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Ref: Neppe VM. The serotonin 1A  neuromodulation of aggression : Bimodal buspirone dosage as a prototype anti-irritability agent in adults.  Australian J of Psychopharmacology. 1999, January; 9: 8-25.

 

This is a pioneering article on the use of buspirone use in anger and irritability in adults.

Based on the data available, buspirone appears an extremely safe medication in adults. Of course, all patients should be evaluated by a physician. We gratefully acknowledge the opportunity to publish a minor adaptation
of this article which originally appeared in the Australian Journal of Psychopharmacology in 2003. This article
was published in the Australian J of Psychopharmacology—the final draft may not necessarily be identical.  

See Also: the pioneering article on the use of buspirone use as adjunct to methylphenidate (Ritalin) predominanlty in attention deficit disorder.

Buspirone is a major medication discussed in Dr Vernon Neppe's classic sciction book, Cry the Beloved Mind: A Voyage of Hope Of course, all patients should be evaluated by a physician.

 

 

 

Buspirone and aggression

 

Vernon M Neppe

 

 

 

 

SUMMARY :

Exploration of aggression spectrum concepts are compromised by inadequate terminology, diagnostic, measuring, classification and therapeutic difficulties in research.

Evidence exists for serotonin and specifically the 1A receptor involvement in the aggression spectrum using animal and human models. High dose beta 2-adrenergic blockers, lithium and eltoprazine all act non-specifically on serotonin 1A and are apparently anti-aggressive.

 Animal models of aggression  suggest the azapirones are potent anti-aggressive agents hypothetically through its specific serotonin 1A  partial agonist effects  . Irritability is an early target symptom of response with buspirone in generalized anxiety disorder and scattered case reports suggest and anti-aggressive effect for buspirone.

4 clinical open study cohorts using buspirone in aggression are described: Experience suggests a biphasic dose effect for buspirone : Low doses of buspirone ( 15-25 mg per day ) were effective after a few days in alleviating irritability (N=9 inpatients) without associated significant anxiety. Higher doses such as 60-90 mg per day  within a day greatly relieved manic irritability,  agitation,  restlessness and mood lability in 12 in- and out-patients. Two cohorts of outpatients (thirteen without coarse organicity and twenty (initially. later twelve) with carbamazepine adjunct) showed impressive results generally over a prolonged period(18/18 {15-25mg buspirone daily}, 3/3 {30-45mg}, 9-10/12 {≥60mg}. Eight stopped the carbamazepine.

There are major limitations to this study including selected sample, retrospective review, rankings,  milieu, patient motivation, assessment methods, clinical presentations and polytherapy but the results are encouraging and require adequate controlled studies. If real,  these effects can be explained in a unified serotonin 1 A pre- and post-synaptic theory.

 

 

AGGRESSION

Concept of Aggression

            There is no current diagnostic framework for aggression.  The Diagnostic and Statistical Manual III Revision  and DSM-IV and 1V-R  1, 2,  recognizes a variety of different syndrome criteria,  making up subgroups of psychosis,  anxiety and depression.  However,  the fourth potential system cluster in that quartet,  aggression,  is represented only by the condition of intermittent explosive disorder  (IED).  IED is limiting in that one cannot diagnose it in the face of a major contribution from common diagnostic conditions such as depression,  substance use,  anxiety and psychosis and mania. Moreover,  the aggressive episodes are not better accounted for by another mental disorder (e  .g  .,  Antisocial Personality Disorder,  Borderline Personality Disorder,  Head injury,  Alzheimer’s disease,  Conduct Disorder,  or Attention-Deficit / Hyperactivity Disorder) and are not due to the direct physiological effects of a substance (e  .g. a drug of abuse or a medication) or a general medical condition (e  .g  .,  head trauma or Alzheimer's disease). In DSM 111 R  it implied phases of normality between episodes,  something which is almost contradictory to the condition,  and fortunately this has been eliminated in DSM 1V. Nevertheless,  it remains a rare condition,  requiring disproportionate dyscontrol. 2

 

Empirically,   by far the most common form of aggression relates to frustration leading to outbursts of anger : many of these people have mainly controlled aggression directed towards others without amnesia of any kind,  and may be experiencing a relatively chronic high basal level of stress.  Thus,  one could argue that there are two dichotomous poles in relation to aggression,  what Dieter Blumer and I  have called “paroxysmal behavioral disorder” 3,  4-  the explosive loss of control disorder possibly associated with firing in the brain  possibly in relation to epilepsy-related behavioral changes 5  and the frustration -aggression component which is chemically linked to norepinephrine and serotonin but has no overt organic (coarse neurobehavioral ) elements.  . Aggression is by its nature episodic : Even if those episodic elements persist almost continuously over time,  they are perceived as chronic episodic elements. Even planned aggressive elements have episodic expression  .

