We've all been there. It's late in the day, and you're running a bit late, about to see your next-to-last patient.
We’ve all been there. It’s late in the day, and you’re running a bit late, about to see your next-to-last patient. As you enter the
room, you are instantly aware that something is seriously wrong. The patient looks agitated, strained, and slightly disheveled.
She reports that despite being on an antidepressant for more than two months, she “just isn’t doing well at all.” She hasn’t
slept well in more than a week, and her husband has threatened to leave if “things don’t get better.” The tears, irritability,
and slightly pressured speech confirm your fears—this patient is suffering from bipolar disorder and is in trouble. Is she
in a mixed state? Manic or hypomanic?
How do you accurately assess treatment options and intervene effectively to bring the patient’s symptoms under control?
Although manic, hypomanic, and mixed states make up, on average, only about one sixth of bipolar patients’ overall time
when followed longitudinally, the “topend” symptoms associated with these states cause a disproportionate amount of dysfunction that can be devastating for patients. The unrelenting dysphoria, irascibility, severe agitation, refractory anxiety, unendurable sexual excitement, and intractable insomnia that often accompany mixed states can result in a high incidence of suicidal obsessions and impulses.Effective treatment of bipolar patients, however, can radically reduce the morbidity and mortality associated with the illness (eg, reducing the risk of suicide
by a factor of five).
The challenge for clinicians, however, is choosing which therapy is appropriate for individual patients. The rapid expansion of available evidence-based therapies has offered exciting opportunities for clinicians, but epidemiologic evidence must be supplemented with clinician experience to generate robust confidence in particular therapies. In addition, there may be individual patient factors that influence the rational choice of proposed therapy, including response to prior treatments, socioeconomic and psychodynamic resources, and tolerance of potential adverse events.
Given the attention that has been apparent recently in both the academic literature and the lay press about adverse events that can occur during psychotropic pharmacologic therapy, some patients may be reluctant to begin therapy, despite a clinician’s
recommendation to do so. Clinicians should discuss carefully with patients the risks and benefits of various treatments, including the attendant risks of no pharmacologic therapy. As with all treatment options, the most effective treatment should be sought—the treatment which offers the most favorable balance of robust efficacy (as demonstrated in randomized trials), safety (as monitored in large populations of patients), and tolerability (as reported in registration trials, in post-marketing studies, and in individual clinical experience).
Incorporating all these factors into the process of decision making, there is a proposed schema for rational therapeutic choices, in which at critical decision points, the evidence base is combined with individual patient factors to arrive at multiple reasonable
choices. These choices are then discussed with the patient, and a therapy is mutually agreed upon, instituted, and monitored for effectiveness. If the treatment produces the desired result, it is continued; if not, the process restarts at a new critical decision point.
So what of our patient in the situation described above? Assuming that she is experiencing a mixed state, and in the absence of other compelling factors, I would feel most comfortable discontinuing her antidepressant, and replacing it with a mood stabilizer, such as Zyprexa® (olanzapine) for management of her acute symptoms. Olanzapine is indicated as a first-line treatment for patients in a bipolar mixed state.In addition to its proven efficacy, olanzapine offers prompt and predictable relief of both the manic and depressive symptoms of a mixed episode that makes it a particularly useful tool when faced with a patient who needs help today.
After the patient’s acute symptoms have responded to therapy, clinicians must give due diligence to monitoring the patient on maintenance therapy. The goal of maintenance therapy should be full recovery, followed by sustained remission. There is evidence to support that achieving the former can be a key to achieving the latter. In the landmark study, “Systematic Treatment
Enhancement Program for Bipolar Disorder (STEP-BD),” 58% of patients who were symptomatic at study entry experienced
recovery with optimal treatment.
The presence ofresidual manic symptoms was predictive of future relapse (to either manic or depressive episodes) during the two-year follow-up period. Clearly the first step towards keeping these patients well is getting them well, focusing particularly on manic symptoms.Over time, however, the patient’s ability to function well is heavily influenced by the presence of depressive
symptoms. Altshuller and colleagues found that bipolar patients with subsyndromal depressive symptomatology performed poorly in four major social domains. The scores of subsyndromal patients more closely approximated those of depressed patients than those of non-depressed patients.
