Use of Clonazepam for Bipolar Affective Disorder
`
`Gary S. Sachs, M.D.
`
`The use of anticonvulsants as treatments for bipolar affective disorder is growing, and despite relatively scant
`data, anticonvulsants have become widely accepted as adjuncts to lithium therapy, particularly as alternatives to
`neuroleptics. Although most of the research work to date has involved carbamazepine, improvement in bipolar
`symptoms with clonazepam has been exhibited in controlled studies and case reports. The author summarizes
`studies done by the Bipolar Research Group of the Clinical Psychopharmacology Unit at Massachusetts General
`Hospital. The data thus far indicate that clonazepam can be added to the treatment regimen of bipolar patients
`and apparently reduces cycle frequency; many patients using neuroleptics and lithium can be switched to lithium
`and clonazepam without suffering acute relapse; and clonazepam may be associated with fewer depressive
`(J Clin Psychiatry I990,'5I[5, suPPU:31-34)
`recurrences than neuroleptic treatment.
`
`From 1984 to 1988, the literature reflects a growing
`interest in the use of anticonvulsants as treatments for bi-
`
`polar affective disorder. Despite relatively scant data, an-
`ticonvulsants have become widely accepted as adjuncts to
`lithium therapy, particularly as alternatives to neurolep-
`tics. Although most of the research work to date has in-
`volved carbamazepine, controlled studies by Chouinard,”
`as well as a number of case reports," have described im-
`provement in bipolar symptoms with clonazepam, another
`anticonvulsant.
`
`The advantages of clonazepam include a long half-life,
`rapid onset of antimanic action, and no serious toxicity
`necessitating laboratory monitoring. If systematic study
`shows clonazepam to be well tolerated and effective, the
`drug would offer an attractive option for patients with
`suboptimal response to lithium alone. At the Massachu-
`setts General Hospital, the Bipolar Research Group of the
`Clinical Psychopharmacology Unit (Sachs GS, Rosen-
`baum JF, Weilburg IB, et al.) has begun to study the effi-
`cacy of clonazepam in bipolar patients. This report
`summarizes our
`work,
`including a retrospective
`case series, preliminary results from a prospective study,
`which involved use of clonazepam and lithium as mainte-
`nance therapy, and some findings from our clinical data
`base.
`
`ADJUNCTIVE CLONAZEPAM: OPEN CASE SERIES
`
`Initially, we investigated the efficacy of clonazeparn in
`an open retrospective case series. Psychiatrists who had
`prescribed clonazepam for bipolar patients participated in
`a semistructured interview and chart review for each pa-
`tient so treated. Our systematic review of 20 clonazepam-
`
`
`
`homfieClbricalPsychoph1rnncologyllnit,Ma.ssac}uLwnGaraul
`Hospilal.Bostarr.
`77Iea¢InraclunwledgesIlIeas.ristmceof!*kzryMaelhandSaniaruIn
`Illeltzerbrestablishbzgtftecllrdcaldatabasepmjerrt.
`Reprlnlrewwts to: Garys. Sachs, M.D., CmmImp
`Unit, Massachusetts Caaeml Hospwrl, 15ParIrman Sheet, Boston, MA
`02114.
`
`treated bipolar patients from the Massachusetts General
`Hospital Clinical Pharmacology Unit’ included 17 patients
`who had previously received combined lithium and neuro-
`leptic treatment. While using clonazepam, 6 patients en-
`tirely discontinued neuroleptic medication, and 7 reduced
`their neuroleptic dose. The mean frequency of affective
`episodes per year decreased significantly, from 2.25 to
`0.94 per patient per year. Improvement was also shown on
`the Clinical Global Impressions scale: 8 patients were
`rated as improved or very much improved; 1 patient was
`rated as worse. Based on this retrospective review, full or
`partial replacement of neuroleptic by clonazepam could be
`accomplished without clinical deterioration.