            A further complicating element  relates to terminology.  In aggression  research we come across a variety of terms which if not synonymous are very similar.  Rage  is used to imply profound outbursts of anger which are not controlled  .In the medical context, this frequently implies a  coarse neurobehavioral component  with high levels of aggression.  Dyscontrol  is similar but has an impulsive component to it,  with elements of loss of control,  non-directedness,  and,  at times,  amnesia.  Anger implies outbursts which are under control,  which are generally directed,  and usually have verbal components or components expressing themselves somatically. Irritability  is generally used to imply high basal levels of anger and agitation - a simmering over time. Hostility  is further along this continuum,  in that it does not necessarily even imply the expression of anger: passive-aggressive components in  hostility may be state or trait related. Violence  is perceived as physical force exerted for the purpose of violating,  damaging,  or abusing implying elements of some premeditation.  Even assertiveness  has elements of aggression which are perceived as socially appropriate. Finally,  impulsivity  relates to many of the above,  because of the inherent nature of aggressive behavior having episodic elements but impulsivity goes beyond aggression alone. Moreover,  impulsivity also relates to any kind of symptom,  so that it will include such a major phenomenon as episodic lability  as well. It also covers behavior which is non-motivated,  not well thought out and acted out generally to the detriment of the patient. These variations in terminology reflect one of the difficulties of quantifying aggression. Operationally,  probably the easiest measure of entry into pathologic aggression research is the recognition that the anger is impairing functioning at any of the biopsychofamiliosociocultural levels. Given the lack of aggression classification in

in the Diagnostic and Statistical Manual III revision or DSM-IV,  there are no FDA approved drugs for aggression.  Thus all drug discussion is necessarily Innovative Psychopharmacotherapy.  This is a cogent reason for developing a classification into  DSM V and Figure 1 represents my preliminary  proposal presented without further comments  .

 

FIGURE 1

Proposed Multi-axial Classification of Aggression  .

 

Axis 1 : Irritability,  Aggression and Psychopathology  e  .g. psychosis, 

mood disorder,  anxiety,  attention deficit hyperactivity disorder

Axis 2 : Irritability,  Aggression and Personality disorder e  .g. borderline,  antisocial,  developmental problems,  sexual deviation

Axis 3: Irritability,  Aggression and Medical Condition Causes - intracranial e  .g. Alzheimer’s disease,  paroxysmal cerebral firing or  extracranial e  .g. thyroid

Axis 4:  Irritability,  Aggression and Psychosocial Stressors -e  .g.  stress - frustration - irritability,  dynamic elements

Axis 5 : Irritability,  Aggression and Functionality Impairment - ab initio e  .g. mental retardation ; developed e  .g. dementia. Subgroup : organic rage,  catastrophic reactions

Axis 6 : Irritability,  Aggression and Psychopharmacologic Involvement e  .g. alcohol,  sedative hypnotics,  serotonin modulating drugs,  pleasure drugs

© Vernon M  Neppe

 

Measurement of aggression

            Aggression and irritability are extremely difficult to measure. A variety of different scales have been developed,  some relating to patient subjective rankings,  others to objective rankings by researchers.  Subjective rankings such as the Buss-Durkee,  Monroe Dyscontrol Scales,  Spielberger State and Trait Aggression Scales,  and a variety of Short Aggression Questionnaires,  have value in a  population that is cooperative,  motivated,  non-psychotic and of normal intelligence.  However,  subjective rankings cannot easily be used in a psychotic or demented population,  both of whom,  at times,  have complications pertaining to aggression and irritability.

            Objective rating scales have the advantage of being quantifiable.  The earliest modern one of these is the Yudofsky Overt Aggression Scale 6 which however is nominal and not ordinal,  and evaluates outbursts of verbal and physical aggression.  This was  made ordinal by Kay's modification,  The Modified Overt Aggression Scale 7.  In practice,  these scales are difficult to use because patients in an inpatient situation will commonly not exhibit episodes of aggression.  Monitoring episodes of aggression is difficult and measurement is problematic in practice. 6,  7,  8, 9. If the patient is an inpatient,  he is not under the same kind of stressors 10 and is less likely to have anger outbursts.

