The Spectrum of Agitation Associated with Schizophrenia and Bipolar Disorder

Faculty Perspectives: The Spectrum of Agitation Associated with Schizophrenia and Bipolar Disorder

More than 5% of individuals in the United States are diagnosed with schizophrenia or bipolar disorder1,2; these conditions can have a significant impact on health economics and personal productivity. For example, schizophrenia often results in unemployment and is considered a major cause of long-term disability worldwide.1 According to a recent study, the indirect costs attributed to schizophrenia between 2005 and 2008 totaled approximately $75 billion.3

The lifetime prevalence of bipolar disorder is 2.4% worldwide and 4.4% in the United States; this disorder is more common among women than among men.1,4 Bipolar disorder is considered the most expensive behavioral health diagnosis, costing more than twice as much as depression per affected individual.1,5,6 In addition, the hospital admission rate for patients with bipolar disorder is 29% versus <5% for patients with depression.5

Agitation, which is defined as excessive motor and verbal activity, is frequently observed in psychiatric patients and affects the treatment of schizophrenia and bipolar disorder.7,8 The tendency for agitation to lead to violent behavior is compounded if substance abuse is involved.8

Strategies for improving the treatment of agitation, along with disease symptoms, may help to alleviate the suffering—as well as the economic impact—of these disorders. The rapid onset of action for a drug that reduces agitation in patients with schizophrenia or bipolar disorder is a key component for adequately managing these disorders.7

The goals of this article are to provide readers with a better understanding of schizophrenia and bipolar disorder, to discuss the clinical manifestations and treatment of schizophrenia and bipolar disorder, and to review the impact of agitation on these 2 diagnoses.

Clinical Features of Schizophrenia

Schizophrenia is a chronic recurring psychotic disorder that is characterized by impaired thinking, behavior, and emotions. In the majority of patients, schizophrenia negatively affects normal social and occupational functioning.9 Patients with schizophrenia typically present with distinct psychopathologic symptoms; these are classified as positive symptoms, negative symptoms, cognitive impairment, mood symptoms, and anxiety symptoms.10,11

Positive symptoms are exaggerations of normal mental processes or behaviors that are not observed in healthy individuals, including hallucinations, delusions, and disorganization.10,12 A summary of the diagnostic criteria for schizophrenia, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, is shown in Table 1.10

Table 1

Hallucinations are defined as perceptions of sensory events in the absence of external stimuli; hallucinations may be visual, auditory, somatic, olfactory, or gustatory in nature. Auditory hallucinations are the most common type of hallucinations-so common that “hearing voices” has fallen into everyday parlance as a descriptor (though false) for patients with schizophrenia.10,13,14 Besides voices, sounds such as music or machinery may also be perceived and may stem from within the individual’s head or from an outside source.15 Visual hallucinations typically include flashes of color or glowing spheres; they are often identifiable objects.13,15 Somatic hallucinations involve abnormal body sensations or physical experiences. Olfactory and gustatory hallucinations are reported as strange smells and tastes.15

Delusions are a common feature of schizophrenia and are defined as false personal beliefs outside of cultural norms that cannot be contradicted, even in the face of conflicting evidence.10 Delusions may take on numerous forms and are divided into various categories, including persecutory, referential, grandiose, erotomanic, nihilistic, and somatic.10 In one study, nearly 79% of patients with schizophrenia experienced persecutory delusions.16

Disorganization in behavior and/or thinking may be observed in a proportion of patients with schizophrenia.9 Disjointed speech patterns are a common outward manifestation of disjointed thought processes.10 Disorganization appears independently of delusions,10 and some evidence suggests that patients who manifest disorganization are more resistant to treatment.9

Negative or deficit symptoms are often a core feature of schizophrenia; such symptoms include apathy, flat affect, decreased expressiveness, and lack of energy.10 In some cases, these symptoms are secondary to other aspects of the disease, such as depression, social isolation, or drug-induced akinesia.17 Negative symptoms are particularly difficult to alleviate with drugs.18

