|
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 |
