DEALING WITH DIFFICULT DISORDERS
From The Tenth Annual Psychopharmacology Update, sponsored by the American Psychiatric Association and the
Nevada Psychiatric Association
| CHOOSING MEDICATIONS FOR PANIC DISORDER —Jonathan Davidson, MD, Professor of Psychiatry and Director,
Anxiety and Traumatic Stress Program, Duke University School of Medicine, Durham, North Carolina
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| Introduction: in United States, 15% of population have “fearful spell, something like a panic attack,” 7% have full
panic attack, 5% have recurrent panic attacks, and 3.5% have full panic disorder; significant health problem in terms
of cost; results in increased rates of suicide attempts, alcohol abuse, marital disruption, and visits to emergency departments,
and in high levels of disability; most people with panic disorder seen in primary care or emergency department,
and ≈4% of primary care patients have panic disorder
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| Neurotransmitters: studies show relevance of norepinephrine in panic attack; suggestion that patient with panic disorder
has hypersensitive, poorly regulated norepinephrine system; less γ-aminobutyric acid (GABA)-A activity
seen in patients with panic disorder than in normal controls; in third pathway, reduction in serotonin-transport activity
seen
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| Goals of treatment: 1) suppress or remove full panic attacks and limited-symptom panic attacks; 2) relieve anticipatory
dread; 3) lessen phobic avoidance; 4) improve quality of life; 5) reduce disability
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| Treatment: selective serotonin reuptake inhibitors (SSRIs) recommended as first-line treatment, but many clinicians still
prefer to use benzodiazepines first; selective norepinephrine reuptake inhibitors (SNRIs) becoming more prevalent; less
often used are atypical antidepressants, neuroleptics, and anticonvulsants; Food and Drug Administration (FDA) has approved
for panic disorder alprazolam, alprazolam XR, immediate-release and controlled-release paroxetine, sertraline,
and fluoxetine (approval for venlafaxine pending)
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 | Paroxetine, clomipramine, and placebo: paroxetine proved better than clomipramine and placebo
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| Imipramine and sertraline: response rates equivalent
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| Venlafaxine, paroxetine, and placebo: 75- and 150-mg venlafaxine tested against 20- and 40-mg paroxetine; 40-mg
dose of paroxetine better than placebo, 20-mg dose less successful; venlafaxine better than placebo, but no difference
between 75-mg and 150-mg doses
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| Escitalopram, citalopram, and placebo: escitalopram better than placebo at earlier point in study; citalopram better
than placebo, but at later point
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| Norepinephrine: not much in literature except “a couple of negative studies with tricyclics and tetracyclics”; in European
studies, reboxetine showed robust effect, but currently not available in United States
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| Main message: if SSRI not effective, consider switching to SNRI or to tricyclic or tetracyclic antidepressant; in
studies, all drugs better than placebo, but not much difference between classes of drugs; one analysis seemed to
indicate SSRIs may be better than tricyclic antidepressants and benzodiazepines, but “it’s debatable”
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| Comorbidity: 50% to 60% of patients with panic disorder have major depression at some time in lives; epidemiologic
survey found that those treated for 12 mo for panic attacks less likely to develop major depression in 12-mo
follow-up period; study showed improvement in people with both panic disorder and depression when treated with
imipramine or sertraline
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| Benzodiazepines: survey showed that 70% to 80% of clinicians use benzodiazepine as first-line treatment for panic
disorder; alprazolam continues to be prescribed most frequently; since introduction of SSRIs in early 1990s,
≈10% of patients with panic disorder given SSRI monotherapy, ≈40% given benzodiazepine monotherapy, ≈25%
given combination of SSRI and benzodiazepine, and 30% to 40% received none of those
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| Clonazepam: 2 very large studies established efficacy of clonazepam; 1 to 2 mg/day seemed optimal dose
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| Alprazolam IR and alprazolam XR: XR has advantages of slower rise to peak concentration, fewer initial side effects,
and sustained effects for 24 hr
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| Favor benzodiazepine over SSRI when: patient has pure panic disorder with minimal phobic avoidance and not much
comorbidity; patient cannot tolerate SSRI; patient does not respond to SSRI; benzodiazepines sometimes used initially
to augment and accelerate action of antidepressant
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| SSRIs vs benzodiazepines: SSRIs cover broader spectrum of disorders; benzodiazepines have more rapid onset of
