This interview took place on September 6, 2007, and was conducted by Norman Sussman, MD.

 

This interview is also available as an audio PsychCastTM at http://psychcast.mblcommunications.com.

Disclosure: Dr. Goldberg is consultant to Abbott, AstraZeneca, Cephalon, Eli Lilly, and GlaxoSmithKline; on the speaker’s bureaus of Abbott, AstraZeneca, Eli Lilly, and GlaxoSmithKline; and on the scientific advisory boards of Eli Lilly and GlaxoSmithKline.

 

 
 Dr. Goldberg is director of the Affective Disorders Program at Silver Hill Hospital in New Canaan, Connecticut, and associate clinical professor of psychiatry at the Mount Sinai School of Medicine in New York City. His research focuses on the treatment and clinical features of bipolar disorder. He is a co-investigator in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder and has received a Career Development Award from the NIMH. He has also received research grants from the National Alliance for Research in Schizophrenia and Depression, the American Foundation for Suicide Prevention, and the Stanley Foundation.
  

How has the approach to the diagnosis of bipolar disorder changed in recent years?

The rigor of the diagnosis and the systematic approach to making a diagnosis have changed. Bipolar disorder is not just about mood; rather, it is a disorder with components that involve disregulation of mood, the sleep-wake cycle, impulse control, cognitive disturbances, and behavioral problems. Some of these phenomena persist independent of the mood state. For example, cognition or impulsivity are present much of the time but that may flare during a mood state.

When assessing a patient, I conduct a systematic overview of the patient’s pathology and symptoms in the sense of differential diagnosis. I also describe the systematic approach of recognizing dimensions of psychopathology and symptom constellations, alongside differential diagnosis.

We think about mood disorders in terms of their polarity of mood, cyclicity, recurrence rates over time, pharmacologic response, environmental correlates, cognitive aspects, and sleep aspects. This mode of thinking correlates with the idea of the spectrum, as well, where we step outside the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).1

My approach to diagnosis includes not just a cross-sectional survey of DSM-IV symptoms—though that is obviously a part of it— but a longitudinal, panoramic, perspective of how symptoms fit together. Does the context suggest a bipolar illness based on age of onset, family history, aspects that may better or worsen the illness, or medication response? Taking a systematic approach and incorporating these dimensions can give us a best-informed assessment of a likely diagnosis.

 

How is bipolar disorder generally diagnosed?

How much rigor goes into a diagnosis usually depends on what kind of specialist is conducting the assessment. For example, some base the diagnosis on mood swings alone. Thus, there is potential for misdiagnosis, incomplete diagnosis, quasi diagnosis, or nonsystematic diagnosis if one fails to take all symptoms into account. Mood instability is not diagnostic and occurs in many psychiatric disorders including bipolar disorder, among others. However, if we identified it all as synonymous with bipolar disorder, we would miss a lot of posttraumatic stress disorder, substance abuse, adjustment disorders, and personality disorders.

In the last 5–10 years, our sensitivity has gone up, meaning we are more often asking mood disorder patients about current and past symptoms of mania or hypomania, paying more attention to patterns of high recurrence, and considering when cyclical mood disorders are not unipolar depression. We are doing a better job overall in recognizing non-unipolar patients, but we are not necessarily encouraging our colleagues to think as critically about the differential diagnoses among these patients. The DSM-IV defines clinical subtypes of bipolar disorder quite strictly, and as all-or-none categories. For example, mixed episodes are defined only as occurring in bipolar I (not II) disorder, and require the presence of a full manic and depressive syndrome for at least 1 week. The “not otherwise specified (NOS)” designation thus has meaning when DSM-IV duration criteria or numbers of symptoms may not be fulfilled, but clinically important symptoms differentiable from unipolar depression are nonetheless present. Nosology advances and good clinical care occurs when we encourage clinicians to go beyond a DSM-IV diagnosis.

Mixed states are an excellent example because in the case of bipolar depression most depressed bipolar patients have some mania symptoms alongside their depression. Data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) program (JF Goldberg, unpublished data, May 2007) has demonstrated that two-thirds of fully-depressed bipolar patients have at least some manic symptoms. This may not catch a clinician’s attention unless the patient has enough manic symptoms to call it a mixed state. However, if it is subsyndromal mania one must determine whether it is an agitated depression or a subsyndromal mania within a depression. The condition is considered NOS and not a DSM-IV entity, but it is extremely common.

