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Faculty and Disclosures

S. Nassir Ghaemi, MD, MPH, Assistant Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts;
Director, Bipolar Disorder Research Program, Cambridge Health Alliance, Cambridge, Massachusetts
Disclosure: S. Nassir Ghaemi, MD, MPH, has disclosed that he has received research grants from Janssen
Pharmaceutica, Novartis, Abbott Labs, Eisai Inc, and GlaxoSmithKline, and has served on the speaker's bureau for
Janssen Pharmaceutica, GlaxoSmithKline and Abbott Labs.

From Medscape Family Medicine > Topics in Adult Primary Care - Bipolar Disorder
Expert Column

Anxiety and Bipolar Disorder

S. Nassir Ghaemi, MD, MPH
Posted: 11/05/2004

Introduction
Anxiety and mood go together. Most patients treated by mental health professionals are the worried well; they
experience some combination of depression and anxiety, which used to be called "neurotic depression," a label later
divided among a number of different categories: major depressive disorder, bipolar disorder, dysthymia, generalized
anxiety disorder (GAD), panic disorder, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder
(PTSD). These patients present with symptoms of anxiety and mood; clinicians then categorize them into those
DSM categories. Because the categories divide mood and anxiety into different disorders, clinicians then are left to
diagnose the "comorbidity" of anxiety and mood disorders at the same time. Thus, it may not be surprising that of
persons who are diagnosed with major depressive disorder, approximately half meet diagnostic criteria for an
anxiety disorder;[1] nor that antidepressants can have antianxiety effects; nor that antianxiety agents can have
antidepressant effects. This comorbidity is even higher for bipolar disorder: Approximately half of those with bipolar
disorder also meet diagnostic criteria for GAD, the most common kind of anxiety syndrome in persons with bipolar
disorder; about 20% meet diagnostic criteria at some point in their lives for OCD, and 20% or more for panic
disorder.[2,3] The vast majority of persons with bipolar disorder -- over 90% according to the National Comorbidity
Survey[4] -- meet diagnostic criteria for at least 1 anxiety disorder at some point in life. Whether these persons have
more than 1 illness or the same syndrome that is divided by our diagnostic schema into multiple labels is an
unanswered question. Clearly, however, anxiety symptoms are common in persons with bipolar disorder and need
attention.

The Importance of Recognition and Treatment of Anxiety in Bipolar Disorder

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In bipolar disorder, recognizing and treating anxiety symptoms is important not only to improve the anxiety
symptoms themselves but also to improve bipolar disorder itself. This is because anxiety symptoms are associated
with an increased risk of suicide,[5] and also because one of the prominent aspects of anxiety conditions, insomnia,
is a major trigger for manic episodes and general destabilization of bipolar disorder.[5] Thus, adequate treatment of
anxiety symptoms may help stabilize bipolar disorder as well, in addition to reducing the long-term risk of suicide.
The most common anxiety condition in bipolar disorder is GAD. This is characterized by multiple worries about
usually important but typical life issues: the kids, the bills, taxes, the election. A person who spends more than half
of his time most days for 6 months or longer worrying about multiple such matters meets current GAD criteria.[6]
Note that this is a chronic condition; the 6-months-or-longer criterion is designed to weed out short-term anxiety in
relation to life stresses. In GAD, the life stresses may be present, but the constant worrying is excessive and
interferes with a person's ability to function at home or work or in relationships.
Panic disorder is the next most frequent condition, and is usually more severe than GAD. Unlike common parlance,
"panic" does not simply refer to severe anxiety, but rather to unprovoked severe anxiety, happening out of the blue,
occurring repeatedly and in a time-limited fashion, with remission within 30 minutes usually.[6]
OCD involves the presence of obsessions (thoughts that do not make any sense to oneself but which one cannot
avoid having) or compulsions (actions that one cannot stop doing, usually to relieve obsessions).[6]
A final relevant anxiety condition is PTSD, or the occurrence of nightmares and/or flashbacks (reexperiencing
traumatic experiences during waking hours), associated with heightened sensitivity to sudden noises (startle
response) and other features, such as a sense of doom, shortened future, or hopelessness.[6]