Cognitive impairment in schizophrenia includes deficits in information processing speed, attention, memory (ie, working, visual, and verbal), reasoning and problem solving, verbal comprehension, and social cognition.19 A variety of neurocognitive tests have been developed or adapted to assess cognition in schizophrenia.20 Cognitive impairment often precedes the appearance of prodromal phases of psychosis.21

Mood and anxiety symptoms are fairly common in schizophrenia. One meta-analysis revealed that greater than 38% of patients with schizophrenia had comorbid anxiety disorder.22 Anxiety symptoms that often accompany schizophrenia include obsessive-compulsive disorder, panic disorder, and agoraphobia, among others.22 In addition, depressive symptoms are frequently observed in patients with schizophrenia; based on different studies, the lifetime prevalence of depressive symptoms may be as high as 50%.23 Separate risk factors for depressive symptoms include family history of depression,24 high family and personal expectations of success in life, negative family attitudes, multiple hospitalizations or a recent hospital discharge, and a lack of social support.25

Managing Patients with Schizophrenia

Management of patients with schizophrenia relies on pharmacotherapy, with antipsychotic drugs used in first-line treatment.18 Antipsychotic drugs relieve major psychotic symptoms in approximately 75% of patients with schizophrenia,26 and symptoms improve in most patients within 2 weeks after the start of treatment.27 When response is suboptimal, a second antipsychotic agent is typically prescribed, although little empirical evidence exists for this practice.28

The acute phase of schizophrenia refers to the periods during which the patient experiences an acute episode of positive symptoms, with either the onset of symptoms after an asymptomatic period or a marked increase in symptoms over a baseline of less severe symptoms.26 Symptom remission is the goal of treatment during the acute phase of schizophrenia.26

In first-episode psychosis, early treatment with antipsychotic drugs is associated with significant symptom reduction.18 Patients with first-episode schizophrenia typically have increased treatment responsiveness and increased sensitivity to adverse effects compared with patients with multiepisode schizophrenia.18 Therefore, the Schizophrenia Patient Outcomes Research Team recommends that antipsychotic treatment should be initiated with doses lower than those recommended for patients with multiepisode schizophrenia.18

In patients with treatment-responsive, multiepisode schizophrenia who experience an acute exacerbation of their illness, the initial choice of antipsychotic drug or the decision to switch to a new antipsychotic drug is based on several factors, including individual preference, previous treatment response, side effect experience, adherence history, relevant medical history and risk factors, and long-term treatment planning.18

Patients who recover from an acute episode of schizophrenia typically reach a stable phase, during which time the treatment goal is to suppress or prevent acute symptoms. Often, this requires that patients continue to take antipsychotic drugs, at the lowest effective dose.18 It is important to minimize the adverse events associated with antipsychotic drugs to maximize patient compliance, particularly in younger patients. Clinical trials have pointed to the value of antipsychotic drugs as maintenance therapy for schizophrenia. One meta-analysis of 65 clinical trials showed that patients with schizophrenia who received antipsychotic drugs as maintenance had a lower relapse rate compared with patients who received placebo.29

Clinical Features of Bipolar Disorder

Bipolar disorder, formerly referred to as manic-depressive disorder, is characterized by extreme shifts in mood and energy levels.6 Patients with bipolar disorder often experience shifts in thinking and in sleep patterns. In addition, behavioral changes are frequently observed, differentiating the manic phase from the depressive phase.6 Even with characteristic behavioral and mood shifts, the disorder can be difficult to diagnose. In one survey, individuals waited at least 10 years before obtaining an accurate diagnosis30; therefore, patients who present with mania, hypomania, or depression should be evaluated for bipolar disorder.10

Bipolar disorder has 2 major subtypes: (1) bipolar I disorder and (2) bipolar II disorder. Patients with bipolar disorder can present with a clear depressive episode, manic episode, hypomanic episode, or with mixed features (ie, mood of one polarity accompanied by symptoms of the opposite polarity).10 In bipolar I disorder, patients experience manic episodes, hypomanic episodes, and depressive episodes; patients with bipolar II disorder experience hypomanic episodes and depressive episodes.10 Mood episodes with mixed features occur frequently; by some estimates, mixed feature episodes occur in 50% to 70% of patients with bipolar disorder.31,32 Overall, depressive symptoms dominate over hypomanic/manic symptoms and mixed symptoms in bipolar disorder.33,34

