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Somatic treatments for obsessive-compulsive disorders
Somatic
Treatments for Obsessive-Compulsive Disorders
Michael A. Jenike, Lee Baer, and William E. Minichiello Patients
with
physicians
obsessive-compulsive
other than psychiatrists. abundance
disorder
to treat
and the
effective
in all cases. Patients frequently
of therapeutic
approaches
and dynamic
structured
and nondirective,
rarely reduce
particularly
with compulsive
rituals. Likewise,
the treatment
electroconvulsive 0 1987
yet psychodynamic
of OCD. There are, however, of these
patients.
therapy,
We
and
related
available
electroconvulsive
therapy
a number of modalities somatic
treatments
present
that
therapy
none
is clearly
if they are loosely fares
much
is not regarded including
better,
as useful in
that may be extremely of OCD
to
laden with unconscious
particularly
Behavior
often
and even more difficult
indicates
seemingly
treatments,
the symptoms.
review
syndromes
are difficult to recognize
present with symptoms
symbolism
the treatment
meaning;
(OCD)
These patients
helpful in
medications,
and psychosurgery.
by Grune & Stratton,
Inc.
PHARMACOLOGIC
TREATMENTS
A WEALTH OF ANECDOTAL EVIDENCE and a few controlled underscore the effectiveness of pharmacotherapy in some patients.lm6
studies
Heterocyclic Antidepressants
A link between depression and OCD is frequently noted.‘,2*5-gNumerous antidepressants have been reported to be useful, including imipramine,‘@13 amitriptyline,‘2-‘4doxepin,‘5,‘6 desipramine,” zimelidine,” fluoxetine,lg and trazodone.*’ All of these reports, however, involve a small number of patients without controls. Responses were unpredictable and not clearly related to depression; there was, however, dramatic improvement in some cases. Clomipramine, a tricyclic antidepressant not yet available in the United States, may have some specific antiobsessional properties. In 1969 Lopez-Ibor21 gave clomipramine intravenously and reported improvement over two to five days in 13 of 16 OCD patients; others reported similar findings.‘*-*’ Others attempted uncontrolled trials with oral clomipramine with mixed results. Some reported little improvement” while others reported a good response.2g‘33 In a 4-week randomized double-blind trial, Ananth et al34compared clomipramine to amitriptyline in 20 severe OCD patients. Clomipramine, but not amitriptyline, produced statistically significant improvement in obsessive symptoms, depression, and anxiety. Stroebel et al.35 studied oral clomipramine (maximum dose = 300 mg/d) in an open trial in 50 patients with various diagnoses who all had prominent obsessivecompulsive symptoms and reported that the overall reduction in obsessive symptoms was 60%. Fifteen patients with a primary diagnosis of OCD had an 80% success From the Obsessive-Compulsive Disorders Clinic and Research Unit at Massachusetts General Hospital, Boston. Address reprint requests to Michael Jenike. M.D., Massachusetts General Hospital, Department of Psychiatry, Buljinch 3. Fruit St, Boston, MA 02114. 0 1987 by Grune & Stratton, Inc. OOIO-440X/87/2803-0007$03.00/0
250
Comprehensive
Psychiatry,
Vol. 28,
No. 3 (May/June),
1987:
pp 250-263
OBSESSIVE-COMPULSIVE
DISORDERS
251
rate, while 17 schizophrenic patients had only a 41% success rate. In only five patients, however, was there a complete remission. Twenty-five of the 30 successfully treated patients (83%) had previously been treated with adequate doses of other antidepressants for an average of 10 months without improvement in obsessive-compulsive symptoms but with improvement in depression. Unfortunately, diagnostic criteria were not outlined in this report and it has been reported that severe obsessive-compulsive patients are frequently mislabeled schizophrenic.36 150 mg of nortriptyline, and Thoren et a1.37,38compared 150 mg of clomipramine, placebo in 24 patients who were distributed among the three groups. Even with this relatively small number, significant change was noted on an obsessive-compulsive scale. On this scale, the clomipramine group showed 42% improvement, the nortriptyline group 21% and the placebo group was unchanged. The clomipramineplacebo difference was statistically significant (P = .05). After a 5-week, doubleblind trial, 22 of the patients were given an open trial of clomipramine and behavior therapy during which 50% of the patients improved, including three patients who failed to respond to nortriptyline. This study suggested a substantial clomipramine effect; however, clomipramine did not produce an effect on either the Leyton Obsessional Inventory,39 a standard scale for evaluating the severity of obsessional symptoms, or on social functioning scales. Thoren et a1.,38 in an attempt to obtain a neurochemical correlate to clinical improvement of symptoms, measured spinal fluid concentration of monoamine metabolites before and during treatment with clomipramine, nortriptyline, and placebo. Nortriptyline produced a reduction in methoxyhydroxyphenylethylene glycol (MHPG), clomipramine reduced both MHPG and 5-HIAA, and placebo treatment did not change either. The change in 5-HIAA, but not that in MHPG, appeared to be important for the treatment outcome; there was a significant correlation between reduction in spinal 5-HIAA and effect on the two central OCD symptoms, rituals and obsessive thoughts. Greater symptom reduction with clomipramine in the OCD patients was associated with a more pronounced lowering of 5-HIAA. Marks et a1.40 later compared clomipramine to placebo in 47 outpatients in a controlled study and found modest yet significant improvement in self-rating scales, but no change in observer ratings in the clomipramine group after a 4-week study period. All patients were admitted to the hospital for behavior therapy after the initial 4-week evaluations with the active drug or placebo condition continued. After intensive behavior therapy, all ratings of compulsions and mood showed significantly greater improvement in patients on clomipramine compared to those on placebo. In those patients who were not depressed prior to the study, however, the investigators were unable to show any benefit of clomipramine over placebo and concluded that clomipramine is useful only in OCD patients with concomitant depressed mood. Three other carefully controlled double-blind studies of clomipramine34~4’*42 indicate that clomipramine is more effective than placebo in reducing obsessional symptoms. Insel’ combined data from these three studies and those of Thoren et al. 37.38and Marks et a1.40 and found that of 64 OCD patients treated with clomipramine, approximately two thirds improved significantly as measured by blind clinical rating scales. Also, clomipramine was more effective than the MAO
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BAER,
AND
MINICHIELLO
inhibitor clorgyline4* and possibly more effective than amitriptyline.43 Two of the studies3’14* Indicated that clomipramine helped pure obsessionals as well as ritualizers. In a review article, Asberg et a1.44summarized the data on the use of clomipramine in OCD and formulated tentative guidelines for its clinical use. In patients with long-standing, severe obsessive-compulsive illness who also are dysphoric, clomipramine appears to be the drug of choice. It can also be tried in patients who are not dysphoric, but the effect is not equally convincing. Treatment effect is not fully apparent until after 5 to 10 weeks, Combination with behavioral exposure treatment is desirable and treatment should be prolonged, probably over several years. With the exception of dental problems from the reduced production of saliva, which can be avoided by careful mouth hygiene, no serious long-term side effects have been described. In summary, there is considerable evidence that heterocyclic antidepressants, especially clomipramine, are useful in some OCD patients and there are case reports of improvement in patients who are not clinically depressed. Heterocyclics are clearly indicated in the depressed OCD patient and may be the drugs of first choice even in nondepressed obsessional patients. Monoamine Oxidase Inhibitors There are no controlled studies using monoamine oxidase inhibitors (MAOI) in OCD patients. As early as 1959, however, there was a report of an open trial of iproniazid producing marked improvement in patients who had obsessive-compulsive symptoms4’; diagnostic criteria and symptoms, however, were not described. In 1969, Annesley46 described a 49-year-old man with anxiety, phobias, and disabling obsessions and compulsive rituals, whose symptoms gradually remitted over a (j-week period after starting phenelzine. At 6-month follow-up, improvement was maintained on 30 mg twice daily. Prior treatment failures included behavior therapy, electroconvulsive therapy, insulin therapy, phenothiazines, tricyclic antidepressants, benzodiazepines, and bilateral rostra1 leucotomy. In 1970, Jain et a1.47 reported a 26-year-old man with anxiety, phobias, and severe disabling obsessive ruminations who responded with a complete loss of symptoms over a 2-week period and was still symptom free at 4-month follow-up. There is one case report where a 48-year-old man with severe obsessive thoughts responded well to combination therapy of thought-stopping plus tranylcypromine.2*48 Rihmer et a1.49 reported a 50-year-old man with agoraphobia and severe anxiety associated with obsessions who responded to the MAO1 nialamide. Jenike et als0-52 reported six more cases where MAO1 produced dramatic improvement and four cases where there was no effect. In contrast to the patients where there was no improvement with MAOI, all of the cases where MAOIs were effective had associated panic attacks or severe anxiety. Affective disease in patients or their families did not predict responsiveness to MAOI. A trial of MAO1 is indicated in OCD patients, especially when phobic anxiety or panic attacks are part of the clinical presentation. Lithium Carbonate A link between manic-depressive illness and obsessive-compulsive disorder has been suggested.9Vs3 Cycling primary obsessive-compulsive symptoms have been
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DISORDERS
253
described, but there are very few reports on the successful use of lithium carbonate in OCD. A double-blind crossover trial of six OCD patients reported lithium was as ineffective as placebo. 54 On the other hand, Forssman and Walinde? described a 35year-old woman who stopped a long-standing washing compulsion when treated with lithium carbonate. They gave no information about the course of the illness, family history, or prior treatments. Van Putten and Sanders56 reported a 25-year-old man with partial remission of symptoms after the administration of lithium carbonate which they had tried because the patient’s 27-year-old brother had a lithium-sensitive psychosis. Their patient had become virtually incapacitated by an obsessional disorder that started together with a facial tic at the age of 18. Prior treatments included psychoanalytically oriented psychotherapy and intermittent use of phenothiazines. At 16-months follow-up on lithium carbonate, he remained obsessive, but the obsessions were lacking in emotional force and no longer dominated his life. The patient’s brother, mentioned above, had been diagnosed as schizophrenic. In retrospect, the brother had shown pressured speech and euphoric mood, but this was attributed to marijuana smoking. In the patient himself, the onset of the OCD in conjunction with the facial tic raises the distinct possibility that he may have been suffering from a variant of Tourette disorder which may be related to OCD.’ A case report of a patient with lithium-responsive OCD was recently published.53 This patient clearly had the essential features of OCD, including recurrent obsessions and compulsions which she viewed as senseless. Obsessive-compulsive behaviors are sometimes found in patients suffering from bipolar affective disorder.‘*” A recent report of two patients who met Diagnostic and Statistical Manual of Mental Disorders (ed 3) (DSM-III) criteria for both bipolar disorder and OCD who were treated with a combination of therapist-aided and self-administered exposure and response prevention, demonstrated that behavior therapy was effective only after their affective disorder was effectively controlled with lithium and neuroleptics. ” This finding is consistent with the observation that severely depressed patients with concomitant OCD frequently do not respond to behavior therapy.58 Rasmussens9 reported a 22-year-old woman with classical OCD who did not respond to clomipramine alone, but who improved greatly a few days after lithium carbonate was added with a stabilized blood level of 0.9 mEq/L. Whether or not lithium augmentation of other tricyclic antidepressants or MAOIs for obsessivecompulsive symptoms is helpful remains to be tested. In summary, a trial of lithium carbonate should be given to any patient who fails to respond to tricyclic antidepressants and MAOIs. In addition, those with a personal or family history of bipolar illness may be especially likely to respond. It is particularly important to control bipolar illness pharmacologically before proceeding with behavior therapy in patients with both disorders.