Treatment of Anxiety in Bipolar Disorder

It is important to remember that the easiest -- and potentially most risky -- treatment for these various anxiety
conditions is the use of an antidepressant. This is because antidepressants likely can cause acute manic symptoms
in persons with bipolar disorder, and if used for a long time, can lead to a worsening of bipolar disorder in some
people.[7] Thus, the seemingly easy solution of simply taking another antidepressant should not be exercised lightly.
Rather, perhaps with the exception of OCD and in those with substance abuse, the benzodiazepine class of
antianxiety medications is effective for all of these conditions and has no detrimental effect on bipolar disorder. The
problem with benzodiazepines is that they can themselves lead to physiologic tolerance, such that there is a need
for more and more of the medications over time, and, if they are stopped, patients can experience a withdrawal
syndrome of heightened anxiety and physical symptoms, including, in the worst-case scenario, seizures.[8] These
are not reasons to avoid benzodiazepines altogether, but rather issues to think about before taking them, and
reasons to avoid long-term treatment with benzodiazepines when possible. However, due to their potential for
tolerance as well as psychological addiction in some people, benzodiazepines generally are not recommended for
those with current substance abuse. Alcohol abuse is especially a problem because benzodiazepines are chemically
similar to alcohol in their effects.
Further, benzodiazepines are not effective in OCD. Thus, those with bipolar disorder and OCD are faced with a
difficult, though not insurmountable, dilemma. Serotonin reuptake inhibitors (SRIs), the drugs most commonly used
for the treatment of OCD, can destabilize bipolar disorder by causing manic episodes or a long-term worsening of
the course of bipolar illness (rapid cycling, or more and more mood episodes over time). However, SRIs may be
needed to treat OCD. In this situation, the clinician and patient need to work together to reach the best compromise.
Of the SRIs, the one that has been studied most extensively in bipolar depression (and that is associated with at
least a relatively low rate of immediate mania) is paroxetine.[9] Thus, I generally recommend using this agent as
opposed to other SRIs in bipolar depression in general, but especially in bipolar disorder with OCD. Further, there is
some evidence that some atypical neuroleptic agents can improve OCD symptoms, especially when combined with
SRIs.[10] My practice, in order to avoid antidepressant-related worsening of bipolar disorder, is to begin with standard

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mood stabilizers (namely lithium, divalproex, or carbamazepine) plus atypical neuroleptics in persons with bipolar
disorder plus OCD, and then to follow up with paroxetine or other SRIs if OCD symptoms persist. The added benefit
of this sequence is that the presence of atypical neuroleptics plus mood stabilizers provides added protection
against possible induction of mania when antidepressants are added later.[11]
In some patients with anxiety disorders, in whom benzodiazepines are ineffective or not tolerated or otherwise not
acceptable, antidepressants like SRIs may be needed for treatment of anxiety, and most SRIs are FDA-approved for
1 or more anxiety disorders, but the lowest doses should be used for anxiety symptoms in bipolar disorder, because
risk of mania likely increases with higher doses of antidepressants. Furthermore, when possible, the antidepressants
paroxetine or bupropion should be used, because they are the only ones that have demonstrated lower risks of
causing acute mania than tricyclic antidepressants in well-designed randomized studies. Also, again, when possible,
careful consideration should be given to stopping antidepressants after short-term benefit, because there appears to
be a subgroup (maybe one quarter of persons) in whom long-term antidepressant use can lead to a worsening of
episodes of bipolar disorder (both depression and mania).[5]
It is also worth mentioning that, many times, antidepressants and benzodiazepines are not even needed in the
treatment of bipolar disorder with comorbid anxiety conditions. This is because anxiety symptoms often resolve
when the mood disorder is treated. This falls within a hierarchical approach to diagnosis and treatment that has a
long tradition in psychiatry, as follows: Mood disorders trump psychotic disorders which trump anxiety disorders. In
other words, if someone has a mood disorder (such as bipolar disorder) plus delusions, one should diagnose and
treat bipolar disorder first, not schizophrenia, and often the psychotic symptoms resolve with treatment of the mood
symptoms. Further, if someone has bipolar disorder plus GAD, I would recommend initially treating the bipolar
disorder with a standard mood stabilizer, and then only adding an antianxiety treatment if anxiety symptoms persist
despite improvement of mood symptoms with adequate treatment with a mood stabilizer. There are exceptions to
this general approach, in particular panic disorder. Panic attacks are themselves so disturbing, and sometimes are
associated with increased risk of suicide, that it is important to treat them directly and immediately, usually with
benzodiazepines. This short-term treatment need not necessarily lead to long-term treatment, however, once the
mood disorder is controlled with mood stabilizers.
Among mood stabilizers, some have more antianxiety effects than others, based on their biological mechanisms.
Among the more proven mood stabilizers, divalproex has the most biologically specific antianxiety mechanism
(stimulation of GABA receptors), and thus might have a relative advantage over other agents.[12] Gabapentin also
has strong antianxiety effects, and has been proven effective in the treatment of panic disorder and social phobia.[13]
However, it does not have strong mood-stabilizing effects, and should mainly be used as an add-on treatment to
other mood stabilizers. Yet it is important to note that, unlike antidepressants, gabapentin will not worsen the course
of bipolar disorder (even if it does not improve it much), and thus it is a safer treatment for anxiety symptoms in
bipolar disorder when combined with more proven mood stabilizers.
The treatment of insomnia, often associated with anxiety, is a major clinical issue in patients with bipolar disorder.
This is mainly because, as mentioned earlier, insomnia is associated with relapse into mania and destabilization of
bipolar disorder. For the reasons given above, I would caution against use of antidepressants with sedative
properties, such as trazodone, for insomnia in bipolar disorder, because antidepressants can destabilize bipolar
illness. Rather, if the insomnia is related to an anxiety condition like GAD, I generally recommend gabapentin or, in
some cases, sedating neuroleptic agents, because these agents do not worsen (and may actually improve)
symptoms of bipolar disorder.
In summary, anxiety conditions commonly occur in bipolar disorder, and need to be treated. However, with some
exceptions, especially OCD, caution should be exercised in use of antidepressants, and the use of other agents,
such as benzodiazepines or gabapentin, is preferable. Furthermore, anxiety symptoms often improve when mood
symptoms are adequately treated with mood stabilizers in bipolar disorder.