`Aronson et al.,'° however, encountered early severe
`relapse in 5 of 5 lithium—refractory bipolar patients openly
`switched from unspecified doses of neuroleptic to clona-
`zepam over 2 to 4 weeks. All 5 subjects had a history of
`recurrent psychotic mania and had failed prior attempts to
`taper their neuroleptics. Four subjects required electro-
`convulsive therapy (ECT), including 1 patient who began
`clonazepam 1 week after completing a course of ECT and
`relapw the following week. These uncontrolled results
`prompted termination of the study, but it is unclear
`whether this experience should be extrapolated to the en-
`tire subgroup of patients maintained on lithium and neuro-
`leptics. It seems likely that factors such as the baseline
`neuroleptic dose, rate of tapering, severity of illness, and
`refractoriness of patients to prior treatments will be im-
`portant in determining how or whether to switch patients
`from neuroleptics to alternative maintenance therapies.
`We tried to take these considerations into account in de-
`
`signing a prospective study.
`
`CLONAZEPAM VS. NEUROLEPTIC AS ADJUNCTS 10
`LITHIUM MAINTENANCE
`
`Patients
`
`Over the past 13 months, we have followed patients
`monthly who have a diagnosis of bipolar affective disor-
`der or schizoaflective disorder. These patients had been
`treated with lithium and a neuroleptic as their maintenance
`regimen. The study involved randomly assigning them ei-
`
`J Clin Psychiatry 51:5 (Suppl), May 1990
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`GaryS.Sachs
`
`ther to openly switch to clonazepam and neuroleptic or to
`continue their present treatment. Prior to being ap-
`proached for the study, patients were randomized to a
`treatment group. Patients were entered into the follow-up
`only if they and their treating clinician consented to pa-
`tient participation in the assigned group.
`Additionally, patients met eligibility criteria that in-
`cluded having had onset of illness prior to age 45; a mini-
`mum of three well-docurnented affective episodes, includ-
`ing at least one episode of mania during the last 5 years;
`age between 21 and 65 years; history of at least one epi-
`sode while on adequate lithium therapy; history of neuro-
`leptic use during the preceding year and current daily
`neuroleptic dosage equivalent to haloperidol 10 mg or
`less; no substance abuse during the past 6 months; and not
`being acutely suicidal. Patients were scheduled for base-
`line evaluation only if they had been out of the hospital
`and had no changes made in their medication for at least 8
`weeks.
`
`'Irained interviewers administered the 31-item Hamil-
`ton Rating Scale for Depression (HAM-31), the Brief Psy-
`chiatric Rating Scale (BPRS), and a modified Schedule for
`Affective Disorders and Schizophrenia, Change Version
`(SADS-C). Interviewers were instructed to rate all symp-
`toms on the SADS-C without regard to the presence of
`pathologic mood state or other presumed etiology (such as
`drug-induced akathisia). Patients were also asked to keep
`a diary in which they answered questions pertaining to
`common symptoms of affective disorder and use of caf-
`feine, alcohol, and prescribed medication (diary available
`upon request).
`At monthly follow-up interviews, rating instruments
`were repeated with questions soliciting symptomatology
`that had occurred the preceding week. Diaries, when
`available, were used both to enrich the data for the most
`recent week and to augment questions directed at deter-
`mining a clinical status for each week during the study.
`Each status was defined to be clinically pertinent and to
`allow criteria for the determination of onset and offset of
`affective episodes. Assignment of the weekly clinical sta-
`tus was carried out at the time of the monthly interview on
`the basis of all available information and was reviewed by
`one of the primary investigators. For each week, patients
`were designated as acutely ill (meeting full DSM-III-R
`criteria for the diagnosis of an acute episode of mania or
`major depression); continued symptomatic (patient does
`not meet criteria for acutely ill, but has three or more
`symptoms rated moderate or greater and has not met crite-
`ria for recovered since last met criteria for acutely ill);
`recovering (patient does not meet criteria for acutely ill
`and has no more than two symptoms rated moderate or
`greater and has not met criteria for recovered since last
`met criteria for acutely ill); recovered (has met criteria for
`recovering for 8 consecutive weeks since last acutely ill or
`continued symptomatic and has no more than two symp-
`toms rated moderate or greater); or roughening (has met
`criteria for recovered but during current week has three or
`more symptoms rated moderate or greater). Statistical
`comparisons of group means were made by using Stu-
`dent's t test.
