Although current psychiatric classification systems employ operational definitions of syndromes and disorders, the creation of distinct entities may simply be an illusion-masking complex and overlapping phenomena. 

The status of current research suggests that this may be a particular problem with bipolar disorders.

The minimum ICD-10 criteria for diagnosing bipolar affective disorder are two separate mood episodes, one of which must be mania, hypomania or mixed affective state. 

Depression is common in the longitudinal course of bipolar disorder, although debate has arisen about its optimal treatment and management.¹ Uncertainties exist about:

• Whether or not depressive episodes differ phenomenologically in unipolar and bipolar patients
• Whether or not mood stabilisers alone afford suitable treatment for both manic and depressive phases of illness
• How antidepressant medications may affect the short and long-term courses of illness
• What prognostic significance depressive episodes may hold in terms of functioning and outcome for bipolar patients.

Prevalence

Population studies such as the Epidemiologic Catchment Area (ECA), and its related cross-national studies, and the National Comorbidity Survey (NCS) reported that the lifetime prevalence of bipolar disorder varies from 0.3-1.5%. 

The NCS data include only bipolar I data, while the ECA includes bipolar I and bipolar II disorder. In all studies, the six-month prevalence is not much lower than the lifetime prevalence of bipolar disorder. 

These findings reflect the high degree of chronicity and/or recurrence associated with bipolar disorder. 

The average age of onset in bipolar disorder is around late teens to mid-20s while that of unipolar depression is approximately the late 30s.

Also, in bipolar disorder, the prevalence in males and females is similar – this is in contrast to the reasonably consistent female excess found in major depression.²

The presentation of individuals with bipolar disorder frequently includes depressive features that are mistaken for unipolar depression. 

Differentiating bipolar from unipolar depression, as well as recognising mixed affective features, holds pragmatic importance not only for pharmacotherapy decisions, but also for risk and prognostic assessment.

Clinical presentation

The classical features of unipolar depression are: 

• Low mood
• Reduced energy
• Fatiguability
• Reduced attention and concentration
• Lowered self-esteem
• Ideas of guilt and worthlessness
• Pessimistic thoughts•
• Thoughts of self-harm or suicide. 

In addition there are the somatic changes which include: reduced appetite leading to weight loss, disturbed sleep pattern with early morning wakening, diurnal variation of mood, anhedonia, loss of normal reactivity of mood, reduced libido, amenorrhoea and psychomotor retardation.³

In bipolar depression, psychomotor agitation and anxiety appear to have a key role, patients having a more intense mood state (ie. higher levels of worthlessness, lower self-esteem levels), lability of mood is more likely as well as psychotic and atypical features (ie. hypersomnia, hyperphagia) than unipolar depressed patients.⁴

Therefore, bipolar depressive episodes are frequently more severe, shorter in duration and appear to have a more acute onset and termination and may have a seasonal pattern.

The possibility that patients could simultaneously exhibit both depressive and manic (or hypomanic) symptoms has long been recognised (Kraepelin 1921/1976), however, mania and depression are usually imagined as polar opposites. This thinking may explain why it is difficult even to agree on a definition of a mixed mania (also called dysphoric mania).⁵

Most studies of mixed affective states are limited by this lack of consistent criteria. For example, whether dysphoric mania is a distinct disorder, a subtype of mania, a particularly severe form of rapid cycling, or a transitional point between mania and depression is unclear. 

A mixed episode is characterised by a period of time (lasting at least one week) in which the criteria are met for both manic episode and for a major depressive episode nearly every day. The individual experiences rapidly alternating moods, sadness, irritability, accompanied by increased psychomotor activity leading to high levels of agitation, anxiety, anger, initial insomnia, racing thoughts, appetite dysregulation, psychotic features and suicidal thinking. Individuals may be disorganised in their thinking or behaviour. 

Because individuals in mixed episodes experience more dysphoria, they may be more likely to seek help than in a classical manic episode.⁶ Symptoms like those seen in a mixed episode may be due to direct effects of antidepressant medication, electroconvulsive therapy, or medication prescribed for other general conditions (eg. corticosteroids). 

Such presentations are not considered mixed episodes and do not count towards a diagnosis of bipolar disorder. 

For example, if a person with recurrent depressive disorder develops a mixed symptom picture during a course of antidepressant medication, the diagnosis of the episode is substance-induced mood disorder with mixed features rather than a switch from depression to bipolar disorder. 

However, there is evidence that suggests that there may be a bipolar diathesis/spectrum, and that such individuals may have and increased likelihood of future manic, mixed or hypomanic episodes that are not related to substances or somatic treatment for depression. 

