Many patients with borderline personality disorder or other forms of moodiness are wrongly diagnosed as having bipolar disorder. On the other hand, it is simultaneously true that many patients with bipolar disorder (especially bipolar II disorder) continue to be misdiagnosed as having a depressive disorder. Because the treatment of depression and of bipolar disorder is very different, this rampant misdiagnosis is a tragedy.

I am amazed by how many patients I have diagnosed with bipolar disorder for the first time who had not been previously diagnosed as such, even those who were seeing a psychiatrist. And I’m not talking about the so called “Bipolar spectrum” — I’m talking about DSM-5 bipolar II disorder. Those should NOT be missed.

In a 2000 survey of 600 patients with bipolar disorder(Hirschfeld et al., 2003), the following key findings emerged:

• 69% of patients had been misdiagnosed, most frequently as having unipolar depression.
• Those who who had been misdiagnosed had consulted an average of four physicians prior to receiving the correct diagnosis.
• Over one third of patients had waited ten years or more before receiving an accurate diagnosis.
• One reason for misdiagnosis was underreporting of manic symptoms. However, more than half of these patients said that they thought that their physicians’ lack of understanding of bipolar disorder was a reason why the correct diagnosis was not made earlier.

It requires some skill to correctly interview the person and his/her family to identify bipolar disorder. Sometimes it takes a LOT of skill.  Asking things like, “Have you ever felt on top of the world?” “Have you ever felt that you didn’t need to sleep or that you were full of energy?” and so on will identify only a fraction of the cases. For years I have been teaching medical students, residents, and fellows about how to methodically interview patients to identify bipolar disorder. A lot more attention needs to be paid to this issue. Patient’s lives are harmed significantly when clinicians fail to identify bipolar disorder.

When deciding whether to use lithium in a  person with a bipolar disorder, we should systematically look for the following TEN factors in the Past, Present, and Future:

Past

1. Adult (rather than an adolescent)

2. Later age of onset

3. Less than three prior episodes. (The problem is that many clinicians will try other treatments first and start lithium only after many episodes have already occurred.)

4. Mania-Depression-Interval pattern of episodes. (Mania followed by depression followed by a euthymic interval. As opposed to depression followed by mania.)

5. Fewer hospitalizations

6. Absence of rapid cycling (four or more episodes per year).

7. Good response to lithium in a first-degree relative

Present

8. Classical mania (with only euphoria rather than with mixed features)

9. Absence of comorbid substance abuse

Future

10. And, most important of all, the person takes the lithium and does not have  unacceptable adverse effects.

Now, which side effects are most likely to make a person stop taking lithium? Interestingly, the commonest reasons for stopping lithium are not hypothyroidism, renal impairment or similar more serious adverse effects. The commonest reasons are…ready for them?…

Tremors (because they can be quite embarrassing), Weight gain, Cognitive dulling

We need to watch *specifically* for these three adverse effects. When they occur, an alarm bell should go off in our minds, reminding us to be careful because the person may stop taking the lithium.

It is very sad that the diagnosis of bipolar disorder continues to be frequently missed. Many persons with bipolar disorder continue to be wrongly diagnosed as having a depressive disorder. The consequences of this are horrible — years wasted in treatment with antidepressants (SSRIs, SNRIs, etc), “treatment-resistance,” development of rapid cycling, and lost years of patients’ lives.  Not to mention the possibility of suicide.

This is an EMERGENCY in the field of mental health! No patient with bipolar disorder should go undiagnosed or misdiagnosed.

EVERY patient with a depressive episode must be asked specifically for a history of a hypomanic/manic episode. It does not naturally occur to us to do this, so we have to prompt or train ourselves to remember to do it.

Problems

1) The patient may report normal happiness (especially after having recovered from depression) as elevated mood;

2) Persons without bipolar disorder may have the same symptoms at different times in their lives;

3) Persons with bipolar disorder may not have every specific symptom you are asking about;

4) Patients may be suggestible and endorse symptoms when asked leading questions.