            Consequently,  measures of hostility such as those found in the Brief Psychiatric Rating Scale 11 and quantified by Kay12, 13, 14,  may be useful at this point,  and in fact has been used in Cohort 1 of the research below. Additionally,  monitoring specific episodes allows the patient or members of family to monitor outpatient aggression. This I have found has been most suitable,  and the patient or responsible other generally monitors episodes such that instrument sensitivity becomes adequate. 

 

THE BIOCHEMICAL LINKS

Chemistry: The role of serotonin

Serotonin,  chemically 5 hydroxy tryptamine (5HT),   was isolated in platelets in 1947,  almost a century after its initial discovery as a substance that contracted smooth muscle.  The serotonin receptors apparently modulate a variety of basic functions at a large number of levels. Serotonin has physiologic effects on the hypothalamo-pituitary axis impacting neuroendocrine functions and circadian rhythms,  and it regulates temperature and even blood pressure. It has psychological  effects on memory,  irritability,  stress,  mood lability,  anxiety,  depression and obsessionality. It also  has behavioral effects on sleep,  sex,  appetite and weight and it  modulates aggression 15, 16, 17, 18,  19, 20

The serotonin syndrome is a syndrome of serotonin overload in experimental animals associated with a variety of hyperactivity features. [19, 21 A significant pharmacologic measure,  namely partial agonism,  can be demonstrated most easily by inducing and blocking such a syndrome. Partial agonism implies that in the presence of an agonist these drugs,  by occupying the receptor,  act as functional antagonists. However,  in the absence of agonists,  there will be no functional antagonism.  In contrast,  given an adequate dose,  there will be an incomplete agonist action producing a weak serotonin syndrome.  Partial agonism is a post-synaptic phenomenon which can be perceived clinically  as potentially neuromodulating  a condition back to normal. 22

 

Serotonin receptorology,  however,  is complicated by numerous different actions. Today,  we know of at least fifteen different serotonin receptor subtypes all with specific anatomy,  physiology,  pharmacology,  receptor responsiveness and probably even genetic predisposition based on cloning.  *

The promise of a breakthrough in brain receptorology led to the rapid delineation of serotonin receptor subtypes,  beginning in 1979 17. The 1980's saw the further subtyping of receptors into types 1 and 2. 23, 24 The serotonin 3 receptor was a third class 25 then came serotonin 4 26,  5,  6 and 7 as well as  several receptor subtypes like 1F 27 (Serotonin 1A in 1981 through to current discoveries in 1995) 28, 29

 

Serotonin  and aggression

            There is substantial research suggesting a link of aggression and serotonin. 20, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 For example,  in several studies of aggression,  the CSF  5-hydroxy-indole acetic acid level is inversely related to the extent of aggression. 44 As 5-HIAA is a metabolite of serotonin,  and deficiency would imply possible serotonin two excess states with long term down regulation,  this result may have some relevance. Animal models support this : decreased serotonergic activity increases predatory behavior. 38, 40, 44, 45, 46

 

There are difficulties in interpreting serotonin  and aggression states. For example,  fluoxetine,  an inhibitor of serotonin uptake and other serotonin-mimetics inhibit mouse killing behavior without apparent secondary effects and when these compounds were tested on killer rats,  a stronger antimuricidal effect was observed in rats having altered serotonin neurotransmission. These results support a role for the serotonergic supersensitivity in a model of aggressive behavior. 40. Yet,  in delta 9-Tetrahydrocannabinol (THC) induced aggressive behavior in rats previously deprived of REM sleep,  aggressiveness was significantly potentiated by tryptophan and fluoxetine. 42  Further complicating animal interpretations is the use of the overlapping paradigms for aggression and anxiety. 20, 33, 36, 47,  45

 

Serotonin 2 and aggression

Several drugs which have been noted empirically but not in double blind studies to have anti-aggressive effects act on the serotonin 2 receptor (now the 5-HT 2A Receptor subtype). The phenothiazines and other neuroleptics may have 5 % to 30 % of their total receptor profile as serotonin 2 blockade. 48, 49  For many years,  phenothiazines were used as anti-agitation drugs  and their effects in taming animals are well-known. 50, 51, 52 Trazodone has serotonin 2 blocking effects and in case reports has anti-aggressive effects. 53, 54, 55, 56, 57, 58, 59

The relevance of these effects in the context of the data below is the apparent inverse control with serotonin 1A drugs:  1A agonism seems to have similar effects or controlling effects to  2A antagonism using several pharmacologic models. 22, 60  This is also seen clinically with anti-aggressive,  anti-anxiety and anti-depressant parallels but not with other areas,  some controversial,  such as sedation and psychosis with 5HT 2A not 1A,  and anti-impulsivity aspects and neuroregulation with 1A not 2A.

