UK, the cost of bipolar disorder is approximately billions, mostly due to hospitalization during acute episodes 

MODELS FOR BIPOLAR

Bipolar 1 & 2 Personality Factors

  • Related to high extraversion and high openness to experience

  • Behavioural Inhibition (BIS) versus Behavioural Activation (BAS) theory (Depue & Lacono, 1989)

    • Hi BAS = impulsive, Hi BIS = depression

Bipolar Neurotransmitters (Dozols, 2023)

  • Norepinephrine (NE), dopamine (DA), and Serotonin (5-HT) are also theorized to play a role in the manic episodes of bipolar disorder

  • Abnormal dopamine levels may trigger the hyperactivity and psychosis of severe mania, whereas abnormal norepinephrine levels may trigger euphoria and grandiosity

  • Normal serotonin levels inhibit some neuronal activity, leading to some behavioural inhibition

  • Conversely, non-normal low serotonin can lead to activation of a variety of behaviour. Therefore, a defect in this inhibitory effects of serotonin could hypothetically lead to wide swings between depression and mania

Genetic Risk Studies (Harrison et al, 2017)

  • Genes implicated in bipolar disorder are implicated in schizophrenia and trans-diagnostic mood instability. No single gene causes bipolar disorder: instead, many common variants of small effect contribute.

  • No evidence that bipolar is inherited, but rather a collective of genes are responsible for regulating a range of neurological processes underpinning mania

  • Genome-wide association studies (GWAS) have revealed that genes related to ion channelopathy are central to bipolar disorder

Calcium Channelopathy (Barridge, 2014; Harrison et al, 2017)

  • bipolar may be partly a problem with ion channelopathy with dysregulated calcium signalling implicated in mood instability; this may be related to depression as well

  • Neurons have systems that regulate neuroplasticity, information processing, perception, cognition and excitability

  • Errors in gene transcription (not the genes themselves) can cause changes in signaling pathways becoming overactivated and poorly regulated

  • Dysregulation in the Calcium pathways are partly causal in bipolar disorder (Heyes et al, 2015); calcium pathways exist independent of mood, suggesting a trait-like mechanism of vulnerability. Drugs that attenuate calcium channels like lithium and antiepileptics also reduce manic symptoms

  • Genetic disruption of calcium channels destabilizes mood circuits, making bipolar disorder a condition of neural and affective instability that responses best to treatments which re-stabilize excitability and signaling

TREATMENT FOR BIPOLAR

Calcium signaling dysregulation in bipolar

  • Genetic studies implicate ion channel genes (CACNA1C, ANK3, TRANK1) in bipolar disorder

  • These genes affect L-type voltage-gated calcium channels, which regulate neuronal excitability, plasticity and network stability

  • Dysregulated calcium signaling leads to unstable firing in mood-relevant circuits and therefore vulnerability to rapid shifts between depression and mania

Processes Affected by Drug Treatment

  • Lithium modulates intracellular signaling cascades, including calcium-dependent pathways. Dampens excessive neuronal excitability and reduces the likelihood of manic switching and relapse

  • Antiepileptics (valproate, lamotrigine) stabilize neuronal membranes and reduce abnormal firing, partly via effects on ion channels. This helps prevent mood episodes by reducing the “noise” in dysregulated neural networks

Atypical Antipsychotics and calcium-linked circuits

  • Act on dopamine and serotonin systems that interact with calcium-dependent signaling in frontal-limbic circuits

  • Reduce hyperdopaminergic states and psychosis in mania, indirectly stabilizing networks already vulnerable due to calcium channel abnormalities

Clinical Reasoning

  • If bipolar involves ion channelopathy and calcium signaling instability, then: use drugs that stabilize neuronal excitability (lithium, antiepileptics)

  • use agents that modulate downstream monoamine systems interacting with these calcium

Pharmacological Treatments

  • Treatment consists of mood stabilizers, such as lithium, valproate and lamotrigine

  • Antipsychotics like quetiapine, aripiprazole, asenapine, lurasidone and cariprazine are recommended, but some are associated with weight gain (Nierenberg et al., 2023)

  • Lithium is for relapse prevention and suicide reduction. Lamotrigine for bipolar depression, quetiapine, lurasidone and cariprazine for acute bipolar depression, and valproate for mania (Yatham et al., 2022))

Mood Stabilizers

  • Reduces excitation on dopamine and glutamate. Increases inhibitory neurotransmitters (GABA). Like quetiapine, effective at treating acute mania (Fountoulakis & Vieta, 2009)

  • The therapeutic dose is close to toxicity, as it interferes with sodium and water retention. This leads to weight gain and tremors. Stopping lithium increases relapse risk (Baldessarini et al., 1999)

  • Anticonvulsants work by increasing GABA which is inhibitory, and affects calcium signaling pathways (Ketter et al., 2009)

  • Superior to placebo for treating depressive phase of bipolar disorder

  • 40% don’t respond to lithium or find side effects intolerable, resulting in 70% relapse in five years (Gitlin et al., 1995)

Antipsychotics (Quetiapine)

  • Used in long-term treatment of mood inability and relapse reduction, but this isn’t guaranteed. Effective for acute mania and maintenance phases

Adjunctive CBT for bipolar disorder

  • Cognitive Behavioural Therapy is adjunctive, not a standalone treatment

  • Used alongside mood stabilizers to reduce relapse, improve functioning and manage depressive symptoms

  • Targets the psychological and behavioural mechanisms that medication does not address (sleep-wake instability, stress reactivity, cognitive distortions, early warning signs)

Core Components

  • Psychoeducation: improves adherence / reduces recurrence

  • Mood / routine stabilization

  • Cognitive Restructuring: targets beliefs about mood instability

  • Relapse prevention: learn early signs, plan accordingly

Clinical Summary

  • Cognitive Behavioural Therapy does not prevent mania on its own but reduces depressive symptoms, improves adherence and stabilizes routines

  • When combined with medication it reduces relapse

  • Combined therapy enhances functioning and quality of life

  • Best outcomes occur when CBT is delivered early in the course and integrated into pharmacotherapy