How to ask

So, how specifically should we ask the patient about whether they have ever had a manic or hypomanic episode?

Step 1: help the patient understand that you are talking about 3 different states (depression, normal, and mania/hypomania)

Step 2: help patient identify a specific episode (period of time) when he was manic. Preferably choose the MOST SEVERE episode because the symptoms will be more pronounced

Step 3: ask an open-ended question about what the symptoms were like during that period. Keep referring the patient back to THAT episode.

Step 4: ask follow up questions to identify and characterize all the symptoms

Step 5: if needed, ask if there was any other reason for these symptoms, and whether the symptoms were observable by others who knew the patient well

Additional steps

Consider calling one or more informants (family member, friend, colleague, etc) for additional history. Think broadly and creatively about this. Talk to the informants on the phone if they cannot come in.

If the diagnosis of bipolar disorder is not reliably ruled in or out at the initial evaluation, specifically plan to pursue this in subsequent visits by: using part of a follow up session to re-interview the patient, interviewing additional informants, obtaining previous records

How to organize your information about mania/ hypomania

Write down the history of mania obtained from the patient, informant, records, or your observations (i.e., all possible sources of information) on a SEPARATE sheet of paper in the H&P. By writing on a separate sheet, you can add more information to that sheet as it is obtained (with a new date) and can even insert a new sheet if needed.

Write down direct quotes as much as possible.

When further relevant history is obtained after the initial evaluation, do NOT write it in the progress notes (why?); write it as an addendum to the above mentioned sheet about bipolar disorder.

In the future, whenever a doubt occurs about whether or not the patient really has bipolar disorder or is only suspected to have bipolar disorder, look back at this sheet. Quickly re-reading the notes will make it clear whether or not the patient has had a manic episode.

1. It is common

• Persons with bipolar disorder have a greater lifetime prevalence of panic disorder than persons with major depressive disorder (21% vs. 10%).

• (For panic attacks (as opposed to panic disorder), the comorbidity is even greater. Up to 47% of persons with bipolar disorder have had at least one panic attack.)

• In fact, of the anxiety disorders that occur with bipolar disorder, panic disorder is the commonest. Panic ≥ social and specific phobias ≥ generalized anxiety ≥ posttraumatic stress ≥ obsessive-compulsive disorders.

2. Having both disorders in the same person is probably not a coincidence

• In a family study of bipolar disorder, almost all cases of panic disorder occurred in persons who had bipolar disorder.

• Bipolar disorder with panic disorder may actually be a distinct subtype of bipolar disorder.

3. Which persons with bipolar disorder are more likely to also have panic disorder?

• Females

• Family history of mood disorder

• Depression as the first episode of bipolar disorder

• (I would have predicted that persons with bipolar II disorder are more likely to have comorbid anxiety disorders, but that is not true; the prevalence is equal in bipolar I and bipolar II disorders.)

4. Persons with both disorders tend to have a worse prognosis. They have more:

• Frequent depressive episodes

• Severe depressive episodes

• Rapid cycling

• Suicidality

• Other psychiatric comorbidities

• Longer time to remission

5. Treatment

• First focus on stabilizing the bipolar disorder, then address treatment of remaining anxiety symptoms. Note: let’s follow this guideline even if the anxiety disorder manifested itself before the bipolar disorder did.

• While serotonergic antidepressants are used first-line for panic disorder, when it occurs along with bipolar disorder, they should probably be avoided if possible due to risk of worsening cycling.

• There is little specific research about treatment of panic disorder in persons who also have bipolar disorder, but what is available is summarized below.

• In a randomized, controlled clinical trial, quetiapine (started at 50 mg/day and titrated up to 300 mg/day) was shown to reduce panic attacks over 8 weeks (Sheehan et al., 2012).