`
`
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`Table 1. Mean of Baseline Characteristics
`
`Age _; Duration of
`
`Group
`(y)
`Lithium Neuroleptic'
`Illness (y)
`Neuroleptic
`maintenance (N=6)
`Clonanpam
`
`maintenance (N=5)
`43.5
`l450
`4.2
`13.0
`‘Equivalent to lnloperidol
`
`2.5
`
`13.2
`
`44.2
`
`1300
`
`
`
`Results
`
`Referral, computer search, and review of clinic charts
`with individual psychiatrists identified 190 bipolar or
`schizoaffective patients. From these potential subjects,
`screening procedures determined 53 were eligible. All eli-
`gible patients were randomized, and the treating psychia-
`trists were again contacted. In 11 instances, psychiatrists
`or patients refused to enter the study because of group
`assignment: 7 were assigned to clonazepam and 4 were
`assigned to neuroleptic. An additional 20 patients refused
`to participate regardless of their group assignment. In all,
`22 patients have been enrolled. This analysis presents the
`data on the first 12 patients enrolled into the clonazepam
`maintenance (CM) (N =6) or neuroleptic maintenance
`(NM) (N =6) groups for at least 12 weeks.
`Baseline characteristics. No significant demographic
`differences were found between the groups (Table 1). At
`baseline the CM group used more neuroleptic (CM =4.2
`mg; NM=2.5 mg, NS) and more lithium (CM= 1450 mg;
`NM= 1300 mg, NS). Along with higher levels of medica-
`tion, the CM group had a higher mean BPRS score and
`more symptoms rated moderate or greater on the SADS-
`C. The only significant difference found at baseline was
`higher mean BPRS score in the CM group (CM=39.6;
`NM=26; p < .02); however,
`the CM group averaged
`about twice as many symptoms rated moderate or greater
`on the SADS-C (CM=8.8; NM=4.2, NS). Thus the CM
`group began the study significantly more symptomatic.
`Comparisons between the groups are therefore based on
`the occun-ence of acute episodes in individual patients and
`as mean changes from baseline.
`Occurrence ofacute affecfive episodes. On the basis of
`the patient interview, monthly SADS-C, and daily diary
`assignment of weekly clinical status, two new episodes
`that met criteria for acute illness were detected (Figure 1).
`These were both episodes of major depression in the NM
`group. In the CM group, one patient entered the study
`meeting formal criteria for mania but was rated continued
`symptomatic at all follow-up visits. No patient has been
`admitted for inpatient treatment.
`
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`Figure 2. Brief Psychiatric Rating Scale Scores (Monthly Group
`Means)
`
`Figure 4. Schedule for Affective Disorders and Schizophrenia,
`Change Version: Symptoms Rated Moderate or Greater
`
`Clonazepam and Bipolar Affective Disorder
`
`40
`
`
`
`Clonazepam Maintenance Neuroleptic Maintenance
`'P<0.05
`
`gm 3. Change From Baseline: Brief Psychiatric Rating Scale
`res
`
`10
`
`I Clonazepam Maintenance
`[3 Neuroleptic Maintenance
`
`ImprovementfromBaseline oor
`
`Month 1
`'P<0.05
`"P<0.02
`
`Month 2
`
`Month 3
`
`Course ofsymptoms by change in group mean scores.
`At all follow-up visits, the CM group mean BPRS (which
`was significantly greater than the NM group mean at base-
`line) was decreased significantly compared to the CM
`baseline and was no longer significantly difierent from the
`NM group mean (Figure 2). Afier the baseline evaluation,
`the BPRS showed little change in either group. Over the
`first three monthly follow-up visits, the change from the
`baseline BPRS was nearly constant in both groups (Figure
`3). The change from baseline in group mean BPRS scores
`at each month was significantly greater for clonazepam,
`but this reflects, in part, a floor effect due to the NM low
`baseline scores.
`
`Based on the SADS-C, there were no significant dif-
`ferences in symptom counts (Figure 4). The CM group
`started with more symptoms, but by the third month the
`mean for the CM group was 1.4 symptoms less than the
`NM mean (NS).