action and are slightly more tolerable; among SSRIs, potential varies by drug for drug-drug interactions mediated
by cytochrome P450 system; benzodiazepines seem to have fewer drug-drug interactions; both classes can cause
problems when drug discontinued; SSRIs have little potential for abuse, potential limited with benzodiazepines; activation
occurs earlier with benzodiazepines
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| Cognitive behavioral therapy (CBT): well established that it works for panic disorder; relapse rate lower after patients
finish course of CBT than when they finish course of medication; shown that patients who have course of CBT
while tapering benzodiazepines more likely to have successful withdrawal from drug and less likely to go back on
drug later; in trial, people received CBT monotherapy, imipramine monotherapy, combination of CBT and imipramine,
or placebo; in acute phase of panic disorder, no difference between 3 treatment arms, and all better than
placebo; in maintenance phase, group that received combined CBT and imipramine better than groups with either
alone or placebo group; at 6-mo follow-up, “a lot of them had relapsed”; those who initially responded to placebo
mostly relapsed; some relapse among those who had CBT, “but by-and-large, they were better off than the ones who
had stopped taking imipramine”; unexplained finding was that those who got combined treatment “relapsed quite a
lot”
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| Long-term management: in studies, continued maintenance treatment with SSRI seemed to protect against relapse
of panic and phobic symptoms; other studies showed that maintaining patients on SSRIs resulted in cost savings
and improvement in work productivity
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| Conclusions: SSRIs and benzodiazepines first-line agents for treating panic disorder; individualized drug selection
important in comorbidities and to minimize side effects; monotherapy not always sufficient and can be supplemented
with CBT; treat into remission whenever possible; treat over long term
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| COMORBID DEPRESSION AND ANXIETY IN BIPOLAR DISORDER —Lori Davis, MD, Associate Professor of
Psychiatry, University of Alabama School of Medicine, Birmingham, and Coordinator of Research and Development,
Tuscaloosa Veterans’ Affairs Medical Center, Tuscaloosa, Alabama
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| Introduction: patients with bipolar disorder spend far more time depressed than manic, and patients with bipolar II
disorder spend more time depressed than those with bipolar I disorder; 25% of bipolar patients attempt suicide,
10% complete suicide; suicide risk highest during depression; antidepressants increase risk for switch from depression
into mania and for increased cycle frequency
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| Treatment options for bipolar depression: include antidepressants (delay using antidepressant until mood stabilizer
“fully on board”), mood stabilizers, lithium, anticonvulsants, olanzapine-fluoxetine combination (OFC), and psychotherapy
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| Lithium: efficacy ≈40% in bipolar depression; some studies suggest it is less effective than divalproex for manic patient
with comorbid depression or dysphoric mixed mood
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| Carbamazepine: response rate 34% to 40% for bipolar I disorder; in study, patients refractory to carbamazepine
tended to respond when lithium added
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| Olanzapine-fluoxetine combination: more effective than olanzapine alone and more effective than placebo
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| Lamotrigine: results of studies mixed; approved by FDA only for maintenance treatment of bipolar disorder; not approved
for bipolar depression; large study did not show difference from placebo
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| Divalproex: in speaker’s study, remission rate 46% with divalproex and 25% with placebo; because study small, statistical
significance not reached, but “numerically, [the result] is in line with the larger, multisite, industry-sponsored
studies”; when effect size compared to published effect size for lamotrigine, divalproex did better; no head-to-head
comparison of lamotrigine and divalproex done; most studies do not rate anxiety as secondary outcome in bipolar
disorder, but speaker’s study did, and found divalproex even more effective for anxiety than for depression (important
because bipolar disorder frequently accompanied by anxiety)
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| Bipolar disorder with high anxiety: results in more suicide attempts, more drug and alcohol abuse, less response to
lithium, and longer time to remission than in patients with less anxiety; conversely, patients with more subsyndromal
symptoms during major episodes are those with comorbid anxiety disorders; patients who achieve “solid” remission
between episodes less likely to have anxiety disorders; anxiety often present during mania
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| Other anxiety disorders: panic disorder—about twice as high in bipolar disorder as in unipolar depression, and further
