1: CGI range 1 (normal )
to 7 . 2: Hostility
based on 0-6 ordinal ranking (6 = most severe Kay criteria of
BPRS (*: p < 0
.001 using a binomial) 3: Improvement (1= much; 4= nil ; 7= worse ) 4: Lower the Therapeutic Efficacy the better
{0-3}, 5: Side-effects{1-4} with
1 being the absence . 6: Efficacy Index; lower the better {1-7} Cohort 2 : High dose buspirone for manic irritability and confrontation We have examined another cohort of twelve patients both inpatient and outpatient who have been receiving high doses of buspirone, approximately 60-160 mg per day of buspirone, for profound irritability linked with a manic like state. This group had associated marked agitation, restlessness, anger, lability of mood and confrontation with enormous potential for tolerating high doses of medication. These patients were all exceptional: they were not typical manics who would respond to lithium, carbamazepine or valproate alone or combinations of these. Buspirone was initiated outside labeling but on solid clinical grounds where lithium or neuroleptics or benzodiazepines were contraindicated or where we did not want to escalate the doses of these drugs. Sometimes buspirone treatment was initiated coming out of the manic phase: for example, when a patient had been lithium toxic and we did not want sedation. At times patients received the buspirone early in the manic like phase - for example, a patient with AIDS involving the brain and ostensible organic brain disorder associated with manic features. Others received it during their manic episode: these patients had sometimes been routinely sedated, with neuroleptics and/ or with benzodiazepines, but for clinical reasons, we did not want to continue the sedation. As the mania began to improve a little, they remained extraordinarily irritable, angry and hostile, pacing and agitated. All patients were generally begun directly on 60 mg of buspirone a day, 20 mg t.i.d. All twelve improved on short-term follow up over days, generally markedly. Improvements were noted within twelve to 24 hours. The agitation and confrontation would improve markedly, however, the psychotic features still required antipsychotics. Frequently, the patients would report remarkable improvement in their sleep on the first night but this was not maintained and would require other interventions. Often, within a day or two, they would complain of a tell-tale “non-vertiginous dizziness” which we used as a criterion for lowering dosage as they were no longer tolerating the higher dose. Some patients therefore received high dose buspirone for days and then required tapering generally when they became dizzy. The endpoint was frequently low dose buspirone -15mg per day. At least 3 patients, on whom follow-up occurred within the system, were still taking buspirone in doses of 60mg per day or above several years later. With three exceptions of buspirone monotherapy, these patients were on other therapies as well - lithium, valproate, carbamazepine, benzodiazepines, antidepressants and/ or neuroleptics . As illustrations, our first two cases had two similarities. In each instance, these patients had been ill for many years and constituted the far end of severity for bipolar illness with chronic intractability. The families did not know what medications the patients had been on and in fact in each case, they had encountered some difficulties with the patients' initial conditions. Spontaneously, they both commented they had never seen these members of family so well, after a manic episode. Of the first twelve patients, four families have reported this amazement with response compared with previous episodes describing how the index patients were greatly improved on the high dose buspirone. We have seen three cases in which 60mg of buspirone daily apparently markedly attenuated episodes of both depression and mania in patients who prior to that were intractably cycling despite the best known previous interventions including drugs such as lithium, carbamazepine, valproate, antidepressants and neuroleptics in varying combinations. In one case the patient was controlled except for minor mood changes for three years She then went off the buspirone herself and relapsed. Could this imply a prophylactic effect of the drug in certain refractory bipolar illnesses, particularly as their may be a pharmacologic justification - lithium has an effect on serotonin 1A? Clearly, this should be explored further - it may be that buspirone has prophylactic effects on bipolar disorder. Cohort 3 : Outpatients with buspirone for
irritability In conjunction with John Walenta (who analyzed data retrospectively), we have followed at the Pacific Neuropsychiatric Institute a group of adult non-organic patients (children are discussed separately 166 ) treated with buspirone for aggression. These patients had consented to allow their clinical data to be analyzed. Follow ups were done based on their short-term response to buspirone (criterion : their first two appointments after initiating buspirone, up to one month after start) and their last appointment ( very often current) while on buspirone. Their condition was ranked based on retrospective chart review using a five point ordinal scale ( 2 being very much improved, 0 being no change or equal features worse and better, and -2 being very much worse). The results are dramatic with 12 of 13 of patients improving. Low dose response (15-25mg per day ) as well as high dose response was excellent (≥ 50mg per day). (Table 5). Our experience has been that patients do better