Antipsychotic Agents Under stress, the severe that prompted clinicians common to have patients neuroleptics, even though
obsessional patient may appear psychotic, an observation to attempt amelioration with neuroleptic drugs.60*6’ It is referred to our OCD clinic who have been on long-term there is no evidence that they have been of any help. A
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JENIKE, BAER, AND MlNlCHlELLO
small percentage of these patients suffer from moderate irreversible tardive dyskinesia. There are a few case reports of success with these agents. AltschuleP2 reported that one of three obsessionals responded to trifluoperazine and Dally63 cited a case that responded well to perphenazine. 0’Regan,6”~6’ noting the similarities between Tourette disorder and OCD, reported two patients with almost complete resolution of compulsions wtihout amelioration of obsessions after haloperidol. Shortly after O’Regan’s reports, Hussain and Ahad” reported that they tried haloperidol on three patients with absolutely no response. Rivers-Buckeley and Hollender64 reported a 21 -year-old male college student who experienced a rapid, dramatic, and sustained response to loxapine. The authors of this report noted that this patient was at the more severe end of the spectrum of OCD and that he exhibited a number of schizophrenic features. It may be that the schizophrenic features were partly, or even substantially, responsible for his favorable response to loxapine. In view of the absence of data on the efficacy of these agents and the frequency of toxic side effects, their use can only be recommended for more acutely disturbed obsessional patients. When these agents are tried, patients should be evaluated at regular intervals of not more than one month and neuroleptic discontinued if there is no definite improvement.
Anxiolytic Agents There are no good studies addressing the use of anxiolytic drugs in OCD patients. The literature contains a few anecdotal reports of success and a couple of controlled trials where outcome criteria were unclear. Breitner (quoted in Jenike et al.‘) reported seven patients who all improved with chlordiazepoxide in doses up to I50 mg/d, and Hussain and Ahad” reported one patient with an excellent response to 100 mg/d. Venkoba Rao (quoted in Jenike et al.‘) compared eight patients taking diazepam to eight on placebo and reported that all eight improved with diazepam compared to none with placebo. Bethume (quoted in Jenike et a1.2) also reported complete relief in one patient with diazepam. Orvin (quoted in Jenike et al.‘) compared oxazepam to chlordiazepoxide in a double-blind, placebo-controlled, crossover trial and reported that 68% of 24 patients improved with oxazepam compared to 13% improvement rate with chlordiazepoxide. Burrel et al. (quoted in Jenike et al.*) reported that over two-thirds of 95 patients improved with bromazepam. These reports are old and diagnostic criteria were not well defined. Two recent reports with a total of five patients indicate that alprazolam may be of benefit to some OCD patients.65,66 Since alprazolam has been reported to be successful in the treatment of anxious and depressed patients,67 its success may be partly due to its antidepressant effects. As noted earlier, a link between OCD, anxiety disorders, and response to MAOIs has been reported. In addition, Insel et a1.68 suggest a link between OCD and affective illness. They reported that EEG-monitored sleep abnormalities in patients with OCD resembled those of age-matched depressed patients. Alternatively, alprazolam may act as an anticonvulsant. In a recent study,67 four of 12 patients with longstanding OCD had EEG abnormalities over the temporal
OBSESSIVE-COMPULSIVE
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lobes consistent with complex partial seizures. All four patients were treated with adequate courses of anticonvulsant medication, but only one partially improved. The authors theorized that longstanding temporal lobe seizures may irreversibly damage brain structures and that perhaps anticonvulsants should be tried early in the course of obsessive-compulsive illness, before such presumed damage could occur. It is difficult to make a strong case for the use of anxiolytic drugs in this disorder on the basis of available data. On the other hand, since the margin of safety with these drugs is high, a trial of anxiolytic agents should be attempted before proceeding to more toxic agents or to invasive procedures. In addition, in patients who are unable to tolerate anxiety produced by exposure and response prevention techniques, these agents may be used temporarily to facilitate behavior therapy. Tryptophan
L-tryptophan is an essential amino acid which has been the subject of clinical psychiatric research for over 20 years and reported from time to time to be useful in depression, mania, schizophrenia, insomnia, and OCD when taken in amounts in excess of the usual human dietary intake of about 1 g/d.69 L-tryptophan is readily absorbed and crosses the blood-brain barrier, but transport is shared with other large neutral amino acids such as leucine, isoleucine, phenylalanine, tyrosine, and valine. The effect of this is that tryptophan given alone elevates both plasma tryptophan and brain serotonin69; however, when an equal amount of the other neutral amino acids are concomitantly given, brain serotonin is not elevated because the other amino acids are shunted into the brain preferentially. Thus, the relative amount of tryptophan as compared to the other amino acids has more effect on brain serotonin levels than does the proportion of free tryptophan in the plasma. Tryptophan is chiefly metabolized by the liver enzyme tryptophan pyrrolase whose activity is induced by tryptophan administration and also by cortisol. Tryptophan pyrrolase activity is reduced both by allopurinol, a drug used to treat gout, and by nicotinic acid or nicotinamide. Pyridoxine (vitamin B6) and ascorbic acid (vitamin C) are cofactors required for the transformation of tryptophan to serotonin. These factors have complicated studies of oral tryptophan in patients with OCD since the cofactors sometimes were given to facilitate production of serotonin, and nicotinamide or allopurinol were sometimes given to inhibit the breakdown of tryptophan. Most work with tryptophan has been done by one group and results have not been replicated. Yaryura-Tobias7’ treated seven patients with tryptophan plus nicotinamide and pyridoxine, and reported good results which were stable at 1 year follow-up. They reportedly treated 294 patients with obsessive-compulsive symptoms with clomipramine plus tryptophan with good results.69’7’ Rasmussen” reported a 38-year-old male with OCD who had a partial response to clomipramine which was dramatically boosted when 6 g/d of L-tryptophan was added. This patient relapsed when tryptophan was stopped and improved again when it was restarted; he continued to do well at 12-month follow-up. Whether tryptophan would boost the antiobsessional effect of other tricyclic antidepressants or MAOIs remains to be determined.
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In summary, although much remains to be done to determine whether tryptophan is an effective treatment for OCD, little is lost by trying this relatively benign agent for a limited time. To be maximally effective, nicotinamide, and probably vitamins B6 and C should also be administered. It is likely that the administration of other large neutral amino acids should also be controlled and not taken in close proximity to doses of tryptophan. Experimental
Therapeutic Agents
Beta-blockers, such as propranolol, have been tried in OCD patients without effect (quoted in Jenike et al.*). Solursh reviewed numerous anecdotal reports that claimed beneficial effects of LSD.72 Anden et a1.73 reported that LSD may mimic serotonin at postsynaptic receptor sites and facilitate its action in the CNS. Later, Brandrup and Vanggaard74 reported one patient with severe OCD treated with weakly injections of LSD for 57 weeks, who was cured and remained symptom free at 13-year follow-up. There is only one report in the literature67 of a patient who had a partial response to antiseizure medication (carbamazepine); this patient had the clinical picture of classical OCD but had an abnormal EEG with “frequent bursts and runs of sharp slowing bilaterally in the frontotemporal areas.” There are no reports of improvement with antiseizure medication where the patient did not have evidence of a seizure disorder. Pacella et a1.75tried four “psychopathic obsessionals” who all had abnormal EEGs on diphenylhydantoin and reported no change in symptoms. Clonidine hydrochloride, a centrally active alpha-adrenergic agonist that reduces noradrenergic activity, has been reported to ameliorate certain symptoms of Tourette disorder.76 Cohen et a1.76reviewed 2 years of a clinical study of 25 Tourette patients with severe illness and noted that clonidine appeared particularly effective in the amelioration of compulsive symptoms, aggressive and behavioral difficulties, and attentional dysfunction. Because of the link between OCD and Tourette disorder, Knesevich77 tried clonidine in a 22-year-old woman with classical OCD with good result. This patient was compelled to ask the same questions repeatedly and also washed her hands for long periods, 20 or more times per day. Her symptoms had previously been refractory to unspecified doses of imipramine, amitriptyline, chlordiazepoxide, diazepam, chlorpromazine, methylphenidate, fluphenazine HCL and decanoate, electroconvulsive therapy, and behavior modification. This patient improved dramatically on clonidine 0.1 mg three times a day. Her case history was unusual in that she experienced asymptomatic periods of up to 18 months during the course of her illness on no medication. We have tried clonidine, in doses up to 1.O mg/d, in two severe OCD patients, neither of whom improved. Insel and Pickar78 performed a double-blind, placebo-controlled trial of naloxone in two patients with OCD. The first patient noted no change after placebo administration, but became acutely absorbed in checking rituals and was unable to reach certainty about the physical relationships of objects in the protocol room while being given naloxone. He had considerable difficulty completing the ratings and this acute exacerbation continued for 24 hours. Similarly, the second patient noted no change with placebo, but became abruptly worse after naloxone with feelings that he could not reach a point of mastery with his intruding thoughts. This preliminary report leads to speculation that opiate agonists may potentially be of assistance in the treatment of patients with OCD. d-Amphetamine has been shown to provide brief but significant relief to patients with severe obsessions and may in fact involve
OBSESSIVE-COMPULSIVE
the opiate system self-stimulation.79
257
DISORDERS
as naloxone
blocks d-amphetamine
increases
DRUG TREATMENT OF PATIENTS WITH OBSESSIVE WITHOUT ASSOCIATED RITUALS
in activation
and
THOUGHTS
Occasional patients present with obsessive intrusive thoughts without any overt rituals. These patients can sometimes be helped with the techniques of thought stopping or imaginal flooding as outlined elsewhere.2 There is a case report where thought stopping in combination with tranylcypromine produced a good response in a 4%year-old obsessive man.48 Thought stopping greatly assisted this patient even after tranylcypromine was discontinued. If these techniques are not helpful, behavior therapy has little to offer in relieving obsessions. Many of these patients, however, respond in dramatic fashion to antidepressant medication, even when they are not concomitantly depressed.8oT8’ Clearly, obsessive ruminations in the context of a depressive illness are likely to improve with adequate treatment of the depression. In our Obsessive-Compulsive Disorders Clinic over the last 2 years, we have seen seven patients with primarily obsessive thoughts. Four of these patients responded dramatically to antidepressant medication even though major depression was not part of the clinical picture. Three of these four patients either had strong family histories of depression or had a first-degree relative who also suffered from obsessional illness. In light of these cases, other patients with primary obsessional disease should be given a trial of these agents. ELECTROCONVULSIVE
THERAPY
Over two thirds of the severe OCD patients who have been referred to our clinic over the past 4 years have had at least one course of electroconvulsive therapy (ECT). Most of these patients did not suffer from major affective disorder and the main reason for administering ECT was for treatment of OCD. Electroconvulsive therapy is generally regarded as not useful in the OCD patient who is not endogenously depressed,3 although scant literature exists concerning the effects of ECT alone on OCD. In a recent review of this subject, Mellman and with other Gormans2 found a few studies reporting that ECT in combination modalities was occasionally associated with clinical improvement. Walter et a1.83 assessed the combined effects of ECT, modified narcosis, and antidepressants on obsessional neurotics. Although, diagnostic criteria were unclear, 40% of their patients improved following combined treatment. The relative effect of each form of treatment separately was obscure. Grimshaw (quoted in Jenike et al.2) studied 100 patients with obsessional symptoms, which were also poorly defined, and concluded that ECT (type unspecified) had little effect on obsessional states. Recent literature suggests a link between depression and OCD. As noted earlier, such as short rapid eye Insel et a1.68 reported similar sleep EEG abnormalities, movement (REM) latency and interrupted sleep, in age-matched patients with OCD and major depression. Some reports also suggest a high rate of dexamethasone nonsuppression, similar to that seen in depressives, in OCD patients (quoted in Jenike et a1.2); it is not clear, however, that the nonsuppressing patients were not also concomitantly depressed. In any event, a number of researchers have theorized that OCD may be a variant of affective illness and as such may be expected to respond to ECT at least some of the time.