 

Serotonin 1A receptors

            The serotonin 1 receptors,  particularly serotonin 1A,   are relevant in aggression.  The serotonin 1A receptor was discovered in the early 1980's,  and serotonin 1 and then serotonin 1A was differentiated at that point,  relating to their specific interactions with guanasyl nucleotides, adenylyl cyclase  and differential effects with different  ligands. 61, 62, 63, 64, 65, 66

 

Serotonin 1A has its own special serotonin syndrome 67, 68, . Both the azapirones and the benzodioxines conform to the properties of  a partial agonist at the serotonin 1A level. 69, 70,. 71, Partial agonists may imply a mechanism for neuromodulation. These effects may have implications for high dose (post-synaptic) effects such as possible anti-aggressive effects in high threshold subpopulations such as mania. (hypothesized in Cohorts 2,  3 and 4 below ). The functions of serotonin could reflect serotonin 1A neuromodulation as well because serotonin 1A has remained unique amongst the serotonin receptor subtypes as the action of drugs acting on this receptor is both presynaptic directly at the raphe nucleus level and,  in sufficient doses,  post-synaptic at the hippocampus,  amygdala,  cerebral cortical level 20, 72.  Low doses (presynaptic or autoreceptor level doses) of such compounds acting at this level may also have implications for aggression (hypothesized in Cohorts 1,  3 and 4 below).

 

 

Serotonin 1A Drugs

There are three groups of drugs in which the serotonin 1A neuromodulation model can be tested. The azapirone,  buspirone (marketed for control of anxiety and mixed anxiety-depression)  is ideal because of its specificity for the serotonin 1A receptor at therapeutic doses 20, 72-- its effects on the dopamine receptor in a non-sensitized individual should occur only an order of magnitude higher,  say at doses of 300 or 400 mg per day,  although electrically firing at a dopaminergic cholinergic and noradrenergic levels occurs in pharmacologic doses. 20, 73, 74, 19, 75

Serotonin 1A receptor action can also be appraised non-specifically by the beta 2-adrenergic receptor blockers like propranolol (which overall antagonize) 70, 76, 77, 78,  the benzodioxines such as eltoprazine (which act probably as partial agonists) 69, 71, 79, 80, 81 and lithium 82, 83 (which acts as an agonist amongst possibly fifty other hypothesized actions).  . All three of the prototypical drugs,  the azapirones,  benzodioxines and beta blockers,  have K1 values which suggest serotonin 1A effects within therapeutic ranges 20 Psychopharmacologically,  the availability of non-specific comparative 5HT 1A drugs,  the beta-adrenergic blocking agents (used for many reasons medically,  but psychiatrically including control of somatic anxiety)  and the benzodioxines (being explored but not yet marketed for aggression),  allow comparisons across serotonin receptor subtypes,  and allow further exploration of diagnoses,  symptomatology,  and hypothesis testing for other receptor subtypes 20

 

Testing the theory of  non-specific serotonin 1A drugs modulating aggression:

This theory can be tested using other examples based on empirical data.

Lithium

Lithium has been well demonstrated to have some degree of anti-aggressive effect 84, 85,  but it is  little-known that lithium acts as a post-synaptic serotonin 1A agonist in rodent models.83 Administration of lithium chloride for 3-14 days enhances the components of the serotonin syndrome produced by 8-hydroxy-2-(di-propylamino)tetralin (8-OH-DPAT) in the rat,  but the hypothermic response ( ? presynaptic) was unaltered. By contrast,   responses at the  5-HT1B receptor agonist were unaltered by repeated lithium administration 83. .

Beta-adrenergic blocking agents

 The beta2 adrenergic blockers  predominantly antagonize the serotonin 1A post-synaptic receptor but non-specifically.  Beta1 and 2 adrenergic blockade makes interpretation of which action is occurring more difficult  .