The diagnostic criteria for bipolar disorder subtypes are summarized in Table 2.10 The severity of symptoms varies widely among patients, and subsyndromal symptoms are common.33,34 In addition, some patients remit between polar episodes and become euthymic, whereas other patients pass from one polar state to another without a euthymic interval.35

Table 2

Table 2b

Mania involves a variety of aberrant behaviors, including euphoria, disinhibition, and excessive sociability (eg, inappropriate flirtations, lengthy telephone conversations with strangers).36 Risky behaviors, such as entering into business ventures with poor odds of success or reckless driving, may also occur. In many patients, increased goal-oriented behavior is observed.37,38 Hypomanic episodes resemble manic episodes except for the duration and severity of symptoms. In addition, unlike in manic episodes, psychotic features in hypomanic episodes are absent. Major depression in bipolar disorder is characterized by dysphoria, sluggish mental and physical activities, lack of interest in normally pleasurable pursuits, and impaired concentration.10 Sleep disturbances are common and include insomnia or hypersomnia.10,39 Psychotic symptoms (eg, delusions, hallucinations) may occur during manic, major depressive, and mixed feature episodes. A nationwide study of 14,529 patients with bipolar disorder showed that the lifetime prevalence of psychosis in bipolar disorder was 19% for psychotic mania and 15% for psychotic depression.40 It is not known whether psychosis that accompanies manic episodes or depressive episodes indicates a more severe, long-term prognosis.41

The majority of patients with bipolar disorder have at least one comorbid psychiatric disorder, including anxiety disorders, attention-deficit/hyperactivity disorder, substance abuse, personality disorders, and intermittent explosive disorder.41 In one survey, the prevalence of at least one comorbid disorder among patients with bipolar disorder ranged from 88% to 98%42; the prevalence of at least one psychiatric disorder in the general US population is 46%.43

Managing Manic/Hypomanic Bipolar Disorder

Pharmacotherapy in bipolar disorder varies for mania/hypomania and depressive states; treatment also differs by the severity of the disease. The treatment goal for mania should be remission, defined as the resolution of major symptoms (1 or 2 minor symptoms may persist during defined remission). If remission is not possible, the goal of therapy should be improvement in symptoms.44 Mood stabilizers, anticonvulsants, and antipsychotic drugs are the most common pharmacotherapies used to treat patients with mania/hypomania; benzodiazepines may be included as adjunct therapy.45

Clinical evidence suggests using certain drug combinations for the first-line treatment of acute mania. These combinations will vary depending on patient profile, comorbidities, patient preference, and other factors.45 Multiple treatment guidelines are available to help clinicians select the best course of treatment for the individual patient.46-48

Typically, first-line treatment for acute mania includes a mood stabilizer plus an antipsychotic. A meta-analysis of 8 randomized clinical trials that involved 1124 patients with acute bipolar mania showed that adding an antipsychotic to a mood stabilizer was significantly more effective than a mood stabilizer alone.49 In addition, other studies showed that mood stabilizers reduced the risk for suicide in patients with bipolar and other major affective disorders.50,51

Patients with mild to moderate illness are often prescribed monotherapy, with antipsychotic drugs as first-line therapy.48 Alternatively, these patients may receive mood stabilizers or anticonvulsants.48 A meta-analysis of 68 randomized clinical trials that involved 16,073 patients with acute mania or mixed episodes found that antipsychotics were significantly more effective than mood stabilizers in treating manic episodes of bipolar disorder.52

Patients who do not respond to an initial regimen should be prescribed another combination. Furthermore, patients with refractory mania/hypomania should be referred for nonpharmacologic treatment after several combinations of treatments have failed.44