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Mellman and Gormans2 report a patient who appeared not to have major depression who improved with a course of ECT after not responding to a number of antidepressants including 12 weeks of 300 mg/d of clomipramine. The patient, a 60-year-old professional, developed OCD at the age of 57 after the death of his wife. He became “obsessed” with the idea that the Internal Revenue Service was going to send him to jail and requested constant reassurance. He had no compulsions and on one occasion had a complete remission of symptoms for 6 weeks on 1 mg/d of haloperidol. On another occasion, he had improved somewhat on a combination of amoxapine plus lithium carbonate, but relapsed within 2 weeks. He had no improvement with desipramine, imipramine, phenelzine, clonidine, thiothixene, or alprazolam. While being tapered off alprazolam, he had a seizure which resulted in some slight improvement in his obsessions. Following this, the authors of this report gave him ten bilateral ECTs spaced every two to three days and noted near-total remission of his symptoms after the third treatment and total resolution by the ninth treatment. The patient became slightly hypomanic and demonstrated increased energy and pressured speech but no psychosis. He was placed on 100 mg of nortriptyline and 1,200 mg of lithium carbonate (level of 0.8 mEq/L) per day for maintenance and remained free of symptoms at lo-months follow-up. Clearly, this patient did have some atypical features including a late onset at the age of 57 and the complete remission with 1 mg of haloperidol; but the response to ECT is of great interest because patients such as this are not uncommon. It is likely that this patient suffered from an underlying treatment resistant depression and not primary OCD; the illness began after the death of his wife and at no time did he have any compulsions. There are no other such reports of success with ECT and there remain no reports of success in patients with classical rituals despite thousands of patients receiving ECT (probably inappropriately) for this disorder each year. PSYCHOSURGERY Since most OCD patients who undergo psychosurgery have very severe illness that has not responded to multiple therapeutic approaches, the results of surgical intervention are impressive.’ The sparcity of published reports is surprising in view of the fact that nearly 50,000 patients in North America alone have undergone various forms of psychosurgery. In 1952, two studies84v85 demonstrated that small lesions in the cingulum produced no change in psychotics, but resulted in much improvement with a few cures in obsessional and anxiety states. Four later studies reported a 50% to 60% improvement rate after small lesions were made in the lower medial quadrant of each frontal lobe.86-89Bernstein et al. 9oreported follow-up of 43 psychiatric patients who had been referred for open bimedial prefrontal lobotomies between 1948 and 1970 and found that the obsessive-compulsive neurotics (N = 27) did much better than schizophrenic patients and that those obsessional patients with phobic symptoms did the best. Of the 27 obsessive-compulsive patients, however, 12 were reported to have postoperative “organic brain symdromes” where patients described themselves as slowed down, tired, lazy, or apathetic. Their data were in accord with an earlier study” where OCD patients with phobic symptoms responded better than OCD patients without such symptoms. Earlier studies concluded that patients who had been ill for more than 5 years86 or 2 years9* before lobotomy had an unfavorable prognosis. In contrast, the series
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described by Bernstein et al. 90showed no correlation between duration of illness and outcome. In fact, the patient who, at the time of surgery, had been ill for the longest time (27 years), had a complete resolution of symptoms and no longer required psychiatric care. They also found no correlation between successful results and the age of the patient at the time of surgery; there were examples of success in all age categories from the late teens to the seventh decade. Two earlier reports,92*93 however, noted that youth was a less favorable prognostic indicator. In 1976, Mitchell-Heggs et a1.94combined the above approaches and surgically made three small lesions in the lower medial quadrant of each frontal lobe and two small lesions in each cingulum and reported that 89% of 27 patients showed definite clinical improvement. They proposed that site-specificity of the lesions was important, rather than total volume of the lesion, in terms of producing a favorable outcome. Another more recent paper describing five patients who underwent modified leukotomy for intractable obsessional illness, reported that all patients were improved at follow-up ranging from 1 to 7 years after surgery.” One was considered to be in “full remission,” three were “much improved,” and one was still symptomatic but “improved.” Symptoms had been present for 6 or more years in all patients, and three had been ill for more than 20 years. All had received adequate trials of more conventional treatments before the leukotomy but had shown little response. The modified leukotomy was performed by severing only the medial 2 to 3 cm of white matter coursing thorugh the anterior cingulate gyrus. Side effects of modern site-specific lesion techniques are rare. Tippin and Henn” found that psychometric testing revealed no adverse postoperative personality changes in their five patients. In fact, IQ and memory quotients improved, probably because of better attentiveness. Bailey et a1.96studied 200 leukotomy patients, 36 of whom had obsessional neurosis and found that mean full-scale IQ rose 13 points following surgery. In another study,97 mean full-scale IQ rose 4 points while memory quotient improved 9 points Mitchell-Heggs et a194also reported that in their patients each of the subscales on the WAIS were increased 6 weeks postoperatively. The most commonly reported surgical complication of leukotomies is postoperative seizures, which occur in about 1% of patients.9’*98’99 Tippin and Henn9’ reviewed the results of six studies of modified leukotwhich included 110 patients with obsessional disease. Nearly 81% omy 88*92,96-99 (N = 89) were at least “improved,” while more than half of those improved were in complete remission. They note that caution is required in interpreting these results because of the variation in follow-up. Generally, there tends to be a progressive improvement with time; thus, some patients who received a low global outcome rating might have received a higher one at a later time. This phenomenon tends to bias the results in a negative direction, however. Since negative results are rarely reported, this body of literature must be interpreted with some caution. Tippin and Henn concluded, however, that collective experience with modern psychosurgery for obsessional illness has not shown it to be a “mutilation of the brain and mind” as some have testified before congress,‘O” but rather a safe and effective treatment for obsessional neurosis that has become debilitating. A patient who has suffered for years with disabling obsessivecompulsive behaviors and not responded to more conventional therapies has a
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reasonable chance of a favorable outcome with relatively few risks. For the patient with disabling OCD, who fails to respond to more conservative treatment, psychosurgery is a viable option. CONCLUSION In those OCD patients who do not have rituals and suffer solely from intrusive thoughts, a trial of antidepressant medication is a reasonable first choice. A wealth of uncontrolled data indicated that these agents are likely to improve the clinical situation of many of these patients even when they do not suffer from clinical depression. In those patients who do not respond, behavior therapy including thought stopping, assertiveness training, and cognitive restructuring may be of assistance in reducing or alleviating symptoms.* Although medications are sometimes of help in treating nondepressed patients with clearcut rituals, the well documented success of behavior therapies in such patients leads us to begin the overwhelming majority of nondepressed and nonpsychotic OCD patients on behavior therapy as soon as possible. The technique of exposure plus response prevention is the mainstay of treatment. In patients with concomitant psychiatric symptoms such as major depression, psychosis, or mania, it is unlikely that behavior therapy will be of help until these symptoms are well controlled pharmacologically. In such cases, initial therapy should be drug oriented and behavior therapy should begin only after other functional illnesses are optimally controlled. Electroconvulsive therapy is unlikely to improve the nondepressed OCD patient, but psychosurgical techniques are often helpful with little risk of side effects. REFERENCES I. lnsel TR (ed): New Findings in Obsessive-Compulsive Disorder. Washington, DC, American Psychiatric, 1984 2. Jenike MA, Baer L, Minichiello WE (eds): Obsessive-Compulsive Disorders: Theory and Management. Littleton, MA, PSG Publishing, 1986 3. American Psychiatric Association: APA Task Force Report No. 14 on Electroconvulsive Therapy. Washington, DC, American Psychiatric Association, 1978 4. Jenike MA: Obsessive-compulsive disorder. Compr Psychiatry 24:99-l 15, 1983 5. Ananth J: Treatment of obsessive compulsive neurosis: Pharmacological approach. Psychosomatics 17:180-184, 1976 6. Insel TR, Murphy DL: The psychopharmacological treatment of obsessive-compulsive disorder. A review. J Clin Psychopharmacol 1:304-311, 1981 7. Goodwin DW, Guze SB, Robins E: Follow-up studeis in obsessional neurosis. Arch Gen Psychiatry 20:182, 1969 8. Vanggaard T: Atypical endogenous depression. Acta Psychiatr Stand 2675-56, 1976 (suppl) 9. Black A: The natural history of obsessional neurosis, in Beech HR (ed): Obsessional States. London, Methuen, 1974 10. Geissman P, Kammerer T: L’imipramine dam la neurose obsessionelle: Etude de 30 cas. Encephale 53:369-382, 1964 11. Angst J, Theobald W: Tofranil. Berne, Switzerland, Verlag, Stamptl and Cie, 1980, pp 11-32 12. Hussain MZ, Ahad A: Treatment of obsessive compulsive neurosis. Can Med Assoc J. 103: 648-650, 1970 13. Turner SM, Hersen M, Bellack AS, et al: Behavioral and pharmacological treatment of obsessive-compulsive disorders. J Nerv Ment Dis 168:651-657, 1980 14. Snyder S: Amitriptyline therapy of obsessive-compulsive neurosis. J Clin Psychiatry 41:286-289, 1980 15. Ananth J, Solyom L, Solyom C, et al: Doxepin in the treatment of obsessive compulsive neurosis. Psychosomatics 16: 185-l 87, 1975
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16. Bauer G, Nowak H: Doexpine ein neues antidepressivum wirkeings-vergfeich mit amitriptyfine. Arzrreunittefforschung 19: 1642-1646, 1969 17. Gross M, Slater E, Roth M (eds): Clinical Psychiatry. Bailfiere Tindaf and Case], 1969 18. Kahn RS, Westenberg HGM, Joffes J: Zimefdine treatment of obsessive-compulsive disorder. Acta Psychiatr Stand 69:259-26 I, 1984 19. Fontaine R, Chouinard G: Antiobsessive effect of fluoxetine. Am J Psychiatry. 142:989, 1985 20. Prasad AJ: Obsessive-compulsive disorder and trazodone. Am J Psychiatry 141:612-613, 1984 21. Lopez-fbor JJ: Intravenous infusions of monochforimipramine: Technique and results, in Proceedings of the 6th International Congress of CINP Taragona, April 1968. Excerpta Medica Foundation Int Congress Series No. 180, Amsterdam, 1969, pp 5 19-52 1 22. Jiminez F: A clinical study of Anafranil in depressive, obsessional and schizophrenic patients. Fof Neuropsiquiat def Sur y este de Esp 3: 189, 1968 23. Grabowski JR: Treatment of severe depression and obsessive depression with G3486. Fofia Med (Pfovdiv) 57:265-270, 1968 24. Fernandez CE, Lopez-Ibor JJ: Monochlorimipramine in the treatment of psychiatric patients resistant to other therapies. Acta Iuso Esp Neurol 26:119-147, 1967 25. Rack PH: Experience with intravenous cfomipramine, in Obsessional States and Their Treatment with Anafranif. Geigy, 1970, pp IO-13 26. Marshall WK, Micev V: Cfomipramine in the treatment of obsessional illness and phobic anxiety states. J Int Med Res f:403-412, 1973 27. Yaryura-Tobias JA, Neziroglu MA, Bergman L: Cfomipramine for obsessive compulsive neurosis: An organic approach. Curr Ther Res 20:541-548, 1976 28. Rapoport J, Elkins R. Mikkefsen, et al: Clinical controlled trial of chforimipramine in adolescents with obsessive-compulsive disorder. Psychopharmacol Bull 3:61-63, 1980 29. Yaryura-Tobias JA, Nezirogfu MS: The action of chlorimipramine in obsessive compulsive neurosis: A pilot study. Current Ther Res 17: I, 1975 30. Waxman D: A clinical trial of clomipramine and diazepam in the treatment of phobic and obsessional illness. J Int Med Res 5:99-f 10, 1977 (suppf 5) 31. Coombe PD: Cfomipramine and severe obsessive-compulsive neurosis. Aust NZ J Psychiatry 16:293-297, 1982 32. Wyndowe J, Sofyom L, Ananth J: Anafranif in obsessive compulsive neurosis. Curr Ther Res 18:6f 1-617, 1975 33. Capstick N: Clinical experience in the treatment of obsessional states. J Int Med Res 5:71, 1977 (suppf 5) 34. Ananth J, Sofyom L, Bryntwick Am J Psychiatry 136:700-720, 1979
S, et al: Cfomipramine
therapy
for obsessive compulsive
neurosis.