`
`Conclusions
`
`We found switching patients from lithium and neuro-
`leptic to lithium and clonazepam resulted in no significant
`clinical or statistical
`indication of worsening affective
`morbidity. The only statistically significant findings-
`higher baseline BPRS scores in the clonazepam group and
`greater improvement from baseline BPRS in clonazepam-
`
`1 2
`
`10
`
`I Clonazepam Maintenance
`:3 Neuroleptlc Maintenance
`
`NumberofSymptoms
`
`0)
`
`Baseline
`
`Month 1
`
`Month 2
`
`Month 3
`
`1hh|e 2. 1teatments for Bipolar (N =215) and Schizoaffective Pa-
`tients (N -42)
`
`Treatment
`Lithium
`Neuroleptic
`Clonazepam
`Anticonvulsant other than elonazepam
`Benzodiazepine other than clonazepam
`Antidepressant
`
`Patients (N =25?)
`N
`'5
`172
`66.9
`94
`36.7
`51
`19.8
`43
`16.7
`29
`11.3
`82
`31.9
`
`treated patients—are consistent with other trends, suggest-
`ing that the CM group was more symptomatic at baseline.
`Therefore, the statistical advantage of clonazepam over
`neuroleptic may represent actual clinical benefit due to
`clonazepam, benefit due to discontinuation of neuroleptic,
`regression to the mean, or the floor effect in the NM
`group due to the low level of pathology at baseline.
`
`Clinical Data Base
`
`Among the sources of therapeutic pessimism concem-
`ing the treatment of bipolar illness is the surprising inabil-
`ity of retrospective studies examining open clinical data to
`detect the prophylactic benefit of lithium. We are conduct-
`ing a review of data collected from our clinic to compare
`with reports (Markar and Mander," Grof," and Dickson
`and Kendall") that failed to find the anticipated statisti-
`cally significant advantage for patients treated with lith-
`ium. Thus far, we have begun to collect data (Bible 2) on
`the pattern of treatment of 257 patients (bipolar, N=2l5;
`schizoaffective, N=42). Although about two thirds of this
`population receive lithium,
`in relatively few is the re-
`sponse sufficient for lithium maintenance to serve as
`monotherapy: 21.5% of the bipolars, 14.4% of the entire
`population (Figure 5).
`These data support the expectation drawn from Prien
`and colleagues’ study" that about 15% of patients will
`have good response to lithium. Our data could be inter-
`preted to mean that about 80% of bipolar patients and
`100% of schizoaffective patients require additional or al-
`temative treatments.
`
`A simple measure of severity of illness and treatment
`outcome is the number of medications used. Looking at
`the frequency distribution for these data (Figure 6), we
`find the modal number of medications is two (excluding
`agents to ameliorate side effects, such as benztropine or
`
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`
`Gary S. Sachs
`
`I-‘igure5.Current'lreatInent:LithiumMonot.herapy
`
`SUMMARY
`
`We are studying the use of clonazepam for bipolar pa-
`tients in several ways. Thus far,
`the data indicate that
`clonazepam may be beneficial to such patients in several
`ways: clonazepam can be added to the treatment regimen
`and apparently reduce cycle frequency; many patients us-
`ing neuroleptics and lithium can be switched to lithium
`and clonazepam without suffering acute relapse; clonaze-
`pam may be associated with fewer depressive recurrences
`than neuroleptic treatment.
`Clearly the majority of bipolar patients require treat-
`ments other than lithium alone. It appears that not all of
`those patients with tendency for manic recurrence require
`neuroleptics acutely or for maintenance. A large segment
`can be managed on anticonvulsants. Clonazepam appears
`to be an effective agent in general clinical practice.
`
`Drug names: benztropine (Cogentin and others), carbamazepine (1bgre-
`tol and others), clonazepam (Klonopin). propranolol (Inderal and oth-
`ers).
