The Difference Between Zebras & Horses: Differential Diagnosis of Bipolar Depression

DIALOGS Bipolar DepressionSpring 2008
Volume 1
Issue 1

When evaluating patients with depression, it is key that physicians expand their thinking and mindset to consider possible diagnoses beyond unipolar depression.

When a patient presents with a depressed mood in a primary care setting, the provider may initially seek to rule out medical causes of, or contributors to, the mood problem and perhaps not look far enough for diagnostic differentiation. This may be due to time constraints, or to the patient’s demands for treatment for “depression.” As a psychiatrist, I have erred in not looking further for more diagnostic clues, and have missed identifying bipolar depressed patients. In this article, I will present thoughts on differential diagnoses of bipolar depression.

When I was in training, a wise professor talked of looking for horses rather than zebras when one heard hoof beats. The hoof beats of horses represented the more common illnesses, which we would encounter frequently. The hoof beats of zebras represented the obscure and exotic diseases, with fascinating symptoms that we learned diligently, hoping to make that heroic diagnosis. Back then, I believed that bipolar depression was a “zebra,” but my experiences as a clinician have led me to change my mind. How common is bipolar depression? Surveys of patients in a primary care setting with a depression or anxiety diagnosis reveal that 20% to 30% actually have some form of bipolar depression. Bipolar illness may account for a large portion of the difficulty to treat depressed patients that we see.

To take an example from my practice, I recently saw a patient referred to me for treatment failure of depression (a 48-year-old married female) who presented taking three antidepressants, a non-benzodiazepine anxiolytic, and a sedative-hypnotic (for sleep) without relief from her depressed mood and ongoing decreased sleep. She was irritable, with racing thoughts and restlessness, and still depressed. Her affect was mood incongruent for depression and the only indication of her being depressed was that she told me. She demanded to stay on her antidepressants. I pursued her history, which included numerous mixed episodes with irritability, racing thoughts, suicidal thoughts, high energy, poor sleep, poor judgment with excessive spending, and leaving her husband.

After much arguing from her that she was depressed and wondering why treatment wasn’t working, she agreed to slowly taper the antidepressants. As the antidepressants were tapered, and she initiated treatment with a mood stabilizer, she became less agitated and the depression presented more clearly. I then changed her to a combination of mood stabilizer and low-dose

antidepressant with good success. She attended sessions with a cognitive behavior therapy group and also received individual therapy. She has returned to her job and her husband reported that he feels like he has his wife back. She has a better understanding of and appreciation for the need for ongoing treatment, but as with any patient with bipolar disorder, she may suddenly feel she is well with no further need for treatment. Bipolar depression is difficult to diagnose, but this is a common patient situation.

Diagnostic Accuracy is the Key

When evaluating patients with depression, it is key that physicians expand their thinking and mindset to consider possible diagnoses beyond unipolar depression. There are several factors that can prevent providers from considering bipolar depression in the differential diagnosis. In numerous conversations with providers, I have often heard the following concerns:

  • Are we over diagnosing?
  • Why the sudden focus on bipolar disorder?
  • We fear the patient’s reaction, that the patient mayleave treatment
  • We are unsure how to tell (break the news to) the patient
  • We do not have enough time to spend withthe patient
  • We are uncertain in our diagnosis and not sure we are looking at a bipolar picture
  • We are unsure how to treat, or don’t want to treat, and feel mood stabilizers are “dangerous” medications
  • We want to try antidepressant first and see response

In response to these concerns, I recommend being very clear on the diagnostic criteria, incorporating bipolar questions in the assessment of a depressed patient (it may be helpful to use a screening tool, such as the Mood Disorder Questionnaire), educating the patient about your diagnostic concerns, and becoming knowledgeable about and comfortable with ordering mood stabilizers. Trying an antidepressant first to help differentiate a bipolar picture can lead to irritability, racing thoughts, poor impulse control, poor judgment, or switch into mania and rapid cycling. Delaying diagnosis and effective treatment can lead to white and gray matter\ deterioration.