35. Stroebel CF. Szarek BL. Gfueck BS: Use of cfomipramine in treatment of obsessive-compulsive symptomatology. J Cfin Psychopharmacof 4:98-100, I984 36. Carey RJ, Baer L, Jenike MA, et al: MMPI correlates of obsessive-compulsive disorder. J Cfin Psychiatry 47:371-372, 1986 37. Thoren P, Asberg M, Cronhofm B, et al: Cfomipramine treatment of obsessive compulsive disorder. I. A controlled clinical trial. Arch Gen Psychiatry 37: 128 I- 1285, 1980 38. Thoren P, Asberg M, Cronhofm B, et al: Cfomipramine treatment of obsessive-compulsive disorder. II. Arch Gen Psychiatry 37: 1286- 1294, 1980 39. Cooper J: The Leyton obsessional inventory. Psychof Med 1:48-64, 1970 40. Marks TM. Stern RS, Mawson D, et al. Cfomipramine and exposure for obsessive compulsive rituals. Br. J Psychiatry 136:1-25, 1980 41. Montgomery SA: Cfomipramine in obsessional neurosis: A placebo controlled trial. Pharm Med f:f89-192, 1980 42. Inset TR, Murphy DL, Cohen RM, et al: Obsessive-compulsive disorder: A double-blind trial of cfomipramine and cforgyline. Arch Gen Psychiatry 40:605-612, 1983 43. Ananth J, Pecknofd JC, van den Steen N, et al: Double-blind study of clomipramine and amitriptyfine in obsessive neurosis. Prog Neuropsychopharmacof 5:257-262, 198 1 44. Asberg M, Thoren P, Bertifsson L: Psychopharmacologic treatment of obsessive-compulsive disorder. Cfomipramine treatment of obsessive disorder-biochemical and clinical aspects. Psychopharmacof Buff 18:13-21, 1982 45. Joel SW: Twenty month study of iproniazid therapy. Dis Nerv Syst 20:1-4, 1959 46. Annesley PT: Nardif response in a chronic obsessive compulsive. Br J Psychiatry 115:748, 1969
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47. Jain VK, Swinson RP, Thomas JE: Phenelzine in obsessional neurosis. Br J Psychiatry 117:237-238, 1970 48. Swinson RP: Response to tranylcypromine and thought stopping in obsessional disorder. Br J Psychiatry 144:425-427, 1984 49. Rihmer Z, Szantok, Arato M, et al: Response of phobic disorders with obsessive symptoms to MAO inhibitors. Am J Psychiatry 139:1374, 1982 50. Jenike MA: Rapid response of severe obsessive compulsive disorder to tranylcypromine. Am J Psychiatry 138: 1249-1250, 1981 51. Jenike MA: Use of monoamine oxidase inhibitors in obsessive compulsive disorder. Br J Psychiatry 140:159, 1982 52. Jenike MA, Surman OS, Cassem NH, et al: Monoamine oxidase inhibitors in obsessivecompulsive disorder. J Clin Psychiatry 44: 13 1-l 32, 1983 53. Stern TA, Jenike MA: Treatment of obsessive-compulsive disorder with lithium carbonate. Psychosomatics 24:671-673, 1983 54. Geisler A, Schou M: Lithium ved tvangsneuroser. Nordisk Psychiatrisk Tidsskeift 23:493-495, 1970 55. Forssman H, Walinder J: Lithium treatment of atypical indication. Acta Psychiatr Stand 207:34-40, 1969 (suppl) 56. Van Putten T, Sander DG: Lithium in treatment failures. J Net-v Ment Dis 161:255-264, 1975 57. Baer L, Minichiello WE, Jenike MA: Behavioral treatment of obsessive-compulsive disorder with concomitant bipolar affective disorder. Am J Psychiatry 142:358-360, 1985 58. Foa EB: Failure in treating obsessive-compulsives. Behav Res Ther 17:169-176, 1979 59. Rasmussen SA: Lithium and tryptophan augmentation in clomipramine-resistant obsessivecompulsive disorder. Am J Psychiatry 141:1283-1285, 1984 60. O’Regan B: Treatment of obsessive compulsive neurosis with haloperidol. Can Med Assoc J 103:167-168, 1970 61. O’Regan B: Treatment of obsessive compulsive disorder. Can Med Assoc J 103:648-650, 1970 62. Altschuler M: Massive doses of trifluoperazine in the treatment of compulsive rituals. Am J Psychiatry 119:367, 1962 63. Dally P: Chemotherapy of Psychiatric Disorders. London, Logos, 1968 64. Rivers-Buckley N, Hollender MH: Successful treatment of obsessive-compulsive disorder with loxapine. Am J Psychiatry 139: 1345-l 346, 1982 65. Tesar GE, Jenike MA: Alprazolam as treatment for a case of obsessive-compulsive disorder. Am J Psychiatry 141:689-690, 1984 66. Tollefson G: Alprazolam in the treatment of obsessive symptoms. J Clin Psychopharmacol 5:39-42, 1985 67. Jenike MA, Brotman AW: The EEG in obsessive-compulsive disorder. J Clin Psychiatry 45:122-124, 1984 68. Insel TR, Gillin JC, Moore A, et al: The sleep of patients with obsessive-compulsive disorder. Arch Gen Psychiatry 39:1372-1377, 1982 69. Cole JO, Hartmann E, Brigham P: L-tryptophan: Clinical studies. McLean Hosp J 5:37-71, 1980 70. Yaryura-Tobias JA, Neziroglu F, Bhagavan H: Obsessive-compulsive disorders: A serotonergic hypothesis, in Saletu B, Berner P, Hollister L (eds): Neuropsychopharmacology: Proceedings of the 11 th Congress of the CINP. Oxford, England, Pergamon, 1979, pp 117-125 71. Yaryura-Tobias JA, Bhagavan HN: L-Tryptophan in obsessive-compulsive disorders. Am J Psychiatry 134:1298-1299, 1977 72. Solursh LP: The use of LSD-25 in psychotherapy: An evaluation. Int J Neuropsychiatry 2:661-656, 1966 73. Anden NE, Corrod H, Fuye K, et al: Evidence for a central 5-hydroxytryptamine receptor stimulation by LSD. Br J Pharmacol 34:1-71, 1968 74. Brandrup E, Vanggaard T: LSD treatment in a severe case of compulsive neurosis. Acta Psychiatr Stand 55:127-141, 1977 75. Pacella BL, Polatin P, Nagler SH: Clinical and EEG studies in obsessive compulsive states. Am J Psychiatry 100:830, 1944 76. Cohen DJ, Detlor J, Young G, et al: Clonidine ameliorates Gilles de al Tourette syndrome. Arch Gen Psychiatry 37:1350-1357, 1980
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77. Knesevich JW: Successful treatment of obsessive compulsive disorder with clonidine hydrochloride. Am J Psychiatry 139:394-395, 1982 78. Insel TR, Pickar D: Naloxone administration in obsessive-compulsive disorder: Report of two cases. Am J Psychiatry. 140:1219-1220, 1983 79. Insel TR, Hamilton J, Guttmacher L, et al: d-Amphetamine in obsessive compulsive disorder. Psychopharmacology (Berlin) 80:231-235, 1983 80. Jenike MA, Armentano M, Baer L: Disabling obsessive thoughts responsive to antidepressants. J Clin Psychopharmacol7:33-35, 1987 81. Jenike MA, Pato C: Disabling fear of AIDS responsive to imipramine. Psychosomatics. 27:143144, 1986 82. Mellman LA, Gorman JM: Successful treatment of obsessive-compulsive disorder with ECT. Am J Psychiatry 141596-597, 1984 83. Walter CJ, Mitchell-Heggs N, Sargant W: Modified narcosis, ECT, and antidepressant drugs: A review of technique and immediate outcome. Br J Psychiatry 120:651-652, 1972 84. Whitty CWM, Duffield JE, Tow PM, et al: Anterior cingulectomy in the treatment of mental disease. Lancet 262:475-481, 1952 85. LeBeau J: The cingular and precingular areas in psychosurgery (agitated behavior, obsessive compulsive states, epilepsy). Acta Psychiatr Neurol Stand 27:305-316, 1952 86. Sykes M, Tredgold R: Restricted orbital undercutting: A study of its effects on 350 patients over the ten years 195 l-60. Br J Psychiatry 110:609-640, 1964 87. Tan E, Marks I, Marset P: Bimedial leucotomy in obsessive-compulsive neurosis: A controlled serial enquiry. Br J Psychiatry 118: 115- 164, 197 1 88. Kelly DHW, Walter C, Mitchell-Heggs N, et al: Modified leucotomy assessed clinically, physiologically and psychologically at six weeks and eighteen months. Br J Psychiatry 120:19-29, 1972 89. Bridges PK, Goktepe EO, Moratos J: A comparative review of patients with obsessional neurosis and depression treated by psychosurgery. Br J Psychiatry 123:663-674, 1974 90. Bernstein IC, Callahan WA, Jaranson JM: Lobotomy in private practice. Arch Gen Psychiatry. 32:1041-1047, 1975 91. Baker EFW, Young MP, Guald DM, et al: A new look at bimedial pre-frontal leukotomy. Can Med Assoc J 102:37-41, 1970 92. Post F, Rees WL, Schurr PH: An evaluation of bimedial leucotomy. Br J Psychiatry 114:12231246,1968 93. Sargent W: The present indications for leucotomy. Lancet 1: 1197- 1200, 1962 94. Mitchell-Heggs N, Kelly D, Richardson A: Stereotactic limbic leucotomy: A follow-up at 16 months. Br J Psychiatry 128:226-240, 1976 95. Tippin J, Henn FA: Modified leukotomy in the treatment of intractable obsessional neurosis. Am J Psychiatry 139:1601-1603, 1982 96. Bailey HR, Dowling JL, Davies E: Cingulotomy and related procedures for severe depressive illness: Studies in depression, IV, in Sweet WH, Obrador S, Martin-Rodriguez, JG (eds): Neurosurgical Treatment in Pain and Epilepsy. Baltimore, University Park, 1975 97. Smith JS, Kilom LG. Cochrane N, et al: A prospective evaluation of open pre-frontal leucotomy. Med J Aust 1:731-735, 1976 98. Storm-Olsen R, Carlisle S: Bi-frontal stereotactic tractotomy: A follow-up study of it effects in 2lOpatients. Br J Psychiatry 118:141-154. 1971 99. Birley JLT: Modified frontal leucotomy: A review of 106 cases. Br J Psychiatry 1 lo:21 1-221, 1964 100. Breggin P: The return of lobotomy and psychosurgery. Congressional Record, Feb. 24, 1972, pp E1602-El612
Treatments for Obsessive-Compulsive Disorders
Michael A. Jenike, Lee Baer, and William E. Minichiello Patients
with
physicians
obsessive-compulsive
other than psychiatrists. abundance
disorder
to treat
and the
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in all cases. Patients frequently
of therapeutic
approaches
and dynamic
structured
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particularly
with compulsive
rituals. Likewise,
the treatment
electroconvulsive 0 1987
yet psychodynamic
of OCD. There are, however, of these
patients.