A critical factor in alleviating residual symptoms, and therefore reducing subsequent negative outcomes in the acute setting (eg, emergency department visits and psychiatric hospitalization) is adherence to prescribed therapy. The median prevalence of non-adherence reported in bipolar studies is 45%.8 The factors associated with non-adherence vary, but can be grouped broadly into disease characteristics, patient characteristics, clinical factors, and medication factors. Patients with chronic and recurrent illness (particularly if associated with grandiosity, irrationality, and depression) tend to be non-adherent.
Patients who are younger, African American, have lower socio-economic status, or have comorbid substance abuse are also at an increased risk of non-adherence, as are those who lack disease state knowledge or have a negative view of treatment. Clinicians hold the key for fostering adherence and reducing symptoms—a robust therapeutic= relationship in which the patient
can avoid the stigma associated with mental illness and overcome negative views of medical therapy. In some patients, monotherapy with a foundational mood stabilizer, such as olanzapine, may be sufficient to achieve acute symptom control and to support robust clinical stability during the maintenance phase. However, in most patients with bipolar disorder, combination
therapy is considered the rule, rather than the exception. Compared to patients with unipolar depression, for instance, combination therapy in known bipolar patients is utilized four times as often. Given this reality, having a clear rationale for each agent used (and clearly communicating that rationale to the patient) is the first step toward effective therapy. Next, clinicians
must be vigilant in monitoring for any emergent adverse events (deriving from the patient’s disease state, the therapy, or both).
For all my patients with bipolar disorder, my most significant concerns regarding adverse physical outcomes during therapy center around metabolic issues (dyslipidemia, glucose dysregulation, and weight gain). There is a good deal of evidence to support the increased prevalence of these metabolic issues in bipolar patients, perhaps, in part, as a consequence of persistent
hypercortisolemia. For example, bipolar patients who have been hospitalized have two to three times the risk of diabetes mellitus of the general population.
Many mood stabilizers, including the “second-generation” antipsychotic (SGA) mood stabilizers, have been associated with metabolic abnormalities. With respect to diabetes, it appears that the most accurate predictors of which patients will develop glucose dysregulation are the core risk factors for diabetes (eg, family history, ethnicity, age), rather than which SGA is used for
therapy. It is also reassuring to realize that treated patients with severe mental health disorders experience not only a reduction in mortality secondary to suicide, but also in mortality secondary to comorbid conditions. Nonetheless, patients should be monitored carefully for metabolic abnormalities when taking SGA therapy.
For this patient who has received olanzapine to stabilize her mood during a mixed episode, a key factor in maintaining adherence and minimizing the risk of metabolic adverse events will be managing weight gain. As reflected in a post-hoc analysis conducted by Lilly, patients who are most likely to gain substantial weight tend to demonstrate early, rapid weight gain (4-5 lb within the first three weeks of treatment).
In patients who do not demonstrate this early, rapid weight gain, the probability of gaining substantial weight is 10%. Therefore, before therapy is initiated, I would counsel her about the likelihood of appetite increases (including carbohydrate cravings), and encourage her to monitor her weight and to stay physically active. On her follow-up visits, we would track her weight. If
she experienced early and rapid weight gain, but the olanzapine was having a positive effect on her psychiatric symptoms, a comprehensive diet and exercise counseling program, such as Solutions for Wellness, a six-month personalized program designed to help patients acieve weight reduction and improved overall wellness, might be appropriate.
In summary, the bipolar patient who needs help today presents a number of symptomatic, diagnostic, and functional challenges, both in the acute setting and over the intermediate- and longterm. For helping control the manic and depressive symptoms in mixed bipolar episodes, olanzapine can be used alone or in combination with lithium or valproate.
As with all bipolar patients, however, patients placed on olanzapine therapy should be monitored for adverse events, including non-adherence and metabolic abnormalities. Patients demonstrating early and rapid weight gain should be offered, lifestyle
management support if they are to stayon olanzapine.