Bipolar disorder appears to be a neurodegenerative disease involving both white and gray matter of the brain with increase in ventricular size with successive episodes. Over time, in patients who do not adhere to their medication plan, only partially adhere, or who are prescribed incorrect medication, the episodes tend to get longer with shorter inter-episode wellness, and returning to prior levels of function becomes more difficult. Unfortunately, the average bipolar patient goes for nearly 10 years before being correctly diagnosed. Roughly 31% of these patients are diagnosed with unipolar depression, but the interesting statistic here is that nearly half of bipolar patients are not diagnosed as either unipolar or bipolar because of the chameleon-like presentation of symptoms. Almost 90% of patients with bipolar disorder were diagnosed at some time in their lives with ADHD, and many have been diagnosed with an anxiety spectrum disorder, including OCD; substance use disorders; or borderline personality disorder.

One study of bipolar patients reported that 35% were symptomatic for more than 10 years before being correctly diagnosed. The study also revealed patients were incorrectly diagnosed with a variety of other conditions, including unipolar depression (60%); anxiety disorders (26%); schizophrenia (18%); borderline or antisocial personality disorder (17%); alcohol abuse/dependence (14%); and schizoaffective disorder (11%). Although bipolar disorder might be relatively commonplace (it is a horse, not a zebra), diagnosis can be most challenging. Most bipolar patients will not identify a manic or hypomanic episode as problematic. Typically, they do not seek treatment for a manic/hypomanic episode, and their initial presentation to their provider is depression.

Questioning such patients about their legal, financial, or relationship problems can often provide clues that can aid in making a correct diagnosis. A missed diagnosis or delay in treatment can have profound consequences for the patient. However, through careful attention to history and accurate diagnosis, appropriate treatment can greatly improve outcomes, making a critical difference in the lives of patients.

The Common Denominator: Major Depressive Episode

Depression manifests itself differently in every patient. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for major depressive episode include having five or more of the following symptoms present during a two-week period (including at least one symptom marked with an asterisk):

  • Depressed mood* or anhedonia*
  • Weight loss or gain
  • Sleep disturbance (insomnia or hypersomnia)
  • Psychomotor agitation or retardation
  • Fatigue (loss of energy)
  • Guilt/worthlessness
  • Inability to concentrate or indecisiveness
  • Suicide ideation (recurrent thoughts of death)

The Differentiator: History of a Manic or Mixed Episode

If we are to be good diagnosticians, the criteria for manic episodes must be reviewed along with the criteria for major depressive episodes. Again, the DSM-IV requires abnormally and persistently elevated, expansive, or irritable mood for at least one week, and the presence of three or more of the following symptoms (four if the patient is irritable only). My comments are in italics:

  • Inflated self-esteem or grandiosity (May be more social and flirtatious.)
  • Decreased need for sleep (May not want to sleep due to “too much to do.”)
  • Increased or pressured speech (Feels that everything they say is very important and that you need to listen.)
  • Flight of ideas/racing thoughts (Needs to be differentiated from obsessive thinking where one thought predominates. With racing thoughts usually there are many thoughts randomly presenting. This may have been diagnosed as attention deficitproblems earlier in life.)
  • Distractibility (Will be easily refocused on a minor distraction in your office.)
  • Increased goal-directed activity (Along with grandiosity, feels their project is very socially significant and far reaching. Irritable when you attempt to redirect or add reality thinking.)
  • Risk-taking behavior (May involve drugs, illegal activities, sexual activity, wanting to act on suicidal thoughts without goodimpulse control.)

Co-morbidities and Other Challenges Associated with Correctly Diagnosing and Treating Patients for Bipolar Depression

Unfortunately with this patient population, when making a diagnosis there are several commonly encountered co-morbid conditions that must be taken into consideration. For example, substance abuse is a serious co-morbid condition that is common in patients with bipolar depression, and can take many forms (methamphetamine agitation with psychosis, long-term marijuana use with amotivation, chronic alcohol abuse, etc). Patients often self-medicate with alcohol or drugs when symptoms are unremitting because of an incorrect diagnosis, poor treatment response, or problems with medication adherence. Substance abuse may also occur as a result of breakthrough symptoms, or just because the patient wants to “feel better.” It results in increased agitation, delusions, and hallucinations. Often a vicious cycle emerges with each fueling the other. Substance abusers tend to not take their meds, which can make their illness more severe, with kindling effect and a worse course, leading to progression of illness.