therapy,
We
and
related
available
electroconvulsive
therapy
a number of modalities somatic
treatments
present
that
therapy
none
is clearly
if they are loosely fares
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better,
as useful in
that may be extremely of OCD
to
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Behavior
often
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seemingly
treatments,
the symptoms.
review
syndromes
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present with symptoms
symbolism
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meaning;
(OCD)
These patients
helpful in
medications,
and psychosurgery.
by Grune & Stratton,
Inc.
PHARMACOLOGIC
TREATMENTS
A WEALTH OF ANECDOTAL EVIDENCE and a few controlled underscore the effectiveness of pharmacotherapy in some patients.lm6
studies
Heterocyclic Antidepressants
A link between depression and OCD is frequently noted.‘,2*5-gNumerous antidepressants have been reported to be useful, including imipramine,‘@13 amitriptyline,‘2-‘4doxepin,‘5,‘6 desipramine,” zimelidine,” fluoxetine,lg and trazodone.*’ All of these reports, however, involve a small number of patients without controls. Responses were unpredictable and not clearly related to depression; there was, however, dramatic improvement in some cases. Clomipramine, a tricyclic antidepressant not yet available in the United States, may have some specific antiobsessional properties. In 1969 Lopez-Ibor21 gave clomipramine intravenously and reported improvement over two to five days in 13 of 16 OCD patients; others reported similar findings.‘*-*’ Others attempted uncontrolled trials with oral clomipramine with mixed results. Some reported little improvement” while others reported a good response.2g‘33 In a 4-week randomized double-blind trial, Ananth et al34compared clomipramine to amitriptyline in 20 severe OCD patients. Clomipramine, but not amitriptyline, produced statistically significant improvement in obsessive symptoms, depression, and anxiety. Stroebel et al.35 studied oral clomipramine (maximum dose = 300 mg/d) in an open trial in 50 patients with various diagnoses who all had prominent obsessivecompulsive symptoms and reported that the overall reduction in obsessive symptoms was 60%. Fifteen patients with a primary diagnosis of OCD had an 80% success From the Obsessive-Compulsive Disorders Clinic and Research Unit at Massachusetts General Hospital, Boston. Address reprint requests to Michael Jenike. M.D., Massachusetts General Hospital, Department of Psychiatry, Buljinch 3. Fruit St, Boston, MA 02114. 0 1987 by Grune & Stratton, Inc. OOIO-440X/87/2803-0007$03.00/0
250
Comprehensive
Psychiatry,
Vol. 28,
No. 3 (May/June),
1987:
pp 250-263
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rate, while 17 schizophrenic patients had only a 41% success rate. In only five patients, however, was there a complete remission. Twenty-five of the 30 successfully treated patients (83%) had previously been treated with adequate doses of other antidepressants for an average of 10 months without improvement in obsessive-compulsive symptoms but with improvement in depression. Unfortunately, diagnostic criteria were not outlined in this report and it has been reported that severe obsessive-compulsive patients are frequently mislabeled schizophrenic.36 150 mg of nortriptyline, and Thoren et a1.37,38compared 150 mg of clomipramine, placebo in 24 patients who were distributed among the three groups. Even with this relatively small number, significant change was noted on an obsessive-compulsive scale. On this scale, the clomipramine group showed 42% improvement, the nortriptyline group 21% and the placebo group was unchanged. The clomipramineplacebo difference was statistically significant (P = .05). After a 5-week, doubleblind trial, 22 of the patients were given an open trial of clomipramine and behavior therapy during which 50% of the patients improved, including three patients who failed to respond to nortriptyline. This study suggested a substantial clomipramine effect; however, clomipramine did not produce an effect on either the Leyton Obsessional Inventory,39 a standard scale for evaluating the severity of obsessional symptoms, or on social functioning scales. Thoren et a1.,38 in an attempt to obtain a neurochemical correlate to clinical improvement of symptoms, measured spinal fluid concentration of monoamine metabolites before and during treatment with clomipramine, nortriptyline, and placebo. Nortriptyline produced a reduction in methoxyhydroxyphenylethylene glycol (MHPG), clomipramine reduced both MHPG and 5-HIAA, and placebo treatment did not change either. The change in 5-HIAA, but not that in MHPG, appeared to be important for the treatment outcome; there was a significant correlation between reduction in spinal 5-HIAA and effect on the two central OCD symptoms, rituals and obsessive thoughts. Greater symptom reduction with clomipramine in the OCD patients was associated with a more pronounced lowering of 5-HIAA. Marks et a1.40 later compared clomipramine to placebo in 47 outpatients in a controlled study and found modest yet significant improvement in self-rating scales, but no change in observer ratings in the clomipramine group after a 4-week study period. All patients were admitted to the hospital for behavior therapy after the initial 4-week evaluations with the active drug or placebo condition continued. After intensive behavior therapy, all ratings of compulsions and mood showed significantly greater improvement in patients on clomipramine compared to those on placebo. In those patients who were not depressed prior to the study, however, the investigators were unable to show any benefit of clomipramine over placebo and concluded that clomipramine is useful only in OCD patients with concomitant depressed mood. Three other carefully controlled double-blind studies of clomipramine34~4’*42 indicate that clomipramine is more effective than placebo in reducing obsessional symptoms. Insel’ combined data from these three studies and those of Thoren et al. 37.38and Marks et a1.40 and found that of 64 OCD patients treated with clomipramine, approximately two thirds improved significantly as measured by blind clinical rating scales. Also, clomipramine was more effective than the MAO
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inhibitor clorgyline4* and possibly more effective than amitriptyline.43 Two of the studies3’14* Indicated that clomipramine helped pure obsessionals as well as ritualizers. In a review article, Asberg et a1.44summarized the data on the use of clomipramine in OCD and formulated tentative guidelines for its clinical use. In patients with long-standing, severe obsessive-compulsive illness who also are dysphoric, clomipramine appears to be the drug of choice. It can also be tried in patients who are not dysphoric, but the effect is not equally convincing. Treatment effect is not fully apparent until after 5 to 10 weeks, Combination with behavioral exposure treatment is desirable and treatment should be prolonged, probably over several years. With the exception of dental problems from the reduced production of saliva, which can be avoided by careful mouth hygiene, no serious long-term side effects have been described. In summary, there is considerable evidence that heterocyclic antidepressants, especially clomipramine, are useful in some OCD patients and there are case reports of improvement in patients who are not clinically depressed. Heterocyclics are clearly indicated in the depressed OCD patient and may be the drugs of first choice even in nondepressed obsessional patients. Monoamine Oxidase Inhibitors There are no controlled studies using monoamine oxidase inhibitors (MAOI) in OCD patients. As early as 1959, however, there was a report of an open trial of iproniazid producing marked improvement in patients who had obsessive-compulsive symptoms4’; diagnostic criteria and symptoms, however, were not described. In 1969, Annesley46 described a 49-year-old man with anxiety, phobias, and disabling obsessions and compulsive rituals, whose symptoms gradually remitted over a (j-week period after starting phenelzine. At 6-month follow-up, improvement was maintained on 30 mg twice daily. Prior treatment failures included behavior therapy, electroconvulsive therapy, insulin therapy, phenothiazines, tricyclic antidepressants, benzodiazepines, and bilateral rostra1 leucotomy. In 1970, Jain et a1.47 reported a 26-year-old man with anxiety, phobias, and severe disabling obsessive ruminations who responded with a complete loss of symptoms over a 2-week period and was still symptom free at 4-month follow-up. There is one case report where a 48-year-old man with severe obsessive thoughts responded well to combination therapy of thought-stopping plus tranylcypromine.2*48 Rihmer et a1.49 reported a 50-year-old man with agoraphobia and severe anxiety associated with obsessions who responded to the MAO1 nialamide. Jenike et als0-52 reported six more cases where MAO1 produced dramatic improvement and four cases where there was no effect. In contrast to the patients where there was no improvement with MAOI, all of the cases where MAOIs were effective had associated panic attacks or severe anxiety. Affective disease in patients or their families did not predict responsiveness to MAOI. A trial of MAO1 is indicated in OCD patients, especially when phobic anxiety or panic attacks are part of the clinical presentation. Lithium Carbonate A link between manic-depressive illness and obsessive-compulsive disorder has been suggested.9Vs3 Cycling primary obsessive-compulsive symptoms have been
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described, but there are very few reports on the successful use of lithium carbonate in OCD. A double-blind crossover trial of six OCD patients reported lithium was as ineffective as placebo. 54 On the other hand, Forssman and Walinde? described a 35year-old woman who stopped a long-standing washing compulsion when treated with lithium carbonate. They gave no information about the course of the illness, family history, or prior treatments. Van Putten and Sanders56 reported a 25-year-old man with partial remission of symptoms after the administration of lithium carbonate which they had tried because the patient’s 27-year-old brother had a lithium-sensitive psychosis. Their patient had become virtually incapacitated by an obsessional disorder that started together with a facial tic at the age of 18. Prior treatments included psychoanalytically oriented psychotherapy and intermittent use of phenothiazines. At 16-months follow-up on lithium carbonate, he remained obsessive, but the obsessions were lacking in emotional force and no longer dominated his life. The patient’s brother, mentioned above, had been diagnosed as schizophrenic. In retrospect, the brother had shown pressured speech and euphoric mood, but this was attributed to marijuana smoking. In the patient himself, the onset of the OCD in conjunction with the facial tic raises the distinct possibility that he may have been suffering from a variant of Tourette disorder which may be related to OCD.’ A case report of a patient with lithium-responsive OCD was recently published.53 This patient clearly had the essential features of OCD, including recurrent obsessions and compulsions which she viewed as senseless. Obsessive-compulsive behaviors are sometimes found in patients suffering from bipolar affective disorder.‘*” A recent report of two patients who met Diagnostic and Statistical Manual of Mental Disorders (ed 3) (DSM-III) criteria for both bipolar disorder and OCD who were treated with a combination of therapist-aided and self-administered exposure and response prevention, demonstrated that behavior therapy was effective only after their affective disorder was effectively controlled with lithium and neuroleptics. ” This finding is consistent with the observation that severely depressed patients with concomitant OCD frequently do not respond to behavior therapy.58 Rasmussens9 reported a 22-year-old woman with classical OCD who did not respond to clomipramine alone, but who improved greatly a few days after lithium carbonate was added with a stabilized blood level of 0.9 mEq/L. Whether or not lithium augmentation of other tricyclic antidepressants or MAOIs for obsessivecompulsive symptoms is helpful remains to be tested. In summary, a trial of lithium carbonate should be given to any patient who fails to respond to tricyclic antidepressants and MAOIs. In addition, those with a personal or family history of bipolar illness may be especially likely to respond. It is particularly important to control bipolar illness pharmacologically before proceeding with behavior therapy in patients with both disorders.
