Pharmacology of Aggression & Violence

Question 1

Humble and Berk (2003)

Answer 1

Pharmacological treatments for violent patients shouldn’t interfere with the therapy provided; the patient/therapist relationship should be maintained

Drugs that interfere with cognition/affective state would only worsen the situation

Difficulty reviewing psychopharmacology of aggression due to definitional differences

Few studies with controls/placebo

Difficulty measuring aggression objectively

BDZs: anxiolytic, muscle relaxants, anticonvulsants; but, can cause paradoxical aggression

Question 2

Comai et al., (2012b)

Answer 2

Combined drug treatment targeting different receptors is the best strategy

Aggressive behaviour in itself isn’t formally a disorder

Beta-blockers: effective but severe

Typical antipsychotics: target DA only

Atypical antipsychotics: target other pathways too

Conclusion: atypicals seem better when combined, but have adverse side effects

Challenge: selectivity

Question 3

Miczek and de Almeida (2012)

Answer 3

Current treatments: don’t reduce aggression, simply sedate/incapacitate, and have been discovered serendipitously

Not much known about their mechanisms

DSM editions fail to address the issue

Classic 5-HT deficiency hypothesis: disproven

Direction: use ethological approach; examine drug effects on both aggressive & non-aggressive behaviours

Escalated aggression: discrete hypothalamic neurons might be associated with escalated (or non-motivated) aggression in mice

Question 4

van Schalkwkyk et al., (2017)

Answer 4

Meta-analysis

No evidence to support rationale for increasing use of antipsychotics

Side effects > benefit

Question 5

Manchia and Fanos (2017)

Answer 5

Violence & aggression - overrepresented in mental illness

Increasing evidence that gut microbiome might be connected to the CNS & affect its signalling

Existing genetic predisposition + diet might interact with bacteria to produce metabolites which will enter the bloodstream and affect the brain

Question 6

Rodgers and Waters (1985)

Answer 6

Previous implications that BDZs have unidirectional anti-aggressive properties - oversimplified; any drug can reduce aggression

Different underpinnings of offensive vs defensive aggression?

BDZs can reduce defensive aggression but increase offensive aggression (varying across species & context)

ED50 vs NTD50

Challenge: behavioural selectivity

Future directions: use pharmacoethological methods

Question 7

Vitiello and Stoff (1997)

Answer 7

Classification: impulsive-affective vs controlled-predatory aggression

Different interventions might target these two different aspects

Question 8

Takahashi et al., (2013)

Answer 8

5-HT system shown to be associated with different types of aggression

Recent pharmacological tools differentiate the first 3 5-HT receptor families and their modulation by GABA & other NTs

Activation of 5-HT1A, 5-HT1B, & 5-HT2A/2C receptors in the mesocorticolombic area reduces species-normative aggression

Agonists at 5-HT1A & 1B receptors in the mPFC or septal area can increase aggressive behaviour

Question 9

Brain (1977, 1981)

Answer 9

Aggression definition:

Potentially harmful stimuli…

Intent

Emotional arousal

Object reacts aversively

Question 10

Archer (1988)

Answer 10

3 types of aggression:

Competitive

Protective

Parental

Question 11

Arakawa (2017)

Answer 11

Review: housing conditions of lab rodents might affect their behavioural performance

Can affect emotional & defensive behaviours

Social isolation:

Deprivation of social contact… degraded mPFC during development

No opportunity to transmit information about environment

Question 12

Blanchard and Blanchard (1981)

Answer 12

Offensive vs defensive attacks

Colony dominant rats: offensive

Colony intruders & lactating dams: defensive

Shocked animals: always defensive

Question 13

Sofia (1969)

Answer 13

Effects of chlordiazepoxide in 4 tests

Only in 1 (pain-induced) ED50

Question 14

Krsiak and Sulcova (1990)

Answer 14

Effects of BDZs on aggressive or timid mice (from social isolation) - assessed both aggression & locomotion

Effects varied

Drugs were comparatively more selective for defensive aggression

Ethological approach here is superior

Question 15

Miczek et al., (2002)

Answer 15

Preclinical aggression models must shift towards escalated aggression

Major models of escalated aggression:

Hypoglucocorticoid status

Alcohol-heightened

Social instigation

Also: neglect; frustrative non-reward; hypothalamic attack

Alcohol, BDZs, & neurosteroids: induce paradoxical aggression & all 3 are positive modulators of the GABA-A receptor complex

Question 16

De Almeida et al., (2010)

Answer 16

Alcohol and a BDZ each cause remarried l escalated aggression; highest when combined

Question 17

Miczek et al., (2013): Overall

Answer 17

Animal model for escalated aggression: resident-intruder paradigm

Has high face & construct validity, but:

Lab animals & housing? Ethics? Drugs that reduce adaptive aggression haven’t been demonstrated to reduce escalated aggression

Question 18

Miczek et al., (2013): Hypoglucocorticoid status

Answer 18

Violence in antisocial personality disorder is associated with hypoarousal in glucocorticoid production (& heart rate and skin conductance)

Replicated in rats by adrenalectomy (ADXr) - removal of the adrenal glands & implanting corticosterone pellets:

Lower heart rate
No difference in locomotion
Lower intention signalling
High defensive aggression patterns

Reversed by reintroduction of cortisol

Question 19

Miczek et al., (2013): Alcohol-heightened aggression

Answer 19

Approx. ⅔ of all acts of violence involve alcohol

Previous studies: alcohol inhibits aggression (but: only in very high doses)

However: low doses can sometimes increase aggression

Low alcohol doses, in both gavage & operant SA: significantly increase aggression

Limitation: no biomarker found to predict which individuals will exhibit alcohol-heightened aggression

Question 20

Miczek et al., (2013): Social instigation

Answer 20

Impulsively violent patients - excessive aggressive response to perceived provocation

Same aggressive arousal observed in rodents just prior to exposure to an intruder, and it persists even after removal of intruder (no contact)

5 minutes of non-contact exposure - sufficient to significantly increase attack readiness

Beta-blockers: successfully reduce aggressive arousal

Question 21

De Almeida and Miczek (2002)

Answer 21

5-HT1B agonist selectively reduces escalated aggression by social instigation or frustrative non-reward in mice

Question 22

deBoer and Newman-Tancredi (2016)

Answer 22

Used aggressive WTG rats: intruder-resident paradigm

5-HT1A receptor agonist preferential to postsynaptic sites reduced aggression selectively

5-HT1A receptor agonist preferential to presynaptic sites also selective reduced aggression, but with 20x potency

Question 23

Tulogdi et al., (2015)

Answer 23

Confirmed strong link between pathological & predatory aggression

Mostly similar brain activation seen in hypoglucocorticoid and muricide animal models