Mixed States in Bipolar Disorder

Bipolar disorders remain under-recognized, misdiagnosed, and mistreated in both psychiatric and primary care settings. Mixed states—the concurrent existence of symptoms of both manic and depressed mood—are especially misunderstood and unappreciated. These times of depressed mood—energized by impulsive overactivity and poor judgment—or manic mood—colored by undercurrents of despair and psychic pain—frame periods of high risk of self-harm or violence toward others.

Information about the existence, prevalence, and importance of bipolar mixed states may foster early recognition and prompt, efficacious interventions by clinicians, primary care and psychiatric alike. In any area of practice, matching intensity of treatment with severity of illness is a key to good outcomes. For mood disorders, there is no greater severity or need for prompt, intense intervention than that of the bipolar mixed state.

History Repeats Itself

Emil Kraepelin, who coined the term “manic depressive,” wrote extensively about the concept of mixed states,1 observing the blending of different mood states to be a very common occurrence. He noted mixing to be particularly prevalent during

transitions from periods of pure mania to pure depression, or vice versa. “…very often we meet temporarily with states which do not correspond either to manic excitement or to depression, but represent a mixture of morbid symptoms of both forms…This relationship becomes most clear in the transition periods from one state to another, which often extends over weeks or months.”

Rapid transitions or switches in mood, Kraepelin observed, also tended to bring about concurrent features of both extremes. He relates: “If we begin with the cases which develop in the orthodox manner, in which purely manic and purely depressive states appear one after the other, we find at the height of the attack combinations of definite symptoms which, on the whole, may be

regarded as psychological opposites.”

That these individuals and those around them were often painfully affected is quite evident. “Not at all infrequently we observe

in our patients…a kind of grim humor, which is compounded by despair and amused self-derision…This includes cases of pronounced manic excitement, in which the patients on the slightest occasion fall into outbursts of furious anger, overwhelm their surroundings with abuse, and become senselessly violent…constantly peevish, repellent, inaccessible…make scornful remarks, torment and ill-use their fellow patients.”

Into the Mix

Categorical classification systems, such as the DSM-IV, in an effort to standardize diagnostic criteria for researchers, define mixed episodes as the full expression of both mania and major depression during one or more weeks. Perhaps 40% of bipolar

I patients experience a full mixed episode. Clinicians tend to think of mood, cognition, and psychomotor activation (or lack thereof) as being tightly linked in mood disorders. That is, we expect the depressed individual to be sad or unmotivated; reclusive; preoccupied with guilt or ruminating about the regrets, failures, or traumas of the past; and slowed down physically with slumped posture and slowed speech.

Conversely, the manic individual is conceptualized as elated or euphoric, thinking clearly and creatively, socially outgoing and overactive, needing less sleep, and remaining active even at odd hours. In bipolar disorder, however, the relationships between

mood, cognition, and psychomotor energy cease to be fixed, leading to symptomatic mixtures and clinical presentations that may not be intuitive to clinicians unfamiliar with bipolar phenomenology.

Mood, cognition, and psychomotor energy move independently of each other in bipolar disorder, allowing us to predict the presence of states where manias exhibit inhibited psychomotor activity, or of paucity of thought and excited depressions where impulsivity or hypersexuality color the expression of mood. Patients with such a mixed mania might be categorized by the presence of elation, extreme creativity, and grandiosity, but lack the physical energy to accomplish any goals and appear withdrawn or even catatonic. A patient with a depressive mixed state might be suicidal while having an affair or have been recently arrested for shoplifting.

Of particular interest to current practice are mixed states characterized by panic states and other anxious symptomatology and those where delusions (eg, somatic) influence the patient’s chief complaint and interface with primary care. These represent

opportunities for clinicians to focus too narrowly on the chief complaint and fail to appreciate a larger clinical context. Such situations are often fraught with mismanagement.

Mixed states often contain refractory anxiety (panic states are not uncommon), insomnia resistant to intervention with sedative/hypnotics or benzodiazepines, and severe agitation. Irritable mood predominates. Patients may appear histrionic and are often affectively labile and hypersensitive to perceived insults. They may gesture prominently, talk loudly, and cry easily. Even seductive presentations can be seen. Verbal or physical aggressiveness is possible. Behavior may be markedly unrestrained.

Spouses or co-workers often instinctively (and correctly) experience these states as unsettling, stormy, unpredictable,

and dangerous. When evaluating a bipolar patient in a mixed state, clinicians working within a constricted diagnostic paradigm

might be tempted to prematurely diagnose panic disorder, generalized anxiety disorder, or agitated depression. This in turn may prompt a trial of antidepressant monotherapy for the depressed or anxious mood with or without a benzodiazepine for acute relief of anxiety symptoms. This may lead to an exacerbation of anxiety or agitation, worsening insomnia and irritable mood, or increased suicidality. Moreover, whenever antidepressant therapies (alone or in rational combinations) mobilize or exacerbate such symptoms, revisiting the possibility of the presence of a bipolar diathesis is mandatory.

A growing body of scientific literature suggests that mixed and rapid cycling states are often iatrogenic, rendering the patient more difficult to treat. Patients may appear to present with treatment-resistant depression. Indeed, a recent analysis suggests

that in 50% of cases, an antidepressant monotherapy is the initial treatment chosen for bipolar disorder—a truly tragic state of affairs given the poor track record and potential danger of unopposed antidepressant use in bipolar disorder.

Management Approach

Mixed states are often psychiatric emergencies. Because mixed states contain elements of both manic and depressed mood, the potential for suicidal impulses and actions is greatly increased. Depression and hopelessness may be energized with impulsivity,

creating a dangerous catalyst for self-harm.

Early recognition and consideration of the diagnosis is most crucial to effective intervention. Treatment modalities include referral for more thorough assessments and intense, multidisciplinary levels of care, and pharmacologic interventions. The removal of inciting or potentially harmful substances (antidepressants, stimulants, caffeine, etc.) is also important.

Pharmacologic strategies often combine medications that directly address the mixed state (atypical antipsychotics, antiepileptics, etc.) and adjunctive medications to reduce agitation and anxiety, such as benzodiazepines. Atypical antipsychotics have

received approval or been studied in such roles. Several have intramuscular forms affording the possibility of prompt treatment of agitation.

Though the phenomenon is counterintuitive to many clinicians, mania and depression may coexist. These mixed states have the potential for great harm to the patient and others. Clinicians must be wary so as not to miss such states, as they may masquerade as panic attacks, agitated depression, or treatment-resistant depression. Prompt, specific intervention may limit dysfunction and prevent tragic complications.