Antipsychotic Agents Under stress, the severe that prompted clinicians common to have patients neuroleptics, even though
obsessional patient may appear psychotic, an observation to attempt amelioration with neuroleptic drugs.60*6’ It is referred to our OCD clinic who have been on long-term there is no evidence that they have been of any help. A
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small percentage of these patients suffer from moderate irreversible tardive dyskinesia. There are a few case reports of success with these agents. AltschuleP2 reported that one of three obsessionals responded to trifluoperazine and Dally63 cited a case that responded well to perphenazine. 0’Regan,6”~6’ noting the similarities between Tourette disorder and OCD, reported two patients with almost complete resolution of compulsions wtihout amelioration of obsessions after haloperidol. Shortly after O’Regan’s reports, Hussain and Ahad” reported that they tried haloperidol on three patients with absolutely no response. Rivers-Buckeley and Hollender64 reported a 21 -year-old male college student who experienced a rapid, dramatic, and sustained response to loxapine. The authors of this report noted that this patient was at the more severe end of the spectrum of OCD and that he exhibited a number of schizophrenic features. It may be that the schizophrenic features were partly, or even substantially, responsible for his favorable response to loxapine. In view of the absence of data on the efficacy of these agents and the frequency of toxic side effects, their use can only be recommended for more acutely disturbed obsessional patients. When these agents are tried, patients should be evaluated at regular intervals of not more than one month and neuroleptic discontinued if there is no definite improvement.
Anxiolytic Agents There are no good studies addressing the use of anxiolytic drugs in OCD patients. The literature contains a few anecdotal reports of success and a couple of controlled trials where outcome criteria were unclear. Breitner (quoted in Jenike et al.‘) reported seven patients who all improved with chlordiazepoxide in doses up to I50 mg/d, and Hussain and Ahad” reported one patient with an excellent response to 100 mg/d. Venkoba Rao (quoted in Jenike et al.‘) compared eight patients taking diazepam to eight on placebo and reported that all eight improved with diazepam compared to none with placebo. Bethume (quoted in Jenike et a1.2) also reported complete relief in one patient with diazepam. Orvin (quoted in Jenike et al.‘) compared oxazepam to chlordiazepoxide in a double-blind, placebo-controlled, crossover trial and reported that 68% of 24 patients improved with oxazepam compared to 13% improvement rate with chlordiazepoxide. Burrel et al. (quoted in Jenike et al.*) reported that over two-thirds of 95 patients improved with bromazepam. These reports are old and diagnostic criteria were not well defined. Two recent reports with a total of five patients indicate that alprazolam may be of benefit to some OCD patients.65,66 Since alprazolam has been reported to be successful in the treatment of anxious and depressed patients,67 its success may be partly due to its antidepressant effects. As noted earlier, a link between OCD, anxiety disorders, and response to MAOIs has been reported. In addition, Insel et a1.68 suggest a link between OCD and affective illness. They reported that EEG-monitored sleep abnormalities in patients with OCD resembled those of age-matched depressed patients. Alternatively, alprazolam may act as an anticonvulsant. In a recent study,67 four of 12 patients with longstanding OCD had EEG abnormalities over the temporal
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lobes consistent with complex partial seizures. All four patients were treated with adequate courses of anticonvulsant medication, but only one partially improved. The authors theorized that longstanding temporal lobe seizures may irreversibly damage brain structures and that perhaps anticonvulsants should be tried early in the course of obsessive-compulsive illness, before such presumed damage could occur. It is difficult to make a strong case for the use of anxiolytic drugs in this disorder on the basis of available data. On the other hand, since the margin of safety with these drugs is high, a trial of anxiolytic agents should be attempted before proceeding to more toxic agents or to invasive procedures. In addition, in patients who are unable to tolerate anxiety produced by exposure and response prevention techniques, these agents may be used temporarily to facilitate behavior therapy. Tryptophan
L-tryptophan is an essential amino acid which has been the subject of clinical psychiatric research for over 20 years and reported from time to time to be useful in depression, mania, schizophrenia, insomnia, and OCD when taken in amounts in excess of the usual human dietary intake of about 1 g/d.69 L-tryptophan is readily absorbed and crosses the blood-brain barrier, but transport is shared with other large neutral amino acids such as leucine, isoleucine, phenylalanine, tyrosine, and valine. The effect of this is that tryptophan given alone elevates both plasma tryptophan and brain serotonin69; however, when an equal amount of the other neutral amino acids are concomitantly given, brain serotonin is not elevated because the other amino acids are shunted into the brain preferentially. Thus, the relative amount of tryptophan as compared to the other amino acids has more effect on brain serotonin levels than does the proportion of free tryptophan in the plasma. Tryptophan is chiefly metabolized by the liver enzyme tryptophan pyrrolase whose activity is induced by tryptophan administration and also by cortisol. Tryptophan pyrrolase activity is reduced both by allopurinol, a drug used to treat gout, and by nicotinic acid or nicotinamide. Pyridoxine (vitamin B6) and ascorbic acid (vitamin C) are cofactors required for the transformation of tryptophan to serotonin. These factors have complicated studies of oral tryptophan in patients with OCD since the cofactors sometimes were given to facilitate production of serotonin, and nicotinamide or allopurinol were sometimes given to inhibit the breakdown of tryptophan. Most work with tryptophan has been done by one group and results have not been replicated. Yaryura-Tobias7’ treated seven patients with tryptophan plus nicotinamide and pyridoxine, and reported good results which were stable at 1 year follow-up. They reportedly treated 294 patients with obsessive-compulsive symptoms with clomipramine plus tryptophan with good results.69’7’ Rasmussen” reported a 38-year-old male with OCD who had a partial response to clomipramine which was dramatically boosted when 6 g/d of L-tryptophan was added. This patient relapsed when tryptophan was stopped and improved again when it was restarted; he continued to do well at 12-month follow-up. Whether tryptophan would boost the antiobsessional effect of other tricyclic antidepressants or MAOIs remains to be determined.