There are at least 11 marketed beta-blockers in various countries of which eight are non-cardioselective - they act on the beta 2 receptor even in low doses. 86, 87. Of these,  propranolol 70, 76, 77, 78, 88 and  pindolol 64, 69, 77, 89 particularly have been evaluated with regard to their  serotonin 1A post-synaptic receptor action and  alprenolol 79, 90, 91, 92, timolol 92, 93, oxprenalol 94, 95 and possibly nadolol 74 all been demonstrated to have serotonin 1A antagonism effect. The link to serotonin 1A of the beta 2 -adrenergic blocking agents was demonstrated definitively in 1988 when the genomic clone of serotonin 1A was produced from an attempt to isolate the beta 2 adrenergic receptor which it  resembles and is apparently part of 96, 97. The 5HT1A receptor  activity of the beta-blockers may  depend on  the beta 2 -adrenergic effect : d-propranolol,  the dextroisomer of propranolol is ineffective as a beta-adrenergic blocking agent 98, 99,  and also is an ineffective serotonin 1A antagonist. 100. This emphasizes how difficult it is to differentiate beta 2 from serotonin 1A effects. 

 

Clinically,  beta blockers have been used in low dosage to lower somatic symptoms of anxiety,  and with it there is a lowering of frustration with a lowering of aggression.  This is probably an adrenergic,  non-serotonin related phenomenon,  and frequently corresponds empirically with a pulse in the high 60's. 86, 87  A pulse in the low 60's corresponds with high doses of lipid-soluble beta-adrenergic blocking agents such as propranolol and pindolol,  and these drugs in high doses have been used in the control of rage and aggression,  particularly organic rage.  This seems anomalous because (-) Pindolol and (-) propranolol displayed high affinity for 5-HT1A as potent antagonists at 5-HT1A receptors in rat hippocampus 101.. Moreover,  (-) propranolol has certain impinging effects on the serotonin 2 receptor ( e  .g. relatively high doses of propranolol only partially antagonized the effects of LSD) 70.  Consequently,  this may imply that serotonin 2 antagonism is not the mechanism linked to anti-aggressive effects. However,   like the beta-adrenergic antagonist,  pindolol,  propranolol binds with high affinity to 5-HT1B 76, 102 .Propranolol binds stereoselectively both at 5-HT1A and 5-HT1B sites (with a several-fold selectivity for the latter) and,  whereas it is a 5-HT1A antagonist,  it appears to be a 5-HT1B agonist. As such,  it could serve as a lead compound for the development of new 5-HT1A and 5-HT1B agents based on preliminary studies  for the development of novel serotonergic agents 103. . Moreover,  some beta-adrenoceptor antagonists may behave as mixed agonists-antagonists at the 5-HT autoreceptor. 104 .Finally,  (-)-propranolol is a relatively weak antagonist of 5-HT itself,  suggesting that the endogenous neurotransmitter may have actions on dorsal raphe neurons in addition to those mediated by 5-HT1A receptors. 88

             However,  a confounding factor is that beta blockers such as propranolol also act in serotonin 1B as agonists. 76, 105, 106 The serotonin 1B receptor has at this point not been demonstrated in man 106, 107,  but many of the more perplexing features relating to the anti-aggressive action of beta blockers which may be 5HT 1A antagonists,  may be explained on the basis of a possible presence of serotonin 1B in man at which the beta blockers may be agonists. (Neppe,  1990) The serotonin 1B receptor is a very potent anti-aggressive receptor,  using the rodent model. This may or may not be applicable in man because no serotonin 1B receptor has thus far been demonstrated in humans.  Moreover,  the effect potentially could still be non-serotonin related and beta adrenergic,  so that these are complicating hypotheses.  These are needed to explain what has been found clinically with propranolol and aggression.

 

The use of high dose propranolol in rage and aggression is very promising. Several studies of generally high doses of propranolol used for aggression in organic brain syndromes in children,  Korsakoff's psychosis,   in schizophrenia,  severe mental retardation,  adult autism  and chronic organic brain syndromes have suggested its usage. 87, 108, 109, 110, 111 Real rage requires higher  doses of lipophilic drug and the effects are delayed weeks with the pulse being  not in the mid-sixties as for somatic anxiety but lower suggesting a second different mechanism. Additionally,  by contrast,  low doses and the  peripheral effects of several beta-adrenergic blocking agents produce almost immediate relief of  aggression linked to  frustration 87  Moreover,  animal studies support the anti-aggression effect of propranolol. 112  Studies with other lipid soluble beta 2 -adrenergic blocking agents  such as pindolol  exist. 113 Some of the effects may well be beta-adrenergic in higher doses or the serotonin mechanisms or combinations can be invoked. 87

 

Can one reconcile these three groups of drugs in relation to the pharmacology of aggression?  Clearly,  agonism at serotonin 1A level  could be supported by buspirone and by lithium,  but is apparently contradicted by propranolol. These studies complement research in aggression with both the azapirones and lithium - relevant because lithium has amongst other actions,  serotonin 1A effects  .

We now review the literature on the more specific serotonin 1A compounds, the azapirones.