 

Are antidepressants effective for bipolar patients?

No controlled study has ever shown antidepressants to be more effective than mood stabilizers alone for bipolar depression. According to recent STEP-BD data,2 antidepressants on an overall basis add very little benefit for patients with bipolar depression and minimal manic symptoms. They neither help nor hurt. However, there are subgroups for whom the antidepressants may be detrimental. Our recent article3 examining concomitant mania symptoms with depression, found that manic symptoms of patients with bipolar depression with some mania are worsened by antidepressants. Further, the depression is not managed with these drugs. Other reports note that patients with a history of prior switch with an antidepressant are more prone to switch into mania. A forthcoming study from the STEP-BD program by our site at Cornell Medical Center in New York City4 found that patients who have previously experienced mania with an antidepressant have double the chance of that occurring in the future with any antidepressant.

Goldstein and colleagues5 described the abrupt cessation of antidepressants triggering a manic state. It is sometimes difficult to tell whether a withdrawal phenomenon is a physiologic phenomenon as opposed to a psychiatric one. An abrupt change in an equilibrium state could destabilize mood. Therefore, I have become a proponent of gradual tapers whenever possible with almost all psychotropics.

 

Is there a relationship between bipolar disorder and alcoholism?

There is an extraordinarily high comorbidity with substance abuse in general and alcohol abuse or dependence in particular for people with bipolar disorder. The National Comorbidity Survey reported approximately 70% comorbidity.6 Other studies place comorbidity of alcohol use or dependence and bipolar disorder at 40% to 60%. There is no simple explanation for why that co-occurrence is so high. One theory is that people with bipolar disorder are reckless, impulsive, and likely to engage in hedonistic behaviors of high-risk consequence, such as excessive spending, gambling, drinking, or drugs. For some, the potential for alcohol is in the context of a mania. Other people might use alcohol to ward off depression. There is also a genetic component, where some research suggests that alcoholism tends to run in families with bipolar members.

Alcohol acts as a stimulant and then acts as a central nervous system depressant. It is very difficult to diagnose a mood disorder in someone with active substance abuse because the psychotropic effects of alcohol or drugs can mimic depression or mania. Overdiagnosis of bipolar disorder is partially a result of the high co-occurrence with substance or alcohol use. It can be challenging for a clinician to know the extent to which a patient’s mood symptoms are artifacts of substance use or consequences of withdrawal. The most systematic diagnostic approach is to obtain a longitudinal history, assessing the presence of mood symptoms during sustained periods of abstinence. Our group7 recently conducted a study attempting to disentangle “true” bipolar diagnoses from “non-bipolar I or II” mood instability among inpatients with substance use disorders and found that only approximately one-third met DSM-IV criteria for bipolar I or II disorder. Approximately half the time, we could not identify a period of abstinence in which to evaluate mood symptoms, pointing to the complexity of accurately differentiating and diagnosing separate mood disorders in patients with active substance abuse or dependence. A related study by Stewart and El-Mallakh8 recently reported similar findings.

 

Which disorders are comorbid with bipolar disorder?

According to Susan McElroy, MD, from the Stanley Network, two-thirds of people with bipolar disorder have at least a second DSM-IV psychiatric disorder. Approximately 50% have a third psychiatric disorder, and approximately 25% have a fourth. Comorbidity is the rule rather than the exception. There is less prevalence of first-episode patients with substance or alcohol abuse than there are multi-episode patients. According to the McLean-Harvard First-Episode Mania Study, the prevalence of drug or alcohol abuse in first-episode mania patients is approximately 33%—much lower than the rate seen in multi-episode patients with bipolar disorder.9 Thus, if bipolar disorder is caught early and treated effectively, the progression to alcohol and substance abuse can likely be prevented.

The second most common comorbidity, which is not mutually exclusive from alcohol or drugs, is anxiety. Rates vary for any anxiety disorder. The National Epidemiologic Study on Alcohol-related Conditions (NESARC) study by Grant and colleagues10 reports that approximately 50% of people with bipolar disorder have an anxiety disorder. It can be difficult to distinguish between agitation, psychomotor acceleration, and goal directness of mania from free-floating anxiety, generalized anxiety disorder, or panic. Therefore, we must be guided by other features as well—such as sleep patterns, cognitive features, and mood features—bearing in mind that this may represent anxiety or hypomanic activation.