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References
1. Sasson Y, Chopra M, Harrari E, Amitai K, Zohar J. Bipolar comorbidity: from diagnostic dilemmas to
therapeutic challenge. Int J Neuropsychopharmacol. 2003;6:139-144 Abstract
2. Yerevanian BI, Koek RJ, Ramdev S. Anxiety disorders comorbidity in mood disorder subgroups: data from a
mood disorders clinic. J Affect Disord. 2001;67:167-173. Abstract
3. Freeman MP, Freeman SA, McElroy SL. The comorbidity of bipolar and anxiety disorders: prevalence,
psychobiology, and treatment issues. J Affect Disord. 2002;68:1-23. Abstract
4. Kessler RC, Rubinow DR, Holmes C, Abelson JM, Zhao S. The epidemiology of DSM-III-R bipolar I disorder
in a general population survey. Psychol Med. 1997;27:1079-1089. Abstract
5. Myers J, Thase M. Anxiety in the patient with bipolar disorder: Recognition, significance, and approaches to
treatment. Psychiatr Annals. 2000;30:456-464.
6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed.
Washington, DC: American Psychiatric Association; 1994.
7. Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK. Antidepressants in bipolar disorder: the case for caution.
Bipolar Disord. 2003;5:421-433. Abstract
8. Nelson J, Chouinard G. Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency,
rebound and withdrawal. Canadian Society for Clinical Pharmacology. Can J Clin Pharmacol. 1999;6:69-83.
Abstract
9. Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of imipramine and
paroxetine in the treatment of bipolar depression. Am J Psychiatry. 2001;158:906-912. Abstract
10. Hollander E, Baldini Rossi N, Sood E, Pallanti S. Risperidone augmentation in treatment-resistant obsessivecompulsive disorder: a double-blind, placebo-controlled study. Int J Neuropsychopharmacol. 2003;6:397-401.
Abstract
11. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the
treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60:1079-1088. Abstract
12. Petroff OA, Rothman DL, Behar KL, Hyder F, Mattson RH. Effects of valproate and other antiepileptic drugs
on brain glutamate, glutamine, and GABA in patients with refractory complex partial seizures. Seizure.
1999;8:120-127. Abstract
13. Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentin treatment of panic disorder.
J Clin Psychopharmacol. 2000;20:467-471. Abstract
14. Sasson Y, Chopra M, Harrari E, Amitai K, Zohar J. Bipolar comorbidity: from diagnostic dilemmas to
therapeutic challenge. Int J Neuropsychopharmacol. 2003;6:139-144 Abstract
15. Yerevanian BI, Koek RJ, Ramdev S. Anxiety disorders comorbidity in mood disorder subgroups: data from a
mood disorders clinic. J Affect Disord. 2001;67:167-173. Abstract
16. Freeman MP, Freeman SA, McElroy SL. The comorbidity of bipolar and anxiety disorders: prevalence,
psychobiology, and treatment issues. J Affect Disord. 2002;68:1-23. Abstract
17. Kessler RC, Rubinow DR, Holmes C, Abelson JM, Zhao S. The epidemiology of DSM-III-R bipolar I disorder
in a general population survey. Psychol Med. 1997;27:1079-1089. Abstract
18. Myers J, Thase M. Anxiety in the patient with bipolar disorder: Recognition, significance, and approaches to
treatment. Psychiatr Annals. 2000;30:456-464.
19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed.
Washington, DC: American Psychiatric Association; 1994.
20. Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK. Antidepressants in bipolar disorder: the case for caution.
Bipolar Disord. 2003;5:421-433. Abstract
21. Nelson J, Chouinard G. Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency,
rebound and withdrawal. Canadian Society for Clinical Pharmacology. Can J Clin Pharmacol. 1999;6:69-83.
Abstract

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22. Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of imipramine and
paroxetine in the treatment of bipolar depression. Am J Psychiatry. 2001;158:906-912. Abstract
23. Hollander E, Baldini Rossi N, Sood E, Pallanti S. Risperidone augmentation in treatment-resistant obsessivecompulsive disorder: a double-blind, placebo-controlled study. Int J Neuropsychopharmacol. 2003;6:397-401.
Abstract
24. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the
treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60:1079-1088. Abstract
25. Petroff OA, Rothman DL, Behar KL, Hyder F, Mattson RH. Effects of valproate and other antiepileptic drugs
on brain glutamate, glutamine, and GABA in patients with refractory complex partial seizures. Seizure.
1999;8:120-127. Abstract
26. Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentin treatment of panic disorder.
J Clin Psychopharmacol. 2000;20:467-471. Abstract
Medscape Family Medicine. 2004;6(2) 2004 Medscape

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