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In summary, although much remains to be done to determine whether tryptophan is an effective treatment for OCD, little is lost by trying this relatively benign agent for a limited time. To be maximally effective, nicotinamide, and probably vitamins B6 and C should also be administered. It is likely that the administration of other large neutral amino acids should also be controlled and not taken in close proximity to doses of tryptophan. Experimental
Therapeutic Agents
Beta-blockers, such as propranolol, have been tried in OCD patients without effect (quoted in Jenike et al.*). Solursh reviewed numerous anecdotal reports that claimed beneficial effects of LSD.72 Anden et a1.73 reported that LSD may mimic serotonin at postsynaptic receptor sites and facilitate its action in the CNS. Later, Brandrup and Vanggaard74 reported one patient with severe OCD treated with weakly injections of LSD for 57 weeks, who was cured and remained symptom free at 13-year follow-up. There is only one report in the literature67 of a patient who had a partial response to antiseizure medication (carbamazepine); this patient had the clinical picture of classical OCD but had an abnormal EEG with “frequent bursts and runs of sharp slowing bilaterally in the frontotemporal areas.” There are no reports of improvement with antiseizure medication where the patient did not have evidence of a seizure disorder. Pacella et a1.75tried four “psychopathic obsessionals” who all had abnormal EEGs on diphenylhydantoin and reported no change in symptoms. Clonidine hydrochloride, a centrally active alpha-adrenergic agonist that reduces noradrenergic activity, has been reported to ameliorate certain symptoms of Tourette disorder.76 Cohen et a1.76reviewed 2 years of a clinical study of 25 Tourette patients with severe illness and noted that clonidine appeared particularly effective in the amelioration of compulsive symptoms, aggressive and behavioral difficulties, and attentional dysfunction. Because of the link between OCD and Tourette disorder, Knesevich77 tried clonidine in a 22-year-old woman with classical OCD with good result. This patient was compelled to ask the same questions repeatedly and also washed her hands for long periods, 20 or more times per day. Her symptoms had previously been refractory to unspecified doses of imipramine, amitriptyline, chlordiazepoxide, diazepam, chlorpromazine, methylphenidate, fluphenazine HCL and decanoate, electroconvulsive therapy, and behavior modification. This patient improved dramatically on clonidine 0.1 mg three times a day. Her case history was unusual in that she experienced asymptomatic periods of up to 18 months during the course of her illness on no medication. We have tried clonidine, in doses up to 1.O mg/d, in two severe OCD patients, neither of whom improved. Insel and Pickar78 performed a double-blind, placebo-controlled trial of naloxone in two patients with OCD. The first patient noted no change after placebo administration, but became acutely absorbed in checking rituals and was unable to reach certainty about the physical relationships of objects in the protocol room while being given naloxone. He had considerable difficulty completing the ratings and this acute exacerbation continued for 24 hours. Similarly, the second patient noted no change with placebo, but became abruptly worse after naloxone with feelings that he could not reach a point of mastery with his intruding thoughts. This preliminary report leads to speculation that opiate agonists may potentially be of assistance in the treatment of patients with OCD. d-Amphetamine has been shown to provide brief but significant relief to patients with severe obsessions and may in fact involve
OBSESSIVE-COMPULSIVE
the opiate system self-stimulation.79
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as naloxone
blocks d-amphetamine
increases
DRUG TREATMENT OF PATIENTS WITH OBSESSIVE WITHOUT ASSOCIATED RITUALS
in activation
and
THOUGHTS
Occasional patients present with obsessive intrusive thoughts without any overt rituals. These patients can sometimes be helped with the techniques of thought stopping or imaginal flooding as outlined elsewhere.2 There is a case report where thought stopping in combination with tranylcypromine produced a good response in a 4%year-old obsessive man.48 Thought stopping greatly assisted this patient even after tranylcypromine was discontinued. If these techniques are not helpful, behavior therapy has little to offer in relieving obsessions. Many of these patients, however, respond in dramatic fashion to antidepressant medication, even when they are not concomitantly depressed.8oT8’ Clearly, obsessive ruminations in the context of a depressive illness are likely to improve with adequate treatment of the depression. In our Obsessive-Compulsive Disorders Clinic over the last 2 years, we have seen seven patients with primarily obsessive thoughts. Four of these patients responded dramatically to antidepressant medication even though major depression was not part of the clinical picture. Three of these four patients either had strong family histories of depression or had a first-degree relative who also suffered from obsessional illness. In light of these cases, other patients with primary obsessional disease should be given a trial of these agents. ELECTROCONVULSIVE
THERAPY
Over two thirds of the severe OCD patients who have been referred to our clinic over the past 4 years have had at least one course of electroconvulsive therapy (ECT). Most of these patients did not suffer from major affective disorder and the main reason for administering ECT was for treatment of OCD. Electroconvulsive therapy is generally regarded as not useful in the OCD patient who is not endogenously depressed,3 although scant literature exists concerning the effects of ECT alone on OCD. In a recent review of this subject, Mellman and with other Gormans2 found a few studies reporting that ECT in combination modalities was occasionally associated with clinical improvement. Walter et a1.83 assessed the combined effects of ECT, modified narcosis, and antidepressants on obsessional neurotics. Although, diagnostic criteria were unclear, 40% of their patients improved following combined treatment. The relative effect of each form of treatment separately was obscure. Grimshaw (quoted in Jenike et al.2) studied 100 patients with obsessional symptoms, which were also poorly defined, and concluded that ECT (type unspecified) had little effect on obsessional states. Recent literature suggests a link between depression and OCD. As noted earlier, such as short rapid eye Insel et a1.68 reported similar sleep EEG abnormalities, movement (REM) latency and interrupted sleep, in age-matched patients with OCD and major depression. Some reports also suggest a high rate of dexamethasone nonsuppression, similar to that seen in depressives, in OCD patients (quoted in Jenike et a1.2); it is not clear, however, that the nonsuppressing patients were not also concomitantly depressed. In any event, a number of researchers have theorized that OCD may be a variant of affective illness and as such may be expected to respond to ECT at least some of the time.
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Mellman and Gormans2 report a patient who appeared not to have major depression who improved with a course of ECT after not responding to a number of antidepressants including 12 weeks of 300 mg/d of clomipramine. The patient, a 60-year-old professional, developed OCD at the age of 57 after the death of his wife. He became “obsessed” with the idea that the Internal Revenue Service was going to send him to jail and requested constant reassurance. He had no compulsions and on one occasion had a complete remission of symptoms for 6 weeks on 1 mg/d of haloperidol. On another occasion, he had improved somewhat on a combination of amoxapine plus lithium carbonate, but relapsed within 2 weeks. He had no improvement with desipramine, imipramine, phenelzine, clonidine, thiothixene, or alprazolam. While being tapered off alprazolam, he had a seizure which resulted in some slight improvement in his obsessions. Following this, the authors of this report gave him ten bilateral ECTs spaced every two to three days and noted near-total remission of his symptoms after the third treatment and total resolution by the ninth treatment. The patient became slightly hypomanic and demonstrated increased energy and pressured speech but no psychosis. He was placed on 100 mg of nortriptyline and 1,200 mg of lithium carbonate (level of 0.8 mEq/L) per day for maintenance and remained free of symptoms at lo-months follow-up. Clearly, this patient did have some atypical features including a late onset at the age of 57 and the complete remission with 1 mg of haloperidol; but the response to ECT is of great interest because patients such as this are not uncommon. It is likely that this patient suffered from an underlying treatment resistant depression and not primary OCD; the illness began after the death of his wife and at no time did he have any compulsions. There are no other such reports of success with ECT and there remain no reports of success in patients with classical rituals despite thousands of patients receiving ECT (probably inappropriately) for this disorder each year. PSYCHOSURGERY Since most OCD patients who undergo psychosurgery have very severe illness that has not responded to multiple therapeutic approaches, the results of surgical intervention are impressive.’ The sparcity of published reports is surprising in view of the fact that nearly 50,000 patients in North America alone have undergone various forms of psychosurgery. In 1952, two studies84v85 demonstrated that small lesions in the cingulum produced no change in psychotics, but resulted in much improvement with a few cures in obsessional and anxiety states. Four later studies reported a 50% to 60% improvement rate after small lesions were made in the lower medial quadrant of each frontal lobe.86-89Bernstein et al. 9oreported follow-up of 43 psychiatric patients who had been referred for open bimedial prefrontal lobotomies between 1948 and 1970 and found that the obsessive-compulsive neurotics (N = 27) did much better than schizophrenic patients and that those obsessional patients with phobic symptoms did the best. Of the 27 obsessive-compulsive patients, however, 12 were reported to have postoperative “organic brain symdromes” where patients described themselves as slowed down, tired, lazy, or apathetic. Their data were in accord with an earlier study” where OCD patients with phobic symptoms responded better than OCD patients without such symptoms. Earlier studies concluded that patients who had been ill for more than 5 years86 or 2 years9* before lobotomy had an unfavorable prognosis. In contrast, the series
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described by Bernstein et al. 90showed no correlation between duration of illness and outcome. In fact, the patient who, at the time of surgery, had been ill for the longest time (27 years), had a complete resolution of symptoms and no longer required psychiatric care. They also found no correlation between successful results and the age of the patient at the time of surgery; there were examples of success in all age categories from the late teens to the seventh decade. Two earlier reports,92*93 however, noted that youth was a less favorable prognostic indicator. In 1976, Mitchell-Heggs et a1.94combined the above approaches and surgically made three small lesions in the lower medial quadrant of each frontal lobe and two small lesions in each cingulum and reported that 89% of 27 patients showed definite clinical improvement. They proposed that site-specificity of the lesions was important, rather than total volume of the lesion, in terms of producing a favorable outcome. Another more recent paper describing five patients who underwent modified leukotomy for intractable obsessional illness, reported that all patients were improved at follow-up ranging from 1 to 7 years after surgery.” One was considered to be in “full remission,” three were “much improved,” and one was still symptomatic but “improved.” Symptoms had been present for 6 or more years in all patients, and three had been ill for more than 20 years. All had received adequate trials of more conventional treatments before the leukotomy but had shown little response. The modified leukotomy was performed by severing only the medial 2 to 3 cm of white matter coursing thorugh the anterior cingulate gyrus. Side effects of modern site-specific lesion techniques are rare. Tippin and Henn” found that psychometric testing revealed no adverse postoperative personality changes in their five patients. In fact, IQ and memory quotients improved, probably because of better attentiveness. Bailey et a1.96studied 200 leukotomy patients, 36 of whom had obsessional neurosis and found that mean full-scale IQ rose 13 points following surgery. In another study,97 mean full-scale IQ rose 4 points while memory quotient improved 9 points Mitchell-Heggs et a194also reported that in their patients each of the subscales on the WAIS were increased 6 weeks postoperatively. The most commonly reported surgical complication of leukotomies is postoperative seizures, which occur in about 1% of patients.9’*98’99 Tippin and Henn9’ reviewed the results of six studies of modified leukotwhich included 110 patients with obsessional disease. Nearly 81% omy 88*92,96-99 (N = 89) were at least “improved,” while more than half of those improved were in complete remission. They note that caution is required in interpreting these results because of the variation in follow-up. Generally, there tends to be a progressive improvement with time; thus, some patients who received a low global outcome rating might have received a higher one at a later time. This phenomenon tends to bias the results in a negative direction, however. Since negative results are rarely reported, this body of literature must be interpreted with some caution. Tippin and Henn concluded, however, that collective experience with modern psychosurgery for obsessional illness has not shown it to be a “mutilation of the brain and mind” as some have testified before congress,‘O” but rather a safe and effective treatment for obsessional neurosis that has become debilitating. A patient who has suffered for years with disabling obsessivecompulsive behaviors and not responded to more conventional therapies has a