increased in bipolar patients with rapid cycling; presence of panic disorder correlated with nonresponse to lithium;
study showed apparent genetic link between bipolar disorder and panic disorder; obsessive-compulsive disorder
(OCD)—higher lifetime prevalence in patients with bipolar disorder than in those with unipolar depression or in general
population; bipolar disorder with OCD results in higher rates of suicidal thoughts and attempts, panic disorder,
and substance abuse; in people with bipolar disorder, onset of OCD more gradual and course more episodic; clomipramine
used to treat OCD increases risk for switch to manic phase and of increasing cycle frequency; social phobia
disorder—patients request Zoloft (sertraline) after seeing television advertisement, but sertraline causes switch to hypomania
or mania; posttraumatic stress disorder (PTSD)—prevalence higher in patients with bipolar disorder
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| Pathophysiology in short: norepinephrine, serotonin, dopamine, GABA, and glutamate involved in different aspects
of comorbidities in bipolar disorder, leading to speculation that combination treatments may be necessary
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| Bipolar mania: can be treated with lithium, anticonvulsants, and atypical neuroleptics; do not treat with antidepressant
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| Bipolar depression: anticonvulsants and atypical neuroleptics promising; use antidepressants only when mood stabilizer
on board
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| Anxiety disorders: best evidence for SSRIs, but given that they can cause switching and increased cycle frequency,
consider other agents; in small studies, anticonvulsants appear to be effective in panic disorder; anticonvulsants
added to SSRI seem to help OCD and PTSD; atypical neuroleptics may work at low doses for OCD and as add-
on in PTSD, but small-study results mixed and larger studies underway; benzodiazepines work but have potential
for addiction and abuse; CBT and exposure therapy proven efficacious in most anxiety disorders
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| Treatment strategy: first and most important is accurate diagnosis; do not group all anxiety disorders into same category;
treatment varies with anxiety disorder; select mood stabilizer that has some efficacy in patient’s particular
anxiety disorder; studies of mood stabilizers small; speaker posits that anticonvulsants may be useful in anxiety
disorders; atypical antipsychotics have promise, but study results mixed when used in OCD and PTSD; mood
stabilization essential before introducing any antidepressant, and SSRIs safer than tricyclics; avoid tricyclics and
monoamine oxidase inhibitors, which may induce or exacerbate bipolar disorder; consider combining CBT with
pharmacotherapy for depression (CBT not particularly effective for mania) and comorbid anxiety
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| Concurrent bipolar and panic disorders: limited data indicate divalproex helps with panic disorder and prevents lactate-induced
panic attacks; first pick mood stabilizer, then add SSRI or CBT if necessary; single agent may not be
fully effective for patients with this combination of disorders
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| Concurrent bipolar disorder and OCD: requires mood stabilizer of clinician’s choice; SSRI probably necessary,
with or without CBT
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| Concurrent bipolar disorder and PTSD: start with anticonvulsant (some data suggest topiramate or divalproex); if
patient does not respond to anticonvulsant, add SSRI or CBT; some data emerging that atypical antipsychotics
can trigger resistant PTSD
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| Concurrent bipolar disorder and social phobia: start with mood stabilizer; gabapentin, although not shown helpful
for bipolar disorder, has shown some success in social phobia, so consider adding it before going to SSRI; CBT
also helpful
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| Concurrent bipolar and generalized anxiety disorder: based on “reading the literature and trying to piece it together,”
buspirone may be helpful when added to mood stabilizer
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Educational Objectives
| The goal of this program is to educate the listener about choosing medications for panic disorder and about treating
comorbid depression and anxiety in panic disorder. After hearing and assimilating this program, the clinician will be
better able to:
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| 1. Discuss the goals of treatment for panic disorder.
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| 2. Select appropriate modalities of treatment for panic disorder.
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| 3. Describe the pathophysiology of comorbid depression and anxiety in bipolar disorder.
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| 4. Describe the treatment modalities available for comorbid depression and anxiety in bipolar disorder.
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| 5. Determine appropriate treatment combinations that are therapeutic in depression and anxiety when they occur
concurrently with bipolar disorder.