 

The azapirones

The exploration of serotonin 1A functions has had impetus with the development of  a series of compounds,  the azapirones,  which appear specific for this receptor in therapeutic doses. There are at least 11 azapirones being researched : These drugs differ from the benzodiazepines structurally and also in that they have no significant effects on seizures,  have no muscle relaxant effect and their anti-anxiety action is delayed for some two to three or four weeks. 19, 114, 115 However,  the only marketed one currently is buspirone in which there is patient experience on several million. One can measure the functional effects of buspirone because it can block the serotonin 1A specific  agonist effects of 8-hydroxy DPAT116, 117  implying some antagonist effects.  But in high enough doses,  buspirone,  and particularly its azapirone analog,  gepirone,  can induce a serotonin 1A related syndrome. 118, 119,117. This implies that functionally buspirone has both serotonin agonist and serotonin antagonist effects leading to the hypothesis of partial agonism. 117, 120, 121 Additionally,  a great deal of firing has been demonstrated at the presynaptic autoreceptor  level in relation to serotonin 1A. This firing occurs in the dorsal raphe  nucleus.  When presynaptic agonism occurs,  by virtue of feedback loops,  there will overall be  less serotonin available post-synaptically for the synapse because ultimately there will be lowered serotonin tone. 72, 118. This would imply blockade not only at serotonin 1A levels,  but serotonin 2 and possibly serotonin 3 levels with a functional post-synaptic serotonin antagonism overall,  including a serotonin 2 antagonism 60, 118, 122, 123. The azapirones act pre-synaptically as complete agonists. This produces firing at that level with an overall endpoint diminution in serotonergic tone post-synaptically. 60, 118 In the animal model this has been well-demonstrated 117, although there may be some attenuation of this post-synaptic serotonergic tone 124  and overall antagonism at serotonin 1,  2 and possibly 3 levels.  This mechanism may be very important in using low doses of buspirone in aggression  .

 In high doses buspirone acts as a moderate but incomplete serotonin 1A agonist.  The differentiation of pre-synaptic and post-synaptic effects has been argued to be appropriately modeled on such features as pre-synaptic hypothermia and post-synaptic elevations of prolactin which can be blocked by serotonin antagonist type drugs. 125, 126, 127, 128 Post-synaptic agonism may well imply some kind of reciprocal relationship with serotonin 2,  implying again a serotonin 2 antagonism,  using a variety of models,  namely model of hypo/hyperthermia,  hypotension / hypertension 129,  quipazine related effects,  habituation of tactile startle via actions at 5-HT2 receptors 125, 130, 131  and even  migraine  132    .

 

A wide variety of human psychopathologies reflecting serotonin 1A involvement can therefore be analyzed in detail,  particularly so as buspirone is safe,  used extensively in clinical practice and in low doses non-sedative. It has  low toxicity,  few side-effects,  no established lethality (LD 50 that has not even been established in man),  very little cognitive and psychomotor impairment. and no apparent potential for dependence.  Buspirone despite its anxioselective action does not act on benzodiazepine or GABA receptors. Many typical anxiolytic drugs like the benzodiazepines which induce sedation,  muscle relaxation,  anticonvulsant effects,  act almost immediately and may induce dependence. 19, 20

 

            This azapirone’s action appears to be broad,  so that the phrase "anxioselective neuromodulator" can be used. 19 Buspirone has a short half-life,  requiring thrice daily dosing,  and has limited interactions with other drugs. 19 It has been used with several hundred other psychotropic and other compounds without major interactions. 133, 134 Its major metabolite (like gepirone and tandospirone) is 1-2 pyrimidinyl piperazine or 1PP. 135, 136, 137, 138, 139 There is some dispute as to the level of activity of 1PP,  which occurs in significant amounts. 138, 140, 141

 

            There is substantial animal evidence for buspirone being a potent anti-aggressive substance,  and this applies to other azapirones such as gepirone and ipsapirone38, 45, 142, 143 as well.  This anti-aggressive effect should be at the serotonin 1A receptor, and this in fact may be one of the fundamental actions at this level. 20, 68] In fact,  using every single animal model for aggression,  relating to muricidal behavior and conflict-related aggression,   inter-species and intra-species related aggression,   isolation-induced models  and group-related models,  buspirone comes out as a very potent anti-aggressive agent in appropriate doses,  and this property appears shared by gepirone. 45, 115, 144  In the muricidal model,  buspirone requires higher doses,  not having effects in lower doses45  : it potently inhibited attacks against group housed intruder mice (ED50 = 4  .5 mg/kg i.p.) without causing sedation or ataxia. Inhibition of aggression was potentiated by co-administration of methysergide. 45  This is particularly so as many of the paradigms used in animals to demonstrate the anxiolytic effect of buspirone can be also used to demonstrate its anti-aggressive effect. 68 Theoretically,  supporting models exist in man. 145