The Epidemiologic Catchment Area Study (ECA), a large epidemiologic study of the prevalence of psychiatric disorders conducted in more than 20,000 US participants in the 1980s, found that, compared with rates seen in patients with other psychiatric disorders, individuals with bipolar I disorder had the highest lifetime rates of alcohol use disorders (46%), and drug use disorders (41%). The rates of alcohol and drug use disorders in individuals with bipolar disorder were higher than those observed in the general population (14% vs. 6%, respectively). Of course, substance abuse is a disorder in itself, but, with respect to the diagnosis of bipolar disorder, it is a very loud hoof beat.

Overlapping Symptoms of Bipolar Disorder and Depression: A complicated Diagnostic Process

The basic aspects of depression are present in a bipolar patient who presents wanting relief. It is only when we are willing to look further and not take the depression at face value, that we can assure our patients that we are giving them the benefit of our diagnostic skills. Recently, a young female patient of mine presented with depressive symptoms and seeking relief. During our

discussion, she revealed that she had an irritable mood, impulsivity, poor judgment, and racing thoughts. When asked about her family history, she disclosed that her father and one sibling had been diagnosed with bipolar disorder. She resists a bipolar disorder diagnosis because of her experiences with her family. Earlier in life, she was diagnosed with attention deficit disorder and was treated with stimulants with some success. She has been on antidepressants with little success—often getting “agitated” and stopping the medication on her own.

In our discussions regarding her symptoms and possible treatments, I have avoided discussing a diagnosis and focused instead on her treatment. She regularly asserts that she does not have bipolar disorder and that “everything can be explained as attention deficit.” She is now on a mood stabilizer and has had a reduction in all her symptoms. She feels better and seems willing to stay on her medication. The effects of her illness were not as severe or debilitating as those experienced by her other family members, but she sees the diagnosis as a harbinger of a low-functioning life. She may have increased difficulty in the future, but through psycho-education—perhaps in conjunction with cognitive behavioral therapy, whether in a group or individually—and adherence to a medication regimen, she is less likely to have a recurrence of symptoms.

Key Symptoms in Correctly Diagnosing Bipolar Depression

Even when the presenting symptoms seem conclusive, it remains important to pursue other features of a patient’s life that can provide us clues for a more accurate diagnosis of the type of depression the patient is experiencing. Bipolar patients often have a family history of bipolar disorder, unipolar depression, or other mood disorders, and may have powerful memories of family members who were disturbed but did not seek treatment, or remained undiagnosed. They may also have a family history of alcoholism or other substance abuse. We need to determine whether the patient has ever had a manic or mixed episode. This may be difficult to establish, and collateral discussions with family members will help. The patient may not want you to contact

family members. That is when your persuasive skills will be needed. If the patient has been treated with antidepressants and has had inadequate response, or developed new symptoms (especially those resembling manic symptoms or agitation), or was unable to tolerate antidepressants, these are important indications in the patient’s treatment history that a bipolar element may be present.

On average, bipolar disorder tends to manifest itself earlier in life than major depressive disorder and follows a more episodic course. Bipolar disorder tends to have a more abrupt onset and termination than episodes of unipolar depression. Teasing out a patient’s symptoms can be tedious and time consuming, especially when a patient presents with a depressed mood, irritability or racing thoughts, and “just wants an antidepressant.” Various screening tools can be valuable diagnostic resources. I believe the most popular and widely used is the Mood Disorder Questionnaire (MDQ). The MDQ can be useful tool in identifying patients for whom closer screening for a history suggestive of bipolar disorder might be appropriate. The patient rated scale has been wel-validated and has a high degree of sensitivity and specificity for bipolar disorder. The MDQ can be given to a patient to complete in the waiting room, or before or during the consult, or the patient can bring it to the next visit. I have used it in each of these ways, and many patients like to take a copy with them to review later.


Bipolar disorder is a very difficult illness to diagnose, treat to remission, and maintain in remission. The complex presentation of bipolar patients can confound even the most astute clinician. You must have a high index of suspicion for any patient presenting with depression that it may be bipolar disorder. Patient resistance to that diagnosis, and to treatment, means that you will be called upon to be an advocate for helping the patient achieve wellness with effective medication and support. The sooner their mood and functioning return to baseline (remission), the sooner the patient will believe in their treatment.

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