`
`REFERENCES
`
`l. Chouinard G. Young SN, Annable L. Antimanic efiects of clonaze-
`pam. Biol Psychiatry l983:l8:45l-466
`'2. ChouinardG.Clona1.epaminacuteandmaintenancetreatrnentof
`bipolar affective disorder. J Clin Psychiatry l987;48(l0, suppl):29-
`36
`
`3. Chouinard G. The use of benzodiazepines in the treatment of manic-
`depressive illness. J Clin Psychiatry l988;49(ll, suppl):15-19
`4. Victor BS, Link NA, Binder RL. et al. Use of clonazcpam in mania
`and schizoaffective disorders. Am J Psychiatry 1984;141:111]-
`lll2
`
`5. Freinhar JP. Alvarez WH. Use ofclonazepam in two cases of acute
`mania. J Clin Psychiatry l985;46:29—30
`6. Adler LW. Mixed bipolar disorder responsive to lithium and clona-
`zepam [letter]. J Clin Psychiatry l986;47:49—50
`7. Pande AC. Clonazepam treatment of atypical bipolar disorder. Psy-
`chosomatics l988;29:333-335
`8. Kishimoto A, Kamata K, Sugihara T. et al. Treatment of depression
`with clonazepam. Acta Psychiatr Scand l988;77:8l-86
`9. Sachs GS. Rosenbaum JF, Jones L. Adjunctive clonazepam for bi-
`polar affective disorder. J Clin Psychopharmacol l990;l0:42-47
`10. Aronson TA, Shukla S. I-lirschowitz J. Clonazepam treatment of
`five lithium-refractory patients with bipolar disorder. Am J Psychia-
`try l989:l46:77-80
`ll. Markarl-IR. Mander A1. Efficacy of lithium prophylaxis in clinical
`practice. Br] Psychiatry 1989;155:496-500
`l2. Grofl’. Admission rates and lithium therapy. Br J Psychiatry 1987;
`l50:264-265
`
`13. Dickson WE, Kendall RE. Does maintenance lithium therapy pre-
`vent recurrences of mania under ordinary clinical conditions. Psy-
`chol Med l986:l6:52I-530
`l4. Prien RF. Klett CJ, Caffey EM. Lithium prophylaxis in recurrent
`affective illness. Am J Psychiatry 1974;131:198-203
`
`Bipolar Only
`
`Bipolar or Schizoaffective
`
`
`
`N=215
`
`N=257
`
`I-‘i¢ureti.\Bipolar Patients (N-215)
`
`
`
`o
`
`1
`
`2
`
`3
`
`4+
`
`Number of Drugs Used
`
`100
`
`E 80
`& so
`'6
`E 40
`20
`
`3 Z
`
`0
`
`(I-;‘igu£efi)7.Current1leaunent:Lithiumand0neOtherDrug
`Neuroleptic
`41
`
`Antldepressam
`
`29%
`
`CKWIIOPEM
`10%
`
`Antieonvuslant
`7%
`
`low-dose propranolol). Among the patients treated with
`two medications, it is of interest to consider those patients
`treated with lithium and one other drug (Figure 7).
`Among these patients (N=6l), we find about 41% on a
`neuroleptic, 29% on an antidepressant, and nearly another
`25% on drug treatment with anticonvulsant properties
`(i.e., carbamazepine, valproate, clonazepam, and other
`benzodiazepines). The combination of clonazepam and
`lithium was used by 10%. We plan to continue to collect
`data on this particular group to compare the course and
`treatment needs of patients receiving these combined
`treatments.
`
`
`
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`

`
`DISCUSSIONS
`
`TOLERANCE AND SIDE EFFECTS
`
`Dr. Rosenbaum: One of the intriguing issues on the
`subject of tolerance is that there appears to be a differen-
`tial tolerance to side effects, which is well documented in
`the trials with alprazolam and clonaaepam. The sedation
`and ataxia evident in Weeks 1 to 3 are largely gone by
`Week 6, whereas antipanic effects tend to be sustained.
`Dr. Patterson: In our population, there also seems to
`be a euphorigenic effect with alprazolam that, like ataxia,
`resolves with time.
`
`Dr. Murriaclr: On the other hand, the cognitive im-
`pairment that occurs with benzodiazepines sometimes
`does not go away. Sedation does, but some people remain
`fuzzy for many months.
`Dr. Pollack: That may be one of the reasons why
`doses tend to decrease over time, as patients seek the low-
`est effective dose, perhaps in response to cloudiness or
`impairment.