on lower doses of buspirone than mid-doses with regard to aggression but their anxiety and depression respond better at 30mg to 45 mg per day than 15mg per day . A prototype example is of a patient in his mid-thirties who was having, on average, four to five episodes a day of extreme aggression and anger which he found very difficult to control. The major precipitant was when vehicles would overtake him on the road, and as he was a builder, he was involved in such episodes about three times per day as he drove several times per day. I have called this condition the West Coast Syndrome. The patient charted his baseline episodes and then began on buspirone in doses of 15 mg per day. In the first week he had had two such episodes, and then it dropped down to zero as the dose increased through 20 and 25 mg per day. However, by the time he achieved 30 mg per day, he was recording again two episodes per week with equivalent stressors. We dropped him back and he has been stabilized now for several years on 15 mg per day. Follow-up is now the longest of any patient we have treated- nearly 6 years on buspirone. He's having no episodes of marked pathologic aggression, and this is not only in the motoring context. His wife, who had wanted to divorce him because she could not tolerate these, reports an enormous improvement as well. He irregularly becomes frustrated but well within normal range. He at one point, went off the buspirone and was in remission for about a month, and then his symptoms began to return. Re-initiation of the drug produced the same dramatic improvement. This is the typical kind of case of a patient who does better on lower doses compared with higher doses of buspirone . Table 2 : regular adults on buspirone for aggression
Cohort 4 : Buspirone and carbamazepine combination :
special cases Drugs such as carbamazepine have enormous potential in the management of episodic disorders particularly those linked with hostility. 167, 168, 169, 170, 171, 172. A subpopulation of patient exhibits features of a special kind of aggression which is carbamazepine responsive and appears to not respond to buspirone alone. These patients have special episodes with explosive, uncontrolled, poorly directed, limited precipitation kind of aggression with or without amnesia. These kinds of episodes on their own theoretically should not respond to buspirone as they are probably not modulated through serotonin 1A but through episodic firing in the brain, possibly the temporal lobes. These patients commonly have temporolimbic instability. This diagnosis is based on three key elements: 1. History using subjective report measures such as the Inventory of Neppe of Symptoms of Epilepsy and the Temporal Lobe {INSET }where they have several symptoms 173 . 2. Examination including neurologic evaluation is often normal although higher brain function based on measures such as the BROCAS SCAN (Screening Cerebral Assessment of Neppe) 174 sometimes suggests compromise of frontal or parietal lobes and soft neurologic features . 3. Finally, a temporal lobe focus or paroxysmal firing is sometimes present on electroencephalography (routine wake and sleep EEGs with photic stimulation and hyperventilation ; or more sophisticatedly an important new technique of 48 hour, 18 channel home ambulatory computerized electroencephalography monitoring). 175, 176, 177, 178, 179 Many patients in this major subgroup have coarse neurobehavioral symptoms for which carbamazepine not buspirone is prescribed, 180, 181 possibly qualify for diagnoses of intermittent explosive disorder, but are more correctly labeled paroxysmal neurobehavioral disorder * and are carbamazepine responsive. They do not require adjunctive buspirone. A special group, however, do : These patients frequently have added frustration and irritability and build up of distress which they can control. The carbamazepine alone does not seem to help these features, but the buspirone does. Consequently, we have a cohort of patients on the combination of carbamazepine (always as Tegretol generally 600mg per day or titrated to serum levels of about 6-9 ug per liter) and buspirone (variably low dose or high dose). These patients have responded well subjectively to the combination in 10 out of 12 cases (and behaviorally in 11 or 12) continuing the treatment. However, 8 patients discontinued on the CBZ so the overall combination responsiveness was 10 out of 20 although all 8 dropouts improved on the buspirone. Of the 20 patients, 2 were on carbamazepine for classical seizure phenomena with loss of consciousness not dyscontrol, and 9 others exhibited no dyscontrol features and were on the carbamazepine for other reasons - temporal lobe symptomatology or affective illness. It is relevant to mention that in no instances did buspirone directly impact on dyscontrol behavior when present, however, in the 18 of 20 instances where buspirone helped the irritability-frustration continuum, our impression was that the patients would report less dyscontrol when present, but we have not specifically kept such data. In 3 cases, the carbamazepine was initiated first, and because of the distortion of this sample, by definition, none responded dramatically otherwise this would not be necessitating the buspirone. Once the combination was used but 12 improved and 8 remained the same or deteriorated requiring discontinuation of the carbamazepine ( 5 of them took other anticonvulsants instead of carbamazepine and of these 4 have remained on either valproate or phenytoin. ). Longest follow-up has been four and a half years on the combination. (Table 4 reflects months on buspirone) . Table 3: Buspirone and carbamazepine
