Monitoring Pharmacotherapy Response, Safety, and Tolerability to Enhance Adherence in Bipolar Disorder

Paul E. Keck, Jr., MD

Lindner Center of HOPE, Mason, and the Department of Psychiatry and Neuroscience, University of Cincinnati, Cincinnati, Ohio

Among patients with bipolar disorder, many factors influence medication nonadherence, including lack of effectiveness and intolerable side effects.1 Because nonadherence rates range from 20% to 60% in patients with bipolar disorder,2 clinicians should carefully monitor patients’ medication response and adverse events throughout treatment.3

Assessing Response

Assessing patients’ response to medication is key to achieving acute and then sustained remission of symptoms. The most conventional method of monitoring response is for clinicians to catalog presenting symptoms at each visit, but unless they methodically track these symptoms over time, clinicians may miss key areas for monitoring. Clinicians may use various charting methods and rating scales to systematically record improvement throughout treatment.

Charting methods. An accurate way to monitor response is to have patients track their own day-to-day symptoms on a life chart. A life chart is a systematic collection of data recorded by the patient about their course of illness and its treatment. Many patients do not remember the last week or earlier, and, as time passes between office visits, they cannot give their doctor a precise recap of symptom occurrence and severity. A life chart, therefore, accurately summarizes patients’ experiences for clinical reference.

AV 1. Assessing Mood Chart Results in a Patient With Bipolar Disorder (02:48)


The NIMH-LCM-p uses patient ratings to specify the polarity and severity of episodes and to record the use and impact of medication and life events that may precede episodes. A study4 of the NIMH-LCM-p demonstrated its validity and usefulness for long-term assessment of symptom severity, illness course, and response to treatment. A similar, yet simplified, version of life charting is called mood charting. Patients who complete a daily mood chart rate their mood, specify any anxiety or irritability, and record their sleep, weight, alcohol/drug use, and medication adherence on a single form (AV 1).

Rating scales. Another option for clinicians to rigorously monitor treatment response is using rating scales. One of the more common ones used across psychiatric diagnoses is the CGI, which can be used in research settings or in clinical practice. The CGI-BP5 was designed specifically for patients with bipolar disorder and is valuable for evaluating the degree of response to treatment and for its flexibility to accommodate differing illness characteristics.5

Switch risk. Monitoring treatment response includes watching for an “overresponse.” One characteristic unique to bipolar disorder is the risk of treatment causing a switch between the opposite poles of the illness. Antidepressants may pose a risk for mood switch and, for this reason, are not recommended as monotherapy for bipolar depression.3 One study6 detected a treatment-emergent switch in 24% of patients with bipolar disorder when an antidepressant was added to their mood stabilizer and/or atypical antipsychotic regimens. Compared with those who did not have a mood switch, the switch risk was higher for patients with more previous mood switches, earlier ages at onset, and lower response rates to antidepressants.6

AV 2. Sleep Disturbance in Patients With Bipolar Disorder (00:29)

Based on Harvey et al7

Monitoring Safety and Tolerability

The usefulness of any medication is ultimately determined by its level of effectiveness minus the extent of its adverse effects, and clinicians must constantly balance the two. This usually requires adjusting the dosage during maintenance treatment and according to the type of episode the patient is experiencing.3 Two side effects associated with bipolar depression treatments, such as mood stabilizers and atypical antipsychotics, are sedation and weight gain/metabolic problems. These adverse events negatively influence patients’ adherence, making them important targets to monitor and address for the overall safety and well-being of the patient.

Sedation. For some patients, clinicians can take advantage of sedation as a medication side effect to help the restoration of sleep, which is a common problem for patients with bipolar disorder (AV 2).7 Clinicians may recommend taking medications that cause sedation at bedtime to shorten sleep onset latency and minimize daytime sleepiness.8 When starting patients on sedating agents, a slow titration may create a longer time to treatment response but can improve overall tolerability and adherence, thereby gaining long-term efficacy. If medication-induced sedation is impairing a patient’s ability to function, however, clinicians may slowly reduce the dose while closely monitoring symptom response.8

AV 3. Criteria for the Clinical Diagnosis of Metabolic Syndrome (00:34)

Based on Alberti et al10

Weight gain/metabolic syndrome. Obesity and metabolic disturbances increase health care costs and contribute to treatment nonadherence.9 Metabolic syndrome is the presence of a group of risk factors related to developing cardiovascular disease and diabetes (see AV 3).10 The prevalence of metabolic syndrome in patients with bipolar disorder is high, with one review11 finding an overall rate of 37%. The percentage is even higher in patients treated with antipsychotics (45%) than in patients who are not taking antipsychotics (32%).11 Further, all-cause mortality is also increased 2-fold among patients with bipolar disorder compared with the general population.12 A large cohort study12 (N = 6,587,036) found that patients with bipolar disorder died an average of about 9 years before the rest of the population from conditions including cardiovascular disease and diabetes. For the health and safety of patients with bipolar disorder, clinicians must provide consistent medical monitoring and be prepared to treat troublesome side effects, which will also help improve tolerability and adherence.