Seasonal affective disorder and postpartum mood disorders are also more common in patients with bipolar disorder than in the general population.

 

Is there any evidence to support that people with recurrent manic episodes and major depressive episodes get worse cognitively after each episode?

There is evidence that cognitive functioning is poorer in patients with multiple prior affective episodes, particularly manic episodes.11 As to whether or not repeated affective episodes lead to a progressive worsening of cognitive function has not been demonstrated; however, some reports do suggest that eventual risk for dementia is higher among bipolar patients with more prior episodes.12

We are just beginning to appreciate the cognitive problems that are inherent in bipolar disorder. Much interest has focused on how much those cognitive problems are an epiphenomenon of mood symptoms (eg, depression), how much is iatrogenic from pharmacology and the long-term effects of certain medications like lithium, and how much is a neurodegenerative phenomenon. We think of mood stabilizers as being neuroprotective. It in part addresses this concern for a potential neurotoxic effect of multiple episodes. Some research discusses structural brain changes in multi-episode patients in the hippocampus and the amygdala.

Some recent cognitive data show the potential for decline over time. However, I would not encourage patients to worry and anticipate a decline in course. The kinds of deficits we see in most patients are subtle. They tend to involve things like verbal learning, practice effects, and attention. They may be trait features passed along genetically, and even seen in unaffected relatives, as a kind of “hidden” biologic marker or “endo”phenotype. A person’s actions also play a role. As mentioned, alcohol is not neuroprotective. It is difficult to know the extent to which alcohol comorbidity is having a direct neurotoxic effect. It is difficult to distinguish how much of the cognitive potential decline occurs because of the illness, treatment, delays to treatment, or comorbidities. The message for patients is to recognize the illness early, treat it early, and strive to ward off the comorbidities. If a patient takes care of oneself, the outcome can be quite good.

 

When should lithium be used?

Lithium deserves special consideration in the treatment of any first-episode mania patient. There is some suggestion in the literature that if lithium is going to work, it will do so early on coupled with the neuroprotective effects. Unfortunately, I often see patients who have already gone on 10–15 other medications. I use lithium in mania-prone patients. Patients who are more prone toward depression than mania probably struggle more with effective treatments for the depression side of the illness than the mania side. Hence, lithium may not work as well with these patients. Also, we are often fond of asking if relatives benefited from a given psychotropic agent, thinking this may help to guide treatment response for our own patient. Lithium is one of the very few drugs where this has in fact proven to be true, and so family history of lithium responsiveness is a useful parameter. In addition, one must not forget that the anti-suicide properties of lithium may be unique to that drug and can even occur regardless of whether lithium is effective for preventing manias or depressions. Lithium, therefore, deserves consideration in the regimen of any mood-disordered patient with a longitudinal suicide risk.

With so many drugs being approved for the treatment of bipolar disorder, is the term “mood stabilizer” now obsolete?
The term is imprecise and incomplete more than obsolete. Contrary to our assumptions from a decade ago, anticonvulsants do not appear to show robust effects as a class to treat or prevent manias or depressions; those psychotropic properties seem to be confined to divalproex, carbamazepine, and lamotrigine. Meanwhile, all atypical antipsychotics treat mania regardless of the presence of psychosis, and at least some have value for bipolar depression or long-term prevention of episodes. Thus, rather than identify whether or not a drug is a “mood stabilizer” based on its pharmacologic class, it may be more useful to talk about the extent to which any treatment has mood-stabilizing properties and the extent to which those properties are predominantly anti-manic, antidepressant, or both.

We can talk about the extent to which a drug derives its mood-stabilizing properties by virtue of treating or preventing one pole or the other, or both. Classic examples are lithium and lamotrigine. Neither drug has been shown in rigorous controlled studies to induce the opposite polarity of the illness. Lamotrigine is an example of a drug that does not seem to induce the opposite polarity, has a robust effect on the depression side, and a more modest effect on the mania side. It can be described as a mood-stabilizing antidepressant or an agent that has mood-stabilizing properties that are predominantly depression related. It is in many ways the complement or mirror image of lithium—which is an excellent drug choice to minimize cyclicity and polarity change, particularly in patients who are prone to recurrent manias. However, lithium is less robust against recurrent bipolar depressions than bipolar manias.13

 

What off-label drugs for treatment of bipolar symptoms have value?