Managing Bipolar Depression

Studies have shown that patients with bipolar disorder spend more time in, and take longer to recover from, the depressive phase than the manic phase.53 Antidepressants are used to treat bipolar depression, and some combinations of antidepressants and antipsychotic drugs or mood stabilizers have been particularly effective in bipolar I depression.53-55 In a randomized clinical trial of 833 patients with bipolar I disorder, remission occurred at a significantly higher rate in patients who received combination treatment with antidepressant drugs compared with patients who received monotherapy or placebo.53 It is important to note that not all practitioners believe that there are adequate data to justify the widespread use of antidepressant drugs for the treatment of patients with bipolar disorder.56

Mood stabilizers are also used to treat bipolar depression. The efficacy of 1 mood stabilizer was shown in a meta-analysis of 5 randomized clinical trials that involved 1072 patients with bipolar depression. Response was defined as the reduction of symptoms by more than 50%, which occurred significantly more frequently in patients who received the mood stabilizer compared with patients who received placebo.57 Clinicians should exercise caution when choosing combinations of mood stabilizers because drug–drug interactions associated with these agents may augment plasma levels.58

Maintenance Therapy for Bipolar Disorder

Relapses almost always occur in patients with bipolar disorder; they can be life-threatening and should be addressed through prevention. The goal of maintenance therapy for bipolar disorder is to prolong remission while allowing normal functions with regard to day-to-day activities. Typically, remission is achieved through a combination of pharmacotherapy and psychotherapy.59 In some cases, pharmacotherapy alone is used if, for example, psychotherapy is declined or not available.

First-line pharmacotherapy options for maintenance therapy include mood stabilizers and antipsychotic drugs. A meta-analysis of 8 randomized clinical trials showed that mood stabilizers were more effective at preventing relapses compared with placebo.49

Several factors may affect the success of maintenance treatment, including60-62:

  • Patient compliance
  • Support from family
  • Disease awareness
  • Lack of clinicians’ awareness regarding patients’ particular circumstances that may create barriers (eg, if patient has no access to a vehicle and specified treatment site has no access by public transportation)
  • Lack of patient awareness regarding the benefits of maintenance treatment
  • Complexity of drug regimens
  • Hours of accessibility of clinicians/facilities.

Adjunctive psychotherapy in combination with pharmacotherapy has been shown to be an effective option for main­tenance therapy in patients with bipolar disorder.59 Psycho­therapy helps patients to accept the chronic and recurring nature of bipolar disorder, and to recognize the prodromal symptoms that require acute management.59

Overview of Agitation

Agitation is frequently observed in psychiatric illnesses, including schizophrenia and bipolar disorder, and is characterized by motor restlessness, increased response to external stimuli, irritability, and unsuitable speech.63 In one study, approximately 20% of patients with bipolar disorder had psychomotor agitation during a depressive state; whereas in another study, the frequency was more than 31%.64

Agitation may manifest into physical aggression; therefore, it is important to address it appropriately, especially because family members and medical personnel are most often the targets of aggressive patients.7,65 In bipolar disorder, agitation is often observed during manic episodes and depressive episodes, and may be attributed to the reduced need for sleep, irritability, and fluctuating energy levels.8 Agitation that is associated with psychosis is a frequent cause of emergency department visits, admissions to psychiatric wards, and continued hospitalization.7,64

The differential diagnosis of agitation that accompanies schizophrenia or bipolar syndrome should be determined after a careful evaluation of the patient.7 For example, involuntary motor activity may be a side effect of the prescribed treatment for the patient’s disorder. In addition, an underlying or comorbid somatic illness may be present; approximately 50% of patients with schizophrenia have a comorbid alcohol or drug disorder,66 and agitation from substance use or withdrawal is frequently reported.8 A chaotic home environment may also contribute to a patient’s agitated state.7 In addition, iatrogenic causes of agitation should be explored; namely, akathisia, which is defined as the inability to sit still. Akathisia may be caused by the use of antipsychotic drugs and antidepressants7,67; therefore, differentiating between akathisia and agitation is essential because improper dosing may lead to the worsening of akathisia symptoms.7 Clinicians may use a variety of assessment tools (eg, Positive and Negative Syndrome Scale, Excited Component) to assess the severity of agitation in the context of psychotic illnesses.68 These assessment tools measure agitation on a scale that ranges from anxiety to aggression. The scales also reveal the 3 major components of most instances of agitation: (1) strong emotion; (2) excessive motor or vocal activity; and (3) inappropriate motor or vocal activity.68