Treating Metabolic Abnormalities

Although the concept of the metabolic syndrome is evolving, one set of criteria developed recently includes the presence of 3 of the following 5 factors to diagnose metabolic syndrome: (1) abdominal obesity, (2) elevated triglycerides, (3) reduced HDL cholesterol, (4) elevated blood pressure, and (5) elevated fasting glucose (see AV 3).10 Each of these areas has specific treatment goals, monitoring timeframes, and interventions.

Abdominal obesity. Along with reducing overall weight, the recommended goal for waist circumference is < 40 inches for men and < 35 inches for women.10 Clinicians should record patients’ waist circumference at initial assessment and monitor quarterly. Possible interventions to treat abdominal obesity include implementing weight management strategies (eg, diet, CBT), improving sleep hygiene, increasing exercise, switching to medications associated with less weight gain, or adding adjunctive pharmacotherapy (eg, metformin, anticonvulsants, antidepressants, dopaminergic agents).13 For patients who are severely obese, bariatric surgery may be an option to ensure persistent weight loss and improve weight-related medical conditions.

Hypertriglyceridemia. The goal for triglyceride levels is < 150 mg/dL.10 Triglyceride levels should be assessed at baseline and every year, although patients on drug therapy need more frequent monitoring: every 6 to 8 weeks until the goal is met and then every 4 to 6 months. Interventions for hypertriglyceridemia include reducing weight, increasing physical activity, reducing carbohydrates and alcohol intake, and encouraging a diet with low glycemic index and high in omega-3 fatty acids. Pharmacologic options include adding fibrates, nicotinic acid/niacin, and statins.14

Low HDL cholesterol. High HDL cholesterol levels lower the risk for heart disease, while low levels increase the risk. The goal is for HDL cholesterol to be > 40 mg/dL for men and > 50 mg/dL for women, and patients should be monitored annually.10 Patients on drug therapy should have their HDL cholesterol monitored every 6 to 8 weeks and then every 6 to 8 months after the goal is met. Patients should be encouraged to lose weight, exercise more, quit smoking, and increase their intake of monounsaturated fats. Similar to the treatment for hypertriglyceridemia, pharmacologic interventions are nicotinic acid/niacin, fibrates, and statins, which help raise HDL cholesterol.15

Hypertension. The goal is for patients’ blood pressure to be less than 130 mm/Hg systolic and 85 mm/Hg diastolic.10 Clinicians should record blood pressure at initial assessment and then quarterly or as needed with treatment changes. In addition to lowering weight and increasing exercise, patients should limit their sodium intake and alcohol consumption.16 Some agents that help lower blood pressure are ACE inhibitors and angiotensin receptor blockers.16

Hyperglycemia. Patients should attain a fasting glucose of < 100 mg/dL.10 Fasting glucose should be assessed at patients’ first visit followed by annual monitoring. Recommended treatment strategies from the American Diabetes Association and the European Association for the Study of Diabetes17 are lifestyle interventions (diet and exercise) and metformin. Other glucose-lowering medications include thiazolidinediones, sulfonylureas, glinides, and α–glucosidase inhibitors.17


Clinicians can help improve their patients’ adherence to treatment by monitoring their response and any adverse effects that they experience. Rather than rely solely on patient reports, clinicians may effectively track illness course and symptom improvement using rating scales like the CGI-BP or daily life or mood charts. Although agents to treat bipolar disorder are effective, 2 common side effects are sedation and weight gain/metabolic abnormalities. The sedative properties of some medications can actually be used to help patients who have sleep disturbances. And, although weight gain and metabolic problems can increase mortality and cause serious medical conditions such as cardiovascular disorders and diabetes, specific lifestyle interventions and pharmacologic options are available for clinicians to treat conditions that contribute to metabolic syndrome. With diligent, consistent monitoring of symptoms and adverse events, clinicians can provide appropriate interventions to make treatment as safe and tolerable as possible to help patients achieve and maintain remission.

Clinical Points

  • Track symptom improvement and severity using daily life or mood charts and rating scales
  • Prescribe medications associated with sedation to patients who have sleep disturbances, but alter treatment if patients have reduced daytime functioning
  • Regularly monitor weight gain/metabolic abnormalities, and encourage lifestyle changes and adjust medications when necessary to control these factors

Drug Name

metformin (Glucophage and others)


ACE inhibitor = angiotensin-converting enzyme inhibitor

CBT = cognitive-behavioral therapy

CGI = Clinical Global Impressions scale

CGI-BP = CGI-Bipolar Disorder

HDL = high-density lipoprotein

LCM = Life Chart Methodology

NIMH-LCM-p = National Institute of Mental Health prospective LCM

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