combination
* this refers to other prescription medications besides the buspirone taking concomitantly Table 4: Carbamazepine dropouts on buspirone
Table 5
: Outpatient responsive to buspirone
based on dosage
^ responses based on yes or no for early and late patients identical except one less patient in CBZ+ BSP group assessed (new patient) in the late group and one less in high dose CBZ+BSP group (Cohort 4A) subjectively responded ^^ a patient with aggression on 140mg / day for tardive dyskinesia Discussion Our results are remarkable for how well patients seem to have done. These results are highly preliminary although highly statistically significant because of the global response. However, this was not unexpected given the special selection of the population. The sample of patients that present in an academic setting is specialized and does not reflect the general population. In addition, in the inpatients, their status in hospital compromised interpretation of the improvement as milieu or removal away from the stressors may have been the explanation. Moreover, our outpatients were frequently highly motivated to get better. In addition, these patients were very complex and they were often very ill at presentation, implying they had significant room to improve particularly in an environment where each patient was intensely evaluated and medication was very carefully chosen and adjusted for best fit at follow up. Additionally, in general, their conditions necessitated polypharmacy (Tables 2, 3 and 4). The object was to help the patients and it is impossible to assess the contribution of each drug or the environment or therapeutic milieu. Many, if not most patients given these criteria, will improve - and the particular sample is further distorted by those who chose to follow-up. In eleven cases, the patients are not being followed up by us at this point ( six for geographic reasons or 4 because their primary physicians have taken them over and because she is subjectively so improved she deems it unnecessary. However, in reality, several of these patients may in fact, have not followed up with us because they are not doing well which further distorts the positive results which technically is overwhelmingly statistically significant for improvement (vs not improved ) as a group and also significant in each individual group. These factors emphasize the need for controlled prospective studies and the limitations of clinical data. Besides the above, the operational criteria for entry into the analysis namely aggression, irritability and violence are suspect because they have been lumped together. Finally, the methods of ranking are suspect because in general they were too global, and although based on detailed chart review a five point ordinal scoring of change either globally or on one criterion - aggression is simplistic and even inappropriate. On the other hand, the results in 4 different cohorts are consistent and encourage hypothesis testing. Nevertheless, the comments below should be perceived with a full realization of the inadequacies of this research. If the results can be replicated and are real, these open pilot studies suggest that there may be two subpopulations of patient responsive to buspirone for aggression, irritability and impulsivity. Preliminarily, based on our experience, low dose buspirone therapy (10-25 mg per day usually) produces responsiveness in non-organic patients with high levels of frustration and /or high stress levels who have significant chronic irritability and impulsive directed acting out behavior with a range through from verbal to physical aggression. High doses of buspirone, generally 60-90mg per day, appear to act within hours, not within the days that low doses require, and to be associated with alleviation of the high level irritability and agitation of patients who are hypomanic and confronting. Very preliminarily and based on only limited clinical experience, high doses also might be logical when there has been limited low dose response, or when other diagnoses requiring higher doses of buspirone are present such as obsessive compulsive disorder or the marked agitation of the severe Alzheimer patient. In the two very preliminary open studies in which low doses such as 10-25 mg per day of buspirone appear to be very effective anti-aggressive agents in two different population cohorts, namely, mentally-retarded, brain-damaged, aggressive patients 148, 149, and my own study (Cohorts 1-4) with predominantly non-organic aggressive patients 182, 183 who did not have generalized anxiety disorder superimposed, as the dose increased to about 30mg per day, the anti-aggressive effects waned, although there remained some residual effect. This low dose effect may correspond with a presynaptic autoreceptor serotonin 1A agonist firing with consequent diminished postsynaptic tone across all serotonin receptors. These presynaptic results are to some degree contradicted by our ADHD and aggression studies in children described in this issue and usually involving doses of 30mg per day of buspirone. 