           

            However,  double blind studies in aggression in man are lacking. Irritability is an early target symptom of response with buspirone in generalized anxiety disorder possibly implying persistent low-dose  effects. 146, 147, 19.  Also,   Ratey has published his uncontrolled data,  on 14 mental retardates,  nine of whom responded favorably to the drug. 148, 149.Numerous other case reports are scattered in a variety of different uses. 150, 151, 152, 153, 154, 155, 156, 157  A small amount of irritability ranking data exists in a double-blind study on pre-menstrual syndrome 151, 158, 159, 160, 161, 162 159, 161. In all studies buspirone was very promising. Possible applications of aggression,  research in man,  relate to psychogeriatric patients 20], 163, 164, 165 the personality disordered people and people with frustration leading to aggression. 125

 

 

OUR STUDIES

I will also now contribute our small open pilot data in this regard using several cohorts. The data is preliminary with the typical limitations of real clinical patients. It should consequently be interpreted with caution. However,  several new elements are important involving buspirone applications in the this out-of-labeling context  .

1. use in a non-organic sample in low doses  (Cohort 1 and part of Cohort 3)

2. use in a manic-like sample (Cohort 2) and mania and other conditions (part of Cohort 3) in high doses  suggesting bimodal dosage

3. use in a temporal lobe dysfunction subgroup with carbamazepine  .(Cohort 4)

None of these cohorts overlap 

 

Sample

We evaluated the efficacy of buspirone in the management of in - and out- patients referred with main complaints of or  with major problems of aggression. Our study involved an open trial of buspirone to inpatients or outpatients referred for a variety of reasons,  but with a very major part of their presentation being aggression,  irritability or violence as main complaints. These patients generally had little or no clinically significant anxiety (to distinguish the anxiety component of treatment).  Because buspirone is marketed for generalized anxiety disorder (GAD) and this condition frequently has frustration and consequent irritability,  we excluded all patients specifically labeled as having GAD to definitely separate the two conditions.  We included all successive referrals with aggression who had been placed onto buspirone. We also included a small subpopulation of patients going into or coming out of a manic episode who were irritable  .

 

 

 

Cohort 1 :  Short -term inpatients on low dose buspirone

            These patients were given low doses  of buspirone,  generally of the order of 15-25 mg per day.  Our cohort is of nine such successive inpatients. Several of these were intractable and varied from being on no ancillary medication to other medications,  for example carbamazepine or fluoxetine. This study evaluated only short-term improvements for practical reasons:  changes at the end of hospitalization or first follow-up.  At the dose given (15mg to 25mg per day),  all 9 subjects ( mean age : 29±11 years ; 8 males ) exhibited some improvement both globally using clinical global assessments of change,   and also specifically on hostility rankings based on a 0-6 ordinal ranking of the Kay criteria for the Brief Psychiatric Rating Scale (BPRS) (Table 1).  The improvements ranged from slight in one (the female ),  moderate in two,  and substantial in the rest. Using the ordinal scale of range 1{slight} through 6 {very marked},  the  mode was 4,   and the median was 3.  Using a  binomial ranking of improved vs not improved,  these results are significant at the p<0  .001 level. Response generally took about 4-5 days to be most overt although patients continued to note greater improvements.  The biggest difficulty is interpreting the data clinically in the absence of controls - many inpatients improve with milieu and re-evaluating these patients retrospectively,  we could have predicted that as many as five of the nine would have improved without the buspirone intervention. Because of this the Clinical Global Impressions Rankings (CGI) were useful : the patients were generally severely ill initially and exhibited rankings of clinically relevant improvement on overall therapeutic efficacy with low side-effects and excellent efficacy index. (Table 1 )

 

TABLE 1    CHANGES IN HOSTILITY AND GLOBAL RANKINGS

 

N=9

8 male

Age in

Years

CGI1 

Ranking

Begin

Hostility2

End

Hostility

Change in

Hostility *

Improvement degree on CGI 3

Therapeutic  Efficacy4

Side

Effects5

Efficacy Index6

Mean

29

4  .3

4  .7

1  .4

3  .2

2  .0

0  .8

1  .2

2  .0

SD

11

0  .7

0  .7

1  .5

1  .5

0  .7

0  .7

0  .7

1  .2

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

 