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reasonable chance of a favorable outcome with relatively few risks. For the patient with disabling OCD, who fails to respond to more conservative treatment, psychosurgery is a viable option. CONCLUSION In those OCD patients who do not have rituals and suffer solely from intrusive thoughts, a trial of antidepressant medication is a reasonable first choice. A wealth of uncontrolled data indicated that these agents are likely to improve the clinical situation of many of these patients even when they do not suffer from clinical depression. In those patients who do not respond, behavior therapy including thought stopping, assertiveness training, and cognitive restructuring may be of assistance in reducing or alleviating symptoms.* Although medications are sometimes of help in treating nondepressed patients with clearcut rituals, the well documented success of behavior therapies in such patients leads us to begin the overwhelming majority of nondepressed and nonpsychotic OCD patients on behavior therapy as soon as possible. The technique of exposure plus response prevention is the mainstay of treatment. In patients with concomitant psychiatric symptoms such as major depression, psychosis, or mania, it is unlikely that behavior therapy will be of help until these symptoms are well controlled pharmacologically. In such cases, initial therapy should be drug oriented and behavior therapy should begin only after other functional illnesses are optimally controlled. Electroconvulsive therapy is unlikely to improve the nondepressed OCD patient, but psychosurgical techniques are often helpful with little risk of side effects. REFERENCES I. lnsel TR (ed): New Findings in Obsessive-Compulsive Disorder. Washington, DC, American Psychiatric, 1984 2. Jenike MA, Baer L, Minichiello WE (eds): Obsessive-Compulsive Disorders: Theory and Management. Littleton, MA, PSG Publishing, 1986 3. American Psychiatric Association: APA Task Force Report No. 14 on Electroconvulsive Therapy. Washington, DC, American Psychiatric Association, 1978 4. Jenike MA: Obsessive-compulsive disorder. Compr Psychiatry 24:99-l 15, 1983 5. Ananth J: Treatment of obsessive compulsive neurosis: Pharmacological approach. Psychosomatics 17:180-184, 1976 6. Insel TR, Murphy DL: The psychopharmacological treatment of obsessive-compulsive disorder. A review. J Clin Psychopharmacol 1:304-311, 1981 7. Goodwin DW, Guze SB, Robins E: Follow-up studeis in obsessional neurosis. Arch Gen Psychiatry 20:182, 1969 8. Vanggaard T: Atypical endogenous depression. Acta Psychiatr Stand 2675-56, 1976 (suppl) 9. Black A: The natural history of obsessional neurosis, in Beech HR (ed): Obsessional States. London, Methuen, 1974 10. Geissman P, Kammerer T: L’imipramine dam la neurose obsessionelle: Etude de 30 cas. Encephale 53:369-382, 1964 11. Angst J, Theobald W: Tofranil. Berne, Switzerland, Verlag, Stamptl and Cie, 1980, pp 11-32 12. Hussain MZ, Ahad A: Treatment of obsessive compulsive neurosis. Can Med Assoc J. 103: 648-650, 1970 13. Turner SM, Hersen M, Bellack AS, et al: Behavioral and pharmacological treatment of obsessive-compulsive disorders. J Nerv Ment Dis 168:651-657, 1980 14. Snyder S: Amitriptyline therapy of obsessive-compulsive neurosis. J Clin Psychiatry 41:286-289, 1980 15. Ananth J, Solyom L, Solyom C, et al: Doxepin in the treatment of obsessive compulsive neurosis. Psychosomatics 16: 185-l 87, 1975
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16. Bauer G, Nowak H: Doexpine ein neues antidepressivum wirkeings-vergfeich mit amitriptyfine. Arzrreunittefforschung 19: 1642-1646, 1969 17. Gross M, Slater E, Roth M (eds): Clinical Psychiatry. Bailfiere Tindaf and Case], 1969 18. Kahn RS, Westenberg HGM, Joffes J: Zimefdine treatment of obsessive-compulsive disorder. Acta Psychiatr Stand 69:259-26 I, 1984 19. Fontaine R, Chouinard G: Antiobsessive effect of fluoxetine. Am J Psychiatry. 142:989, 1985 20. Prasad AJ: Obsessive-compulsive disorder and trazodone. Am J Psychiatry 141:612-613, 1984 21. Lopez-fbor JJ: Intravenous infusions of monochforimipramine: Technique and results, in Proceedings of the 6th International Congress of CINP Taragona, April 1968. Excerpta Medica Foundation Int Congress Series No. 180, Amsterdam, 1969, pp 5 19-52 1 22. Jiminez F: A clinical study of Anafranil in depressive, obsessional and schizophrenic patients. Fof Neuropsiquiat def Sur y este de Esp 3: 189, 1968 23. Grabowski JR: Treatment of severe depression and obsessive depression with G3486. Fofia Med (Pfovdiv) 57:265-270, 1968 24. Fernandez CE, Lopez-Ibor JJ: Monochlorimipramine in the treatment of psychiatric patients resistant to other therapies. Acta Iuso Esp Neurol 26:119-147, 1967 25. Rack PH: Experience with intravenous cfomipramine, in Obsessional States and Their Treatment with Anafranif. Geigy, 1970, pp IO-13 26. Marshall WK, Micev V: Cfomipramine in the treatment of obsessional illness and phobic anxiety states. J Int Med Res f:403-412, 1973 27. Yaryura-Tobias JA, Neziroglu MA, Bergman L: Cfomipramine for obsessive compulsive neurosis: An organic approach. Curr Ther Res 20:541-548, 1976 28. Rapoport J, Elkins R. Mikkefsen, et al: Clinical controlled trial of chforimipramine in adolescents with obsessive-compulsive disorder. Psychopharmacol Bull 3:61-63, 1980 29. Yaryura-Tobias JA, Nezirogfu MS: The action of chlorimipramine in obsessive compulsive neurosis: A pilot study. Current Ther Res 17: I, 1975 30. Waxman D: A clinical trial of clomipramine and diazepam in the treatment of phobic and obsessional illness. J Int Med Res 5:99-f 10, 1977 (suppf 5) 31. Coombe PD: Cfomipramine and severe obsessive-compulsive neurosis. Aust NZ J Psychiatry 16:293-297, 1982 32. Wyndowe J, Sofyom L, Ananth J: Anafranif in obsessive compulsive neurosis. Curr Ther Res 18:6f 1-617, 1975 33. Capstick N: Clinical experience in the treatment of obsessional states. J Int Med Res 5:71, 1977 (suppf 5) 34. Ananth J, Sofyom L, Bryntwick Am J Psychiatry 136:700-720, 1979
S, et al: Cfomipramine
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35. Stroebel CF. Szarek BL. Gfueck BS: Use of cfomipramine in treatment of obsessive-compulsive symptomatology. J Cfin Psychopharmacof 4:98-100, I984 36. Carey RJ, Baer L, Jenike MA, et al: MMPI correlates of obsessive-compulsive disorder. J Cfin Psychiatry 47:371-372, 1986 37. Thoren P, Asberg M, Cronhofm B, et al: Cfomipramine treatment of obsessive compulsive disorder. I. A controlled clinical trial. Arch Gen Psychiatry 37: 128 I- 1285, 1980 38. Thoren P, Asberg M, Cronhofm B, et al: Cfomipramine treatment of obsessive-compulsive disorder. II. Arch Gen Psychiatry 37: 1286- 1294, 1980 39. Cooper J: The Leyton obsessional inventory. Psychof Med 1:48-64, 1970 40. Marks TM. Stern RS, Mawson D, et al. Cfomipramine and exposure for obsessive compulsive rituals. Br. J Psychiatry 136:1-25, 1980 41. Montgomery SA: Cfomipramine in obsessional neurosis: A placebo controlled trial. Pharm Med f:f89-192, 1980 42. Inset TR, Murphy DL, Cohen RM, et al: Obsessive-compulsive disorder: A double-blind trial of cfomipramine and cforgyline. Arch Gen Psychiatry 40:605-612, 1983 43. Ananth J, Pecknofd JC, van den Steen N, et al: Double-blind study of clomipramine and amitriptyfine in obsessive neurosis. Prog Neuropsychopharmacof 5:257-262, 198 1 44. Asberg M, Thoren P, Bertifsson L: Psychopharmacologic treatment of obsessive-compulsive disorder. Cfomipramine treatment of obsessive disorder-biochemical and clinical aspects. Psychopharmacof Buff 18:13-21, 1982 45. Joel SW: Twenty month study of iproniazid therapy. Dis Nerv Syst 20:1-4, 1959 46. Annesley PT: Nardif response in a chronic obsessive compulsive. Br J Psychiatry 115:748, 1969
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47. Jain VK, Swinson RP, Thomas JE: Phenelzine in obsessional neurosis. Br J Psychiatry 117:237-238, 1970 48. Swinson RP: Response to tranylcypromine and thought stopping in obsessional disorder. Br J Psychiatry 144:425-427, 1984 49. Rihmer Z, Szantok, Arato M, et al: Response of phobic disorders with obsessive symptoms to MAO inhibitors. Am J Psychiatry 139:1374, 1982 50. Jenike MA: Rapid response of severe obsessive compulsive disorder to tranylcypromine. Am J Psychiatry 138: 1249-1250, 1981 51. Jenike MA: Use of monoamine oxidase inhibitors in obsessive compulsive disorder. Br J Psychiatry 140:159, 1982 52. Jenike MA, Surman OS, Cassem NH, et al: Monoamine oxidase inhibitors in obsessivecompulsive disorder. J Clin Psychiatry 44: 13 1-l 32, 1983 53. Stern TA, Jenike MA: Treatment of obsessive-compulsive disorder with lithium carbonate. Psychosomatics 24:671-673, 1983 54. Geisler A, Schou M: Lithium ved tvangsneuroser. Nordisk Psychiatrisk Tidsskeift 23:493-495, 1970 55. Forssman H, Walinder J: Lithium treatment of atypical indication. Acta Psychiatr Stand 207:34-40, 1969 (suppl) 56. Van Putten T, Sander DG: Lithium in treatment failures. J Net-v Ment Dis 161:255-264, 1975 57. Baer L, Minichiello WE, Jenike MA: Behavioral treatment of obsessive-compulsive disorder with concomitant bipolar affective disorder. Am J Psychiatry 142:358-360, 1985 58. Foa EB: Failure in treating obsessive-compulsives. Behav Res Ther 17:169-176, 1979 59. Rasmussen SA: Lithium and tryptophan augmentation in clomipramine-resistant obsessivecompulsive disorder. Am J Psychiatry 141:1283-1285, 1984 60. O’Regan B: Treatment of obsessive compulsive neurosis with haloperidol. Can Med Assoc J 103:167-168, 1970 61. O’Regan B: Treatment of obsessive compulsive disorder. Can Med Assoc J 103:648-650, 1970 62. Altschuler M: Massive doses of trifluoperazine in the treatment of compulsive rituals. Am J Psychiatry 119:367, 1962 63. Dally P: Chemotherapy of Psychiatric Disorders. London, Logos, 1968 64. Rivers-Buckley N, Hollender MH: Successful treatment of obsessive-compulsive disorder with loxapine. Am J Psychiatry 139: 1345-l 346, 1982 65. Tesar GE, Jenike MA: Alprazolam as treatment for a case of obsessive-compulsive disorder. Am J Psychiatry 141:689-690, 1984 66. Tollefson G: Alprazolam in the treatment of obsessive symptoms. J Clin Psychopharmacol 5:39-42, 1985 67. Jenike MA, Brotman AW: The EEG in obsessive-compulsive disorder. J Clin Psychiatry 45:122-124, 1984 68. Insel TR, Gillin JC, Moore A, et al: The sleep of patients with obsessive-compulsive disorder. Arch Gen Psychiatry 39:1372-1377, 1982 69. Cole JO, Hartmann E, Brigham P: L-tryptophan: Clinical studies. McLean Hosp J 5:37-71, 1980 70. Yaryura-Tobias JA, Neziroglu F, Bhagavan H: Obsessive-compulsive disorders: A serotonergic hypothesis, in Saletu B, Berner P, Hollister L (eds): Neuropsychopharmacology: Proceedings of the 11 th Congress of the CINP. Oxford, England, Pergamon, 1979, pp 117-125 71. Yaryura-Tobias JA, Bhagavan HN: L-Tryptophan in obsessive-compulsive disorders. Am J Psychiatry 134:1298-1299, 1977 72. Solursh LP: The use of LSD-25 in psychotherapy: An evaluation. Int J Neuropsychiatry 2:661-656, 1966 73. Anden NE, Corrod H, Fuye K, et al: Evidence for a central 5-hydroxytryptamine receptor stimulation by LSD. Br J Pharmacol 34:1-71, 1968 74. Brandrup E, Vanggaard T: LSD treatment in a severe case of compulsive neurosis. Acta Psychiatr Stand 55:127-141, 1977 75. Pacella BL, Polatin P, Nagler SH: Clinical and EEG studies in obsessive compulsive states. Am J Psychiatry 100:830, 1944 76. Cohen DJ, Detlor J, Young G, et al: Clonidine ameliorates Gilles de al Tourette syndrome. Arch Gen Psychiatry 37:1350-1357, 1980
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