Management of Agitation

Agitation in patients with schizophrenia may have several causes, including extrapyramidal symptoms, substance abuse, and delusions. Therefore, management of patients with agitation should be adjusted accordingly.8 When experiencing extrapyramidal symptoms, patients may have difficulty describing why they are restless or whether they are restless; thus, it may be challenging to differentiate between agitation and akathisia.67

The modern management of acute agitation relies heavily on psychotherapy. Consensus guidelines indicate that calming rather than sedating the patient should be the goal of immediate treatment of acute agitation.68,69 Nonpharma­cologic considerations include maintaining the safety of the patient and others. The environment should be assessed wherever possible and all objects that could be used as weapons should be removed discretely.63 In addition, creating a serene environment (eg, dimmed lights, soft or absent noises) may be helpful.63 As a point of safety, medical personnel should always face the patient, engaging him or her in soft yet authoritative tones.63 Restraint and isolation should be used as last resorts in emergency situations, when there is risk of imminent harm.68,70

In terms of pharmacologic interventions, barbiturates and typical antipsychotics have long been the mainstays of treatment for patients with agitation, followed by anxiolytics and atypical antipsychotics.68 The route of administration is a key consideration in selecting the appropriate drug, because orally administered drugs may take at least twice as long to take effect as intramuscularly administered drugs.68 This delay may be partially overcome by the use of orally administered tablets that disintegrate in seconds and are bioequivalent to conventional oral tablets; such tablets also prevent patients from hoarding and disposing when personnel are not closely monitoring them.68 Nevertheless, patients who are severely agitated are successfully managed with oral drugs alone in only 55% of cases.68

An intramuscular anxiolytic is a frequently administered drug for treating patients with severe agitation; it has a rapid onset of action and no active metabolites. However, its use is associated with some undesirable adverse events, including respiratory depression and rare paradoxic effects.7 In addition, drug administration that requires the use of hypodermic syringes poses hazards to medical personnel, especially when dealing with agitated patients.71

The recent development and approval of a first-generation antipsychotic drug that uses an inhalation-activated aerosol as its delivery modality is a therapeutic advancement in the treatment of patients with schizophrenia or bipolar disorder who experience agitation.7,71 This antipsychotic drug is an antagonist at the dopamine D2 receptor, with clinically relevant serotonin 5-HT2A receptor antagonism.7 The delivery method is activated by the patient’s inhalation and does not require hand and breath coordination.7 Inhalation activates a sensor in the delivery device, which, in turn, initiates the condensation aerosol of the drug. The drug enters the respiratory tract in less than 1 second without the need for forceful inhalation.7 The emitted dose is approximately 90% of the drug in the device; there are no excipients,7,72 and a small amount is deposited in the oropharyngeal tract.73 Before administering the inhaled antipsychotic, patients must be screened for a history of pulmonary disease because the drug may cause bronchospasm.7

Several clinical trials have demonstrated the safety and efficacy of the oral inhalation delivery of this antipsychotic drug.74-76 In one study, the peak plasma concentrations were achieved within minutes, with subsequent rapid calming.71 No excess sedation was noted, and the most common side effect was dysgeusia; other side effects included sedation and somnolence, throat irritation, and extrapyramidal symptoms.7,71


Schizophrenia and bipolar disorder may be accompanied by agitation, a mental and physical state characterized by motor restlessness, mental tension, and excitement. Because agitation may rapidly escalate into violence toward self, family, or medical personnel, clinicians must be able to diagnose it accurately and use appropriate pharmacologic and nonpharmacologic strategies to manage it effectively.

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