N=13

9M, 4F

Age

Frequency of dosing

Dose in mg

Other

medics

Months on buspirone

Early

Response

Later Behavioral Response

Later

Subjective

Response

mean

39  .5

3  .1

33  .1

1  .31

19  .5

1  .67

1  .41

  .67

SD

19  .4

0  .28

25  .9

1  .18

14  .33

0  .49

1  .31

  .63

median

37

3

15

1

18

2

2

1

mode

19

3

15

2

2

2

2

0

range

17 to 78

 

 

 

 

 

 

 

 

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

 

N=14;

10M,  4F

Age

Frequency of dosing

Dose in mg

Other

medics*

Months on buspirone

Early

Response

Later Behavioral Response

Later

Subjective

Response

mean

33  .7

3

47  .9

2  .71

22  .43

1  .86

1  .85

1  .53

SD

14  .3

0  .39

37  .3

1  .59

14  .22

0  .36

  .67

  .77

median

34

3

30

2  .5

22  .5

2

2

2

mode

-

3

75

4

32

2

2

2

range

12 to 57

 

 

 

 

 

 

* this refers to other prescription medications besides the buspirone taking concomitantly

 

Table 4: Carbamazepine dropouts on buspirone

 

N=8

4M,  4F

Age

Frequency of dosing

Dose in mg

Other

medics

Months on buspirone

Early

Response

Later Behavioral Response

Later

Subjective

Response

mean

43  .8

3

36  .3

1  .88

19  .5

  .75

1  .58

1  .58

SD

13  .5

0

23

0  .84

14  .33

0  .89

0  .53

0  .53

median

42  .5

3

32  .5

2

18

1

2

2

mode

-

3

15

1

2

1

2

2

range

26 to 65

 

 

 

 

 

 

 

 

Table 5 :  Outpatient responsive to buspirone based on dosage

 

Buspirone

10-25mg/d  bus

 

30-55mg/day

 

60-140mg/day

^^

 

SIZE

response

SIZE

response

SIZE

response

Cohort 3

9

9

0

0

4

3

CBZ+ BSP

5

5

3

3

4

3 (2 subjectively)

CBZ dropouts

4

4

0

0

4

4

# RESPOND^

 

18

 

3

 

10 (9 subjectively)

TOTALS

18

 

3

 

12

 

^ 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.

            The time has arrived for the azapirones to be thoroughly investigated and possibly to be marketed thereafter as the first anti-aggressive agents without sedation,  addiction and neuroleptic effects and with significant safety  .

 

 

 

 

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179.     Beauregard LA, Fabiszewski R, Black CH, et al. : Combined ambulatory electroencephalographic and electrocardiographic recordings for evaluation of syncope.  Am J Cardiol  68 (10):1067-72, 1991

 

180.     Neppe VM :  :Carbamazepine Use in Neuropsychiatry. 1-64, J Clin Psychiatry Supplement 4, 1988

 

181.     Neppe VM. Carbamazepine, limbic kindling and non-responsive psychosis. In:  Innovative Psychopharmacotherapy, Neppe  VM ed. New York: Raven Press,   123-151 , Ch 5, 1989

 

182.     Neppe VM. Perspectives on the pharmacologic management of agitation and irritability in the geriatric patient. In:  Psychiatric Disorders in the Elderly: Current Treatment Practices, Conference ed. San Francisco: Mt Zion Institute on Aging,  56-62, 1993

 

183.     Neppe VM :  41 (39):Management of irritability and aggressive behavior. October 18, 1993 pp 2-3 plus audiotape, Audio Digest Family Practice, 1993

 

 

 

 

Professor Vernon M. Neppe

Director, Pacific Neuropsychiatric Institute, Seattle, WA, USA; Adjunct Professor of Psychiatry and Human Behaviour, St Louis University School of Medicine, St Louis, MO, USA.

 

Correspondence:

Vernon M. Neppe, MD, PhD, FFPsych, MMed, FRCPC, DPM, MB, BCh, Dip ABPN

Director

Pacific Neuropsychiatric Institute

Seattle Healing Arts Center, Suite 353
6300 Ninth Ave NE
Seattle, WA 98115

 

    The assistance of John A. Walenta in the data analysis for Cohorts 3 and 4 is gratefully acknowledged.

See Also: BUSPIRONE AS A NEW TREATMENT FOR ATTENTION DEFICIT DISORDER AND AGGRESSION IN CHILDREN AND ADOLESCENTS

 

 

 


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