`Dr. Rosenbaum: If benzodiazepines are discontinued,
`there's an apparent functional shift of enhanced receptor
`sensitivity to benzodiazepine antagonists. Benzodiazepine
`antagonists may increase alertness and ability to learn.
`Therefore, there may be a transient augmentation in cog-
`nitive function, with benzodiazepine discontinuation act-
`ing like an antagonist and enhancing learning.
`
`BENZODIAZEPINES IN PANIC DISORDER
`
`Dr. Bodkin: The literature suggests that benzodiaze-
`pines are equally effective in panic disorder at equipotent
`dosages,
`including, presumably, diazepam, chlordiaze-
`poxide, and lorazepam. Is that true?
`Dr. Rosenbaum: Our field is hampered by limitations
`of acute clinical trial methodology. We have a hard enough
`time demonstrating drug-placebo differences with agents
`we believe to be efiective. When you add a treatment that
`has some effect, given the N’s that we typically muster for
`our clinical trials, we're destined to introduce a type H
`error that makes active treatments look statistically indis-
`tinguishable.
`
`PANIC ATTACKS
`
`Dr. Munjack: Your report, Dr. Svebak, seems a little
`out of step with the literature, in that most studies of imip-
`ramine and even benzodiazepines do not show 100% re-
`covery from panic attacks. Can you explain your results?
`Dr. Svebak: Several factors are involved. One is the
`
`very careful medical screening, which itself provides re-
`lief in that patients know they're not suffering from any
`dangerous disease. That may account for the 50% reduc-
`tion in panic attacks from screening to the baseline week.
`In addition, I instruct patients about drinking and eating
`
`habits that might interfere with panic complaints. I coun-
`sel them to undertake physical exercise regimens—moder-
`ate enough not to provoke lactic acid secretion—and in-
`crease their aerobic capacity. I also show them in the lab
`how to assume more normal breathing patterns.
`In general, I think the patients feel better taken care of.
`In Bergen, anxiety patients have actually organized them-
`selves into a group called Only Anxiety to counteract what
`they perceive as a lack of understanding from the public.
`Dr. Rosenbaum: What drugs are typically used to
`treat panic disorder in Norway?
`Dr. Svebak: We use the more traditional benzodiaze-
`
`pines, oxazepam and diazepam. Clornipramine has also
`been frequently prescribed. The dose levels of clornip—
`ramine were probably well above what should be recom-
`mended, because patients tended to report a number of
`obvious side effects.
`
`Dr. Rosenbaum: Is panic disorder viewed as a dra-
`matically treatable disorder?
`Dr. Svebak: There’s been a change in the way we re-
`gard the treatment of panic disorder. It's being more
`widely accepted as a disorder and is getting increased at-
`tention in terms of drug use. One good reason for doing
`these studies is to inform psychiatrists and general practi-
`tioners about choosing more appropriate drug treatment.
`Dr. Iesar: I’d like to suggest another reason for the
`excellent response your patients have. Is it possible that
`European patients, in general, have a higher degree of
`tolerance for discomfort than American patients? Studies
`on back pain demonstrate a low incidence of surgeries and
`corrective procedures for European patients compared
`with our own patients.
`Dr. Svebak: I can’t answer a question like that, but I
`wouldn’t think there would be a difference. Certainly,
`back pain has a very complicated etiology and shouldn't
`really be compared with panic disorder.
`The only interesting and peculiar finding is that all
`these panic disorder patients complain of pain in the neck
`and shoulders, and they have cold hands and feet.
`
`PANIC DISORDERS IN CHILDREN
`
`Dr. Rosenbaum: Are there critical periods of “plas-
`ticity" in an illness during which successful interventions
`can be associated with maintenance of recovery when
`treatment is discontinued?
`
`Dr. Graae: Certainly, there are reports that relatively
`young children, if successfully treated, may maintain that
`recovery in the absence of medication seemingly indefi-
`nitely.
`Whether that will hold true in follow-up studies re-
`mains to be seen. The notion that there may be crucial
`developmental periods at which that kind of intervention
`might stick is worth exploring.