• There is some reason to believe that valproate may work for panic disorder when it occurs with bipolar disorder for the following reasons:

a) In small, uncontrolled clinical trials, valproate has been found to be efficacious for panic disorder when it occurs alone (Woodman and Noyes, 1994) and for lactate-induced panic attacks (Keck et al., 1993). In my opinion, that valproate may work for panic disorder by itself makes me more likely to believe that it is a good choice when panic disorder occurs along with bipolar disorder.

b) However, we don’t have great direct evidence that valproate works well for panic disorder when comorbid with bipolar disorder. One study found valproate to reduce panic attacks in patients with bipolar disorder even after an antidepressant had been used (Perugi et al., 2010). Another very small and uncontrolled clinical trial found valproate to reduce panic attacks in a patients with bipolar II disorder even after an antidepressant had not worked (Baetz and Bowen, 1998). However, one large clinical trial did not find valproate to reduce panic attacks in this population over the short term at least (Sheehan et al., 2012).

c) I always like to look for “biological plausibility,” i.e., why would treatment A work for disorder X? We know that valproate increases activity of gamma-aminobutyric acid (GABA) that is the main inhibitory neurotransmitter in the brain. Benzodiazepines also work by increasing GABA activity.

d) Valproate has been shown in animal models to have antianxiety effects.

• In a randomized, controlled trial, risperidone was less (this is not a typo) efficacious than placebo in reducing anxiety symptoms over 8 weeks in patients with bipolar disorder and comorbid panic disorder (Sheehan et al., 2009).

• No specific research but based on clinical experience benzodiazepines may be efficacious in panic disorder when it occurs along with bipolar disorder.

• No specific research is available about cognitive-behavior therapy for treatment of panic disorder in patients with bipolar disorder. All we have is a small, uncontrolled study of using CBT for patients with panic disorder with or without subsyndromal symptoms of hypomania (Bowen and D’Arcy, 2003), which found that presence of these hypomanic symptoms did not prevent CBT from working for the panic disorder. I guess we can assume that that panic-specific CBT may be efficacious for panic disorder with bipolar disorder like it is for panic disorder alone. However, it requires special training to be able to skillfully deliver it.

Bottom line

1. Bipolar disorder with panic disorder has a worse prognosis, so this is an important topic! We should make sure we explicitly identify presence of this comorbidity.

2. If starting a mood stabilizer in these patients, at this time quetiapine or divalproex may be good first choices.

3. Risperidone is probably not a good choice (Sheehan et al., 2009). should be avoided if possible.

4. Antidepressants for the panic disorder should be avoided if possible. If they must be used, the bipolar disorder should be stabilized first.

5. Persons with bipolar disorder and panic disorder are more likely to be lamotrigine responders than lithium responders (Passmore et al., 2003).

6. If the person is already on another mood stabilizer, I wouldn’t change the mood stabilizer automatically. I suggest carefully charting both the mood episodes and the panic attacks separately before planning changes to medications and conducting medication trials.

Question

Which medications have evidence from randomized, controlled trials for efficacy specifically in bipolar II disorder?

Problem

Studies are rarely conducted in patients with bipolar II disorder alone. In most studies, patients with bipolar I and bipolar II disorder are combined AND commonly the results for patients with bipolar II disorder are not reported separately.

Bipolar II depression

• Data on patients with bipolar II depression who participated in four randomized, controlled trials of quetiapine found that quetiapine was efficacious for this condition. Patients in both the 300 mg/day and 600 mg/day groups improved statistically significantly more than the placebo group.

• As of July 22, 2015, I could not find any randomized, controlled trials that showed other treatments (e.g., lithium) were efficacious for this condition.

• A 2013, practice guideline from the Canadian Network for Mood and Anxiety Treatments(CANMAT) and the International Society for Bipolar Disorders (ISBD) recommended the following:

  First line treatment: quetiapine

  Second line treatments:  lithium, lamotrigine, divalproex, lithium or divalproex + antidepressants, lithium + divalproex, atypical antipsychotic + antidepressants

Bipolar II hypomania

No randomized controlled trials available.

