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 article was published in the
Australian J of Psychopharmacology?the final draft may not necessarily be
identical.?
The serotonin 1A neuromodulation of aggression - Bimodal buspirone
dosage as a prototype anti-irritability agent in adults
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
^ 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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T, Wistedt B : Staff observation aggression scale, SOAS: presentation and
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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.