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Discussed on This Program
Alprazolam [Xanax, Xanax XR, Niravam]
Bupropion hydrochloride [Wellbutrin, Wellbutrin SR, Zyban]
Buspirone hydrochloride [BuSpar]
Carbamazepine (several trade names)
Citalopram hydrobromide [Celexa]
Clomipramine hydrochloride [Anafranil]
Clonazepam [Klonopin]
Clonidine hydrochloride [Catapres, Duraclon]
Desipramine hydrochloride [Norpramin]
Divalproex sodium [Depakote, Depakote ER]
Escitalopram oxalate [Lexapro]
Fluoxetine hydrochloride [Prozac]
Gabapentin [Neurontin]
Imipramine hydrochloride [Tofranil]
Lamotrigine [Lamictal]
Lithium (several formulations and trade names)
Mirtazapine [Remeron]
Olanzapine [Zyprexa]
Olanzapine and fluoxetine HCl [Symbyax]
Paroxetine hydrochloride [Paxil, Paxil CR, Pexeva]
Reboxetine [Edronax, Vestra] (not available in United States)
Sertraline hydrochloride [Zoloft]
Topiramate [Topamax]
Venlafaxine HCl [Effexor, Effexor XR]
Yohimbine hydrochloride [Aphrodyne, Yocon]
Suggested Reading
Blackhart GC, Minnix JA, Kline JP: Can EEG asymmetry patterns predict future development of anxiety and depression?
A preliminary study. Biol Psychol Oct 10, 2005 [Epub before print]; Bradwejn J et al: Venlafaxine extended-release
capsules in panic disorder: Flexible-dose, double-blind, placebo-controlled study. Br J Psychiatry
187:352, 2005; Butler AC et al: The empirical status of cognitive-behavioral therapy: A review of meta-analyses.
Clin Psychol Rev Sep 29, 2005 [Epub before print]; Connor KM, Davidson JR et al: Multidimensional effects of
sertraline in social anxiety disorder. Depress Anxiety Oct 7, 2005 [Epub before print]; Davis LL, Bartolucci A, Petty
F: Divalproex in the treatment of bipolar depression: a placebo-controlled study. J Affect Disord 85:259, 2005 [Epub
before print]; Devane CL et al: Anxiety disorders in the 21st century: status, challenges, opportunities, and comorbidity
with depression. Am J Manag Care 11(12 Suppl):S344, 2005; Dunner DL. Bipolar depression. CNS Spectr
10:528, 2005 [Epub before print]; Gao K, Calabrese JR: Newer treatment studies for bipolar depression. Bipolar
Disord 7(Suppl 5):13, 2005; Hirschfeld RM, Vornik LA: Bipolar disorder—costs and comorbidity. Am J Manag
Care 11(3 Suppl):S85, 2005; Keene MS et al: Adherence to paroxetine CR compared with paroxetine IR in a Medicare-eligible
population with anxiety disorders. Am J Manag Care 11(12 Suppl):S362, 2005; Laufer N et al: Involvement
of GABA(A) receptor modulating neuroactive steroids in patients with social phobia. Psychiatry Res Oct 11,
2005 [Epub before print]; Ledley DR, Davidson JR et al: Impact of depressive symptoms on the treatment of generalized
social anxiety disorder. Depress Anxiety Sep 20, 2005 [Epub before print]; Lim CJ: Antidepressant-induced
manic conversion: a developmentally informed synthesis of the literature. Int Rev Neurobiol 65:25, 2005; Mansell
W, Colom F, Scott J: The nature and treatment of depression in bipolar disorder: A review and implications for future
psychological investigation. Clin Psychol Rev Sep 1, 2005 [Epub before print]; Marazziti D et al: Augmentation
strategy with olanzapine in resistant obsessive compulsive disorder: an Italian long-term open-label study. J Psychopharmacol
. 19:392, 2005; Nemeroff CB et al: Posttraumatic stress disorder: A state-of-the-science review. J Psychiatr
Res Oct 17, 2005 [Epub before print]; Perlis RH: Misdiagnosis of bipolar disorder. Am J Manag Care 11(9
Suppl):S271, 2005; Persons JB et al: Naturalistic outcome of case formulation-driven cognitive-behavior therapy for
anxious depressed outpatients. Behav Res Ther Oct 3, 2005 [Epub before print]; Sajatovic M: Bipolar disorder: disease
burden. Am J Manag Care 11(3 Suppl):S80, 2005; Taylor S, Stein MB: The future of selective serotonin reuptake
inhibitors (SSRIs) in psychiatric treatment. Med Hypotheses Oct 4, 2005 [Epub before print].
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
the faculty reported nothing to disclose.
Drs. Davidson and Davis were recorded at The Tenth Annual Psychopharmacology Update, held February 17-19,
2005, and sponsored by the American Psychiatric Association and the Nevada Psychiatric Association. The Audio-
Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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