`Dr. Biederman: There are phenocopies in children
`
`50
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`
`who have adversity and anxiety, and treating the environ-
`mental situation may result in a totally different clinical
`predicament. Nevertheless, serious, well-defined psycho-
`pathologic conditions of childhood and adolescence tend
`to be more malicious than the adult onset of chronicity in
`terms of their development and impact on life. I don’t like
`even to postulate that a little bit of intervention will pro-
`duce long-lasting effects.
`Dr. Graae: In most of the cases we see, there are pro-
`found and enduring family social problems and also a
`great deal of comorbidity.
`Dr. Pollack: It would be interesting if those with very
`early onset of social phobic symptoms were treated ag-
`gressively early on with behavior therapy or medication,
`to see if anxiety sensitivity resolved. If these children
`learned to be comfortable in social situations, they might
`not become socially phobic as adults.
`Dr. Roseubaum: It‘s a hypothesis worth testing, and
`there have been cases of marked improvement in some
`inhibited children.
`
`Dr. Biederman: What recovers is the adaptability to
`the illness. That means you become less incapacitated, not
`that you’re healthy. You don’t lose the social phobia. I ex-
`pect that early treatment would produce long-lasting adap-
`tation effects rather than the elimination of the condition.
`
`ATTENTION DEFICIT DISORDER
`
`Dr. Pollack: You’ve said that 30% of anxious kids
`have attention deficit disorder and that 50% of children
`
`with attention deficit disorder will manifest those symp-
`toms as adults. Does that mean that between 10% and
`
`20% of our panic patients may have residual attention def-
`icit disorder?
`
`Dr. Biederman: In those difficult patients whom we
`call nonresponsive, the existence of an underlying atten-
`tion deficit disorder, not purely related to the panic disor-
`der, should be entertained.
`As you know, there’s intense controversy on how to
`evaluate the condition. Wk have been working for years to
`establish the diagnosis, and I strongly believe that it's no
`more difficult to diagnose attention deficit disorder than it
`is to diagnose panic disorder or depression: you just ask.
`Most of the time the error is one of omission: you
`don’t consider the possibility, so you don’t know. The
`same is true for studies of depression. In our studies now,
`the comorbidity of depression in ADD is about 30% to
`50%.
`
`Dr. Bodkin: What happens to the anxiety disorders in
`these patients when their ADD is addressed? What effect
`do benzodiazepines have on their ADD?
`Dr. Biederman: Children with both diagnoses require
`both treatments, because the target symptoms are larger
`than either diagnosis.
`Some evidence suggests that stimulants are problem-
`atic drugs in anxious hyperactive children because of the
`anxiogenic effects. But one of my early patients, whose
`panic attacks and agoraphobic symptoms were exquisitely
`well controlled with clonazepam, needed stimulants be-
`
`Discussions
`
`fore his ADD dramatically improved. Other children with
`ADD and anxiety can be treated successfully with tri-
`cyclic antidepressants, such as desipramine.
`If a patient has a disorder, the net effect of treatment is
`typically to the patient’s benefit. Whatever cognitive detri-
`mental effects benzodiazepines can provoke are counter-
`acted by the good clinical effect, so you end up being
`ahead of the game.
`Dr. Murriack: What percentage of your patients’ par-
`ents resist the idea of medication in a child who has only
`anxiety, for example?
`Dr. Biederman: I run a pediatric psychopharmacol-
`ogy program that screens out people who are not inter-
`ested in psychopharrnacologic interventions. In general,
`though, parents are reluctant to put children on medica-
`tion. The exception is the parent whose chronic, debilitat-
`ing condition, unrecognized and unmanaged in childhood,
`is diagnosed in adulthood and dramatically responds.
`'I‘reatrnent may start at an early age by nonpharmaco-
`logic intervention. You can intervene, educate, facilitate
`some kind of separation, and maybe that will be enough,
`not for cure but for a more functional adaptation. You will
`not convert a shy child into an extrovert, but you have
`permitted him to participate in life.
`My guess is that a cautious use of medication in the
`most severe incapacitating cases is what we should be do-
`mg.