166 Our results suggest two potentially different mechanisms for the management of aggression using buspirone: Low doses may correspond with a presynaptic agonism with a feedback loop producing overall postsynaptic antagonism at all serotonin receptors. This would imply a short delay, such as days, which is what one finds. Conversely, high dosage, postsynaptic agonism in the irritable hyperactive agitated kind of patient would imply a secondary regulation of the serotonin 2A receptor, with consequent serotonin 2 antagonism : this may characterize an intimate, inverse feedback relationship with serotonin 2 mechanisms. It may alternatively reflect receptor subsensitivity in manic and related psychotic or agitated states implying higher doses. Appropriate dosage of buspirone is critical to success. I believe that one useful way to modulate the dose is based on the side-effect of dizziness. The dizziness that occurs with buspirone is special and Neppe has used the term “non-vertiginous dizziness” (NVD) for it. 20 This dizziness is by far the most common side effect in adults, possibly occurring in 30-40% of patients but when the dose is built up to 60mg per day in possibly 60% based on my guesstimate on hundreds of my own patients. It apparently can be used as an index of what dosage of buspirone we ought to be able to achieve. Increasing the dosage is often critical management so that this side-effect can be used to monitor dosage exemplified by the following: A patient started on 5 mgs of buspirone 3 times a day, and instead of improving, the patient reported a few days later, "About thirty minutes after I take the drug, I get this horrible sensation in my head. It's a dizziness, it's an uncomfortability, it's a light headedness, it's indescribable. It goes behind my ears and I don't like it. It lasts about 30 minutes and then it goes away .” The same scenario might occur while building up the dose at (say) 40 mgs a day. In every instance when one gets this, we believe this is as much a symptom of serotonin 1A responsiveness as is irritability and concentration. It is a direct serotonin 1A related side effect. It apparently occurs with other azapirones in research and also, in may experience, occurs occasionally, for example, with the other serotonin 1A non specific drugs such as lithium and propranolol. When this side effect occurs, this may be hypothesized to be a symptom of serotonin 1A overmodulation or excess and I find that dropping down the dosage of buspirone is all that is needed ( e .g. if 15 mgs a day produces NVD, drop to 10 mg per day. If the patient is still getting “non-vertiginous dizziness”, drop to 5 mgs a day - 2 .5 mg bid- until the “non-vertiginous dizziness” disappears: this should be the correct dosing. Using this technique, far fewer patients in my experience, drop-out and also far more patients appear stabilized. An integrated model
The perspective of dose dependency appears extremely important, not only on the basis of side effects but also therapeutic effects. This is illustrated by comparing effects of specific versus nonspecific serotonin 1A modulators where different effects speculatively occur at different levels. The consistency of the chemistry, the receptorology, animal models and clinical implications may provide a viable approach to examining this and other receptors during the 1990's . A model for aggression can be drawn using the serotonin 1A receptor. Presynaptic agonism produces a functional overall post-synaptic antagonism, and this could be the mechanism for low-dose buspirone in the agitated, generally non-organically impaired angry, frustrated, hostile, irritable individual. High doses of serotonin 1A agonist in the context of high doses of buspirone, or of lithium, produces post-synaptic serotonin 2 antagonism as a reciprocal effect for the serotonin 1A agonist effect. Beta adrenergic blocking agents in low doses probably do not act by the serotonin 1A receptor, but in higher doses act as serotonin 1A antagonists and also serotonin 1B agonist type drugs. Under those circumstances, if serotonin 1B indeed does exist in man, this would explain the paradoxical effect. However, the high dose serotonin 1A agonist theory appears compromised unless the serotonin 1B agonist effects that propranolol exhibits in rodents can be translated into equivalent, currently undiscovered human effects. This is unlikely at this point and a more logical hypothesis for beta-blockers could relate to down regulation of the serotonin 2 receptors which may produce the equivalent of serotonin 2 blockade. As an aside, because gepirone potently inhibits serotonergic impulse flow recorded from the dorsal raphe nucleus and this effect is partially reversed by serotonergic antagonists, this presynaptic effect may be its primary effect decreasing 5HT neurotransmission. 45 Thus, theoretically, gepirone may turn out even better than buspirone as an anti-aggressive agent . Neurochemically, a very important theoretical and practical area in relation to serotonin and serotonin 1A has emerged. It has implications far beyond serotonin 1A, as a cascade of mechanisms across many chemical levels can occur. For example, the possibility of some degree of inverse relationship with serotonin 2 mechanisms is only a beginning and influence in relation to electrical firing at dopaminergic, acetylcholine and norepinephric levels occur. The exact effects will vary depending on the particular parent compound. 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Neuropsychiatric Institute, Seattle, WA, USA; Adjunct Professor of
Psychiatry and Human Behaviour, St Louis University School of Medicine, St
Louis, MO, USA. Correspondence: Director Pacific Neuropsychiatric
Institute
The assistance
of John A. Walenta in the data analysis for Cohorts 3 and 4 is gratefully acknowledged.
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