Course and prognosis

The untreated depressive episodes in unipolar depression last six to 13 months; most treated episodes last about three months. The withdrawal of antidepressants before three months has elapsed almost always results in return of the symptoms.

As the course of disorder progresses, patients tend to have more frequent episodes that last longer. Major depression is recurrent in about 85% of cases. 

Compared to bipolar disorders, however, depressive patients experienced only half as many episodes over their lifetime. The cycle length (time from the start of an episode to the start of a subsequent episode) is consequently longer than in bipolar disorders. 

Bipolar affective disorder often starts with depression (75% of the time in women and 67% in men) and is a recurring disorder. Depressive episodes in bipolar depression last four to six months. About 20-30% of episodes are biphasic (depression with subsequent switch into mania/hypomania or mania with subsequent switch into depression).⁷

Mixed episodes can evolve from a manic episode or from a depressive episode or may arise de novo. These episodes may last weeks to several months and may remit to a period with few or no symptoms or evolve into a full depressive or manic episode.

Comorbidity

Affective disorders that co-occur with other psychiatric or medical disorders often appear more difficult to treat than those occurring alone, and they may lead to greater functional disability over time. Both current and lifetime abuse of alcohol or other substances is significantly more common among bipolar depressed than unipolar depressed patients. Other forms of comorbidity, such as panic disorder and other anxiety disorders, are common in bipolar illness and may add to the overall risk of suicidality.⁸

Pharmacotherapy

Two of the central controversies surrounding the drug treatment of bipolar depression involve: 

• The limited efficacy of current therapies 
• Questions about the safety of antidepressant therapies in bipolar disorder, because such therapies have been reported to trigger or evoke manic episode. 

These two issues are related in that mood stabilisers, widely considered to be the mainstay of treatment for bipolar disorder in all its phases, may not always lead to remission of depressive symptoms when used without antidepressant agents.

The treatment of a depressed phase of a bipolar illness should proceed with caution and studies show that the drugs best avoided in bipolar depression are tricyclic antidepressants (TCAs) and serotonin-norepinephrine re-uptake inhibitors (SNRIs). 

Some investigators have suggested that selective serotonin re-uptake inhibitors (SSRIs) may be less likely to precipitate mania, although reports of SSRI-induced mania also exist. Which bipolar patients are most vulnerable to pharmacologically induced mania remains poorly understood. 

Treatment algorithms advocate for the use of bupropion or an SSRI (recommended citalopram, escitalopram or paroxetine over fluoxetine) as first-line treatment choices for bipolar depression. 

The second-line agents include monoamine oxidase inhibitor (MAOI) antidepressants.

Many clinicians anecdotally recommend the use of ‘smaller-than-usual’ doses of antidepressant for ‘shorter-than-usual’ periods of time during the depressive phases of bipolar illness. 

Some clinicians advocate ensuring the presence of a therapeutic blood level of a primary mood stabiliser before adding any antidepressant medication.^9,10

The extent to which lithium is effective for bipolar depression, either acutely or prophylactically, remains an empirical question with limited research data available. 

Mixed states are associated with failure to respond to lithium. 

Anticonvulsant mood stabilisers, sodium valproate in particular, have gained popularity among patients who have treatment-resistant forms of bipolar disorder and their use has been emphasised in dysphoric mania as well as in pure depressive phases of the illness. 

Lamotrigine and gabapentin are among the newer anticonvulsants that are used with increasing frequency in the treatment of bipolar disorder. Lamotrigine appears to have antidepressant effects as well and may produce benefit alone.¹¹

If cycling occurs in spite of this, an antipsychotic may be added and the antidepressant cautiously reduced. 

A particular efficacy in mixed affective states was noted for risperidone and olanzapine, which are useful adjuncts in the presence of excessive agitation, hostility or psychotic symptoms. 

The short-term use of benzodiazepines is also recommended for mild, moderate or severe behaviour dyscontrol associated with suicidal tendencies, especially in dysphoric mania when there is no history of benzodiazepine-induced disinhibition.

Electroconvulsive therapy (ECT) treatment may be indicated, as in unipolar depression, for bipolar depression and some of the mixed affective states if the above strategies, even when optimised, are ineffective, and does not appear to lead to rapid cycling.¹²

Difficulty in reaching consensus

Given the existing ambiguities about the defining characteristics of mixed states, the difficulty involved in reaching a consensus in the disorder’s features is not surprising. 

Nevertheless, clinicians need more information about this disorder, particularly because it appears to be more common than originally thought.

Furthermore, mixed affective symptoms are relevant to the course (ie. for prevention of cycle acceleration as well as switching into a full manic or depressive state) and expected treatment response of bipolar disorder.

Declaration of interest: none. 

References available on request