Bipolar II maintenance treatment

• Pooled analysis of data on patients with bipolar II depression who improved greatly (i..e, were in remission) with quetiapine treatment and then either continued on quetiapine (300 mg/day or 600 mg/day) or switched to placebo showed that patients who continued on quetiapine were less likely to relapse than those who switched to placebo. (An example of the general principle that, “What gets them better, keeps them better.”)

• A 2013, practice guideline from the Canadian Network for Mood and Anxiety Treatments(CANMAT) and the International Society for Bipolar Disorders (ISBD) recommended the following for maintenance treatment of bipolar II disorder:

First line: lithium, lamotrigine, quetiapine

Second line: divalproex; lithium or divalproex or atypical antipsychotic + antidepressant; adjunctive quetiapine; adjunctive lamotrigine; combination of two of: lithium, divalproex, or atypical antipsychotic

What is rapid cycling?

Rapid cycling is a stage in bipolar disorder and is defined as having four or more episodes (mania, hypomania, depression) in a 12 month period.

Note: Two episodes of the same type (e.g., mania, hypomania, depression) would be considered separate episodes only if there was a period of at least two months between the two episodes during which the patient did not meet the diagnostic criteria for that type of episode. Unless, the patient switched to an episode of opposite polarity.

How common is it?

Lifetime prevalence of rapid cycling ranges from 26% to 43%. That is, about one third of patients with bipolar disorder will develop rapid cycling at some time in their lives.

One year prevalence of rapid cycling ranges from 5% to 33%. That is, about half of the patients who develop rapid cycling (i.e., about one sixth of patients), will have rapid cycling during a given year.

However, it is common for clinicians to not explicitly identify that the patient has rapid cycling.

What is the significance of rapid cycling in bipolar disorder?

Rapid cycling has important effects on the treatment and prognosis of bipolar disorder.

It is associated with the following undesirable features:

1. Greater prevalence of drug and alcohol abuse
2. Greater suicidality

The longer-term outcome of rapid cycling varies greatly.

What causes rapid cycling in bipolar disorder?

Rapid cycling is more likely to occur in patients who:

1. Are female

2. Had an earlier age of onset

3. Have had a longer course of illness

4. Abuse substances

5. Have  hypothyroidism

6. Have been treated with antidepressants

However, association does not mean causation. That is, these factors are not necessarily the cause of the rapid cycling.

Rapid cycling does not seem to run in families, suggesting that its causes are not primarily genetic. It is usually a temporary stage rather than a stable diagnosis for that patient. That is, it is not a subtype of bipolar disorder.

Evaluation

1. Check thyroid function

2. Check for substance abuse (history, history from friends and family, urine drug screen)

Treatment

1. Educate the patient and family about rapid cycling.

2. Educate the patient about the importance of trying to fully control the cycling course of the illness.

3. If possible, taper off any antidepressant that may be on board.

4. Use mood stabilizers that are specifically known to be efficacious in the rapid cycling stage of bipolar disorder. For example, lithium is less efficacious in patients with rapid cycling than in those without it.

Related Pages

Rapid cycling bipolar disorder

Diagnosing bipolar disorders

BEST books on bipolar disorder: for patients and families

Bipolar disorders: Main Page (Index and Links)

References

Yatham et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord. 2013 Feb;15(1):1-44.  PubMed PMID: 23237061.

Young et al. Quetiapine monotherapy in bipolar II depression: combined data from four large, randomized studies. Int J Bipolar Disord. 2013 Jul 4;1:10. PubMed PMID: 25505677. PubMed Central PMCID: PMC4230312.

Copyright 2016, Rajnish Mago, MD. All rights reserved. May not be reproduced in any form without express written permission.

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