Many anticonvulsants have not borne out in clinical trials to treat mania or depression or to forestall polarity changes, but they act in other relevant ways to treat the illness. Topiramate, which has not been shown in placebo-controlled studies to help severe mania, has significant effects in alcohol dependence, binge eating, and neuropathic pain, all of which are common problems for patients with bipolar disorder. Comparably, gabapentin, a drug in which two placebo-controlled studies14,15 looked at its usefulness as an add-on treatment or monotherapy in severely ill patients, did not significantly reduce manic or depressive symptoms; however, the drug helps to treat anxiety disorders, alcohol dependence, and neuropathic pain.

Comorbidity is a descriptor in helping to create a regimen that is informed by what is being treated. For example, a clinician may choose to include topiramate “off-label” in the regimen of a patient with bipolar disorder, not for mood symptoms but to target comorbid obesity, binge eating,16 alcoholism,17 or migraines. Similarly, one might include gabapentin “off label” in a regimen as a possible alternative to benzodiazepines to treat anxiety symptoms. When comorbidities are considered in addition to mood symptoms, off-label uses from evidence-based controlled studies help guide clinicians to which medications are valuable for treating each patient with bipolar disorder.

 

What are the clinical features that help differentiate between unipolar and bipolar depression?

Mania is in many ways not just a mood disorder but also a rate disorder, with the speeding up of thought, action, behavior, cognition, and so forth. Sleep duration, rate of thinking, and goal-directed activity help differentiate the polarity distinctions, rate of disturbance, and cyclicity phenomenon. Highly-recurrent or cyclical phenomena are probably a variant of bipolar disorder, or at least a separation from unipolarity. As a diagnosis, bipolar disorder can broadly encompass cyclical mood recurrences, polarity changes, impulsivity, cognitive dysfunction, possible psychosis, chronobiologic or sleep disruptions, common psychiatric comorbidities, and consequent behavioral or interpersonal problems. These factors create a complex that is not simple. A longitudinal perspective is neccessary for an accurate diagnosis. PP

 

References

1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
2. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-1722.
3. Goldberg JF, Perlis RH, Ghaemi SN, et al. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD. Am J Psychiatry. 2007;164(9):1348-1355.
4. Truman CJ, Goldberg JF, Ghaemi SN, et al. Self-reported history of manic/hypomanic switch associated with antidepressant use: Data from the STEP-BD. J Clin Psychiatry. In press.
5. Goldstein TR, Frye MA, Denicoff KD, et al. Antidepressant discontinuation-related mania: critical prospective observation and theoretical implications in bipolar disorder. J Clin Psychiatry. 1999;60(8):563-576.
6. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol or other drug abuse. Results from the Epidemiologic Catchment Area (ECA) study. JAMA. 1990;264(19):2511-2518.
7. Goldberg JF, Garno JL, Callahan AC, Kearns DL. Validity of bipolar diagnoses among inpatients with substance use disorders. Poster presented at: the 7th International Conference on Bipolar Disorder; Pittsburgh, PA; June 7, 2007.
8. Stewart C, El-Mallakh RS. Is bipolar disorder overdiagnosed among patients with substance abuse? Bipolar Disord. 2007;9(6):646-648.
9. Baethge C, Baldessarini RJ, Khalsa HM, Hennen J, Salvatore P, Tohen M. Substance abuse in first-episode bipolar I disorder: indications for early intervention. Am J Psychiatry. 2005;162(5):1008-1010.
10. Grant BF, Stinson FS, Dawson DA, et al. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2004;61(8):807-816.
11. Robinson LJ, Ferrier IN. Evolution of cognitive impairment in bipolar disorder: a systematic review of cross-sectional evidence. Bipolar Disord. 2006;8(2):103-116.
12. Kessing LV, Andersen PK. Does the risk of developing dementia increase with the number of episodes in patients with depressive disorder and in patients with bipolar disorder? J Neurol Neurosurg Psychiatry. 2004;75(12):1662-1666.
13. Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161(2):217-222.
14. Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group. Bipolar Disord. 2000;2(3 Pt 2):249-255.
15. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20(6):607-614.
16. McElroy SL, Hudson JI, Capece JA, et al. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry. 2007;61(9):1039-1048.
17. Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet. 2003;361(9370):1677-1685.

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