`Dr. Pollack: Adult social phobics or panic disorder
`patients treated with benzodiazepines or MAOIs often do,
`in fact, report a kind of personality change, or they report
`themselves as not feeling shy anymore. It's not just that
`they no longer have panic attacks, but they are more as-
`sertive, more confident.
`Dr. Rosenbaum: Some lose their “personality disor-
`ders," assuming that those disorders are diagnosed with
`validity by a particular rating instrument.
`Dr. Biederman: I have no doubt that symptomatic im-
`provement produces changes in the person. Depending on
`how many comorbid diagnoses the patient has—multiple
`anxiety disorder and behavioral inhibition or chronic shy-
`ness—some symptoms will be relieved. If the person has
`just an acute illness, if the premorbid personality was out-
`going, but is now homebound and avoidant, those changes
`are based on the illness. When you treat the illness, that
`behavior is ameliorated.
`
`It is a rare patient who has only one condition or who
`wakes up one morning and has a panic attack. Usually the
`onset is more insidious and, in many cases, starts at a
`young age. 'I‘reatrnent then will greatly enhance the scope
`of their lives but will not cure. I am not advocating that we
`not use treatment but that we be modest about the out-
`COIIIC .
`
`CARDIAC-RELATED PANIC DISORDERS
`
`Dr. Murrjack: I haven't noticed a great reduction in
`the amount of medical workup, in spite of all the evidence
`that it may be a waste of time. Do you have any way of
`selling this idea?
`
`] Clin Psychiatry 51:5 (Suppl), May 1990
`
`6 of8
`
`Alkermes, Ex. 1072
`
`51
`
`6 of 8
`
`Alkermes, Ex. 1072
`
`

`
`D.
`
`.
`
`Dr. Katon: Part of the art of knowing how far to work
`up someone you suspect has psychiatric illness but who
`comes to you with somatic symptoms depends on the pa-
`tient. Some patients require some workup before they are
`convinced they don't have a physical illness.
`I’ve also found that the better the training a primary
`care physician has had, the more likely the physician is to
`screen for panic disorder and major depression and the
`less likely he is to undertake elaborate testing. In our pri-
`mary care clinic, any person who comes in with chest
`pain, whether that person is 20 or 80, is screened for panic
`disorder. It's not that we don't do some cardiovascular
`
`testing, but if panic disorder is found, we treat it and may
`not be as aggressive in testing as we would be without that
`screening.
`Dr: Rosenbaum: What about a clinical trial challenge
`with clonazeparn or alprazolam as a diagnostic test, some-
`thing akin to giving nitroglycerin to see if the chest pain
`goes away?
`Dr. Katon: Our primary care physicians often start the
`patient on some medication and continue medical investi-
`gation. What you often find is that the patient comes back
`in a week markedly better, and you know you’re on the
`right track.
`We’ve found that half the people with panic also have a
`major depression, and many have developed social pho-
`bias. Frequently, severe social stress precipitated the de-
`velopment of their disorder. If we look at the broader
`picture instead of just the anxiety attack alone, we can
`often make the diagnosis very conclusively.
`Dr. Murriack: Is there a correlation between small-
`vessel heart disease and panic?
`Dr. Katon: Cannon at the National Institutes of Health
`
`has postulated that some people with chest pain and nega-
`tive workups have increased small-vessel resistance, and
`they seem to develop ischemia.
`Inaddition,hehasfoundthatthissamegrouphasab-
`normalities in a number of areas: on esophageal manome-
`try, and in the smooth muscles of the forearms and
`bronchioles, the latter following methacholine challenges.
`As you know, the autonomic nervous system is the
`control mechanism for all the smooth muscles of the body.
`Cannonhascomearoundtotheideathatmanyofthese
`patients seem to have panic disorder. In fact, when 15 of
`them were evaluated, the rate of panic disorder was about
`70%.
`
`Dr.- Pollack: Does the smooth-muscle responsivity
`change with antipanic treatment?
`Dr. Katon: We don't know. Cannon has not
`
`any antipanic treatment in his patients, although some of
`them, he claims, have developed idiopathic cardiomy-
`opathies over time.
`Conn’s work with Klein's group has suggested that idi-
`opathic cardiomyopathy patients have a higher prevalence
`of panic disorder, which preexists that cardi