Ipsapirone neuroendocrine challenge: relationship to aggression as measured in the human laboratory

Moeller, F. Gerard; Allen, Terry J.; Cherek, Don R.; Dougherty, Donald M.; Lane, Scott D.; Swann, Alan C.

doi:10.1016/s0165-1781(98)00081-x

Cited by 28 publications

(17 citation statements)

References 34 publications

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“…In another recent report, PRL responses to both fenfluramine and m -CPP were blunted in personality-disordered individuals with high self-reported hostility (Coccaro et al 1997a). Finally, other physiological responses to serotonergic agonists fenfluramine (Coccaro et al 1996) and ipsapirone (Moeller et al 1998) were inversely correlated with rates of laboratory aggression.While these correlational data are compelling, the strongest support for the hypothesis that dysfunctional 5-HT neurotransmission facilitates aggression is prospectively-measured behavior change after the impairment or enhancement of the 5-HT system. This research in humans can be difficult in that serotonin-specific drugs can take days to weeks to exert any mood and/or behavior effects, and these effects may be too subtle for detection by many laboratory measures.…”

mentioning

confidence: 78%

Differential Behavioral Effects of Plasma Tryptophan Depletion and Loading in Aggressive and Nonaggressive Men

Bjork¹,

Dougherty²,

Moeller³

et al. 2000

Neuropsychopharmacology

123

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Preliminary findings indicate that men with high trait hostility may be prone to aggression increases following plasma tryptophan (Trp) depletion. We measured laboratory aggression in men selected for presence (n ϭ12Substantial research has implicated decreased serotonin (5-HT) neurotransmission in human aggressive behavior (Brown et al. 1979;Coccaro et al. 1997a;Linnoila et al. 1983;Virkkunen et al. 1994). In recent neuroendocrine challenge studies, aggression has correlated negatively with plasma prolactin (PRL) elevations following the administration of the 5-HT agonist fenfluramine (Coccaro et al. 1996;Manuck et al. 1998). In another recent report, PRL responses to both fenfluramine and m -CPP were blunted in personality-disordered individuals with high self-reported hostility (Coccaro et al. 1997a). Finally, other physiological responses to serotonergic agonists fenfluramine (Coccaro et al. 1996) and ipsapirone (Moeller et al. 1998) were inversely correlated with rates of laboratory aggression.While these correlational data are compelling, the strongest support for the hypothesis that dysfunctional 5-HT neurotransmission facilitates aggression is prospectively-measured behavior change after the impairment or enhancement of the 5-HT system. This research in humans can be difficult in that serotonin-specific drugs can take days to weeks to exert any mood and/or behavior effects, and these effects may be too subtle for detection by many laboratory measures. Nevertheless, some data have shown a tendency for serotonergic drugs to decrease aggression in humans. For example, From NO . 4 fluoxetine (Coccaro et al. 1997c) and sertraline (Kavoussi et al. 1994) attenuated clinician-rated impulsive aggression in psychiatric patients. Heiligenstein et al. (1993) meta-analyzed data from thousands of patients in several clinical trials of fluoxetine and found that aggressive acts were reported in only 0.15% of fluoxetinetreated patients, but 0.65% of placebo-treated patients. When aggression was measured prospectively, fluoxetine was effective in decreasing aggression in a psychiatric outpatients selected for prominent impulsive aggression (Coccaro and Kavoussi 1997).The administration of a beverage of large neutral amino acids (LNAAs) which lacks 5-HT precursor L-tryptophan (Trp) can rapidly alter brain 5-HT (Young et al. 1985). This technique, called "tryptophan depletion," reduces brain Trp uptake in two ways: 1) LNAAs competitively inhibit active transport of Trp across the blood-brain barrier (Yuwiler et al. 1977), and 2) endogenous plasma Trp is incorporated into proteins in the hepatic response to the LNAA load (Gessa et al. 1975). Animal research has shown that Trp depletion dosedependently reduces brain levels of Trp, 5-HT, and the 5-HT metabolite 5-HIAA within a few hours (Biggio et al. 1974;Moja et al. 1989).In humans, Trp depletion has decreased synthesis rates of a 5-HT analogue in the brain in a PET scanning experiment (Nishizawa et al. 1997), and has reduced cerebrospinal fluid concentrations of 5-HIA...

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mentioning

confidence: 78%

Differential Behavioral Effects of Plasma Tryptophan Depletion and Loading in Aggressive and Nonaggressive Men

Bjork¹,

Dougherty²,

Moeller³

et al. 2000

Neuropsychopharmacology

123

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“…The PSAP has been shown to relate to serotonin state the hypothesized mediating factor between cholesterol and violence and to aggression/violence [56][57][58]. An increase in aggressive responding by PSAP occurred in healthy males with a serotonin-lowering drink [59,60].…”

Section: Point Subtraction Aggression Paradigm (Psap)mentioning

confidence: 99%

“…The first session of the PSAP represents a primary outcome [54][55][56][57]. This comprises a 25-min test in which subjects sit before a computer screen with a bar with two response options.…”

Section: Point Subtraction Aggression Paradigm (Psap)mentioning

confidence: 99%

“…Points are subtracted from the subject's point-accumulation counter randomly, every 6 to 120 s (potentially "provoking" the subject); the subject is led to believe these subtractions originated with the fictional partner [55]. Current points earned are displayed in the center of the computer screen.The PSAP has been shown to relate to serotonin state the hypothesized mediating factor between cholesterol and violence and to aggression/violence [56][57][58]. An increase in aggressive responding by PSAP occurred in healthy males with a serotonin-lowering drink [59,60].…”

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confidence: 99%

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The UCSD Statin Study: a randomized controlled trial assessing the impact of statins on selected noncardiac outcomes

Golomb

Criqui

White

et al. 2004

Controlled Clinical Trials

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There has been persistent controversy regarding possible favorable or adverse effects of statins or of cholesterol reduction on cognition, mood and behavior (including aggressive or violent behavior), muscle function, and quality of life. The UCSD Statin Study seeks to ascertain the beneficial or adverse effects of statin cholesterol-lowering drugs on a set of noncardiac endpoints, including cognition, behavior, and serotonin biochemistry. The study will enroll 1000 subjects (minimum 20% female) of mixed ethnicity from San Diego. Subjects must be age 20 and older, postmenopausal if female, without known cardiovascular disease or diabetes, and with LDLcholesterol between 115 and 190 mg/dl. Subjects will be randomized to a double-blind, placebocontrolled trial with assignment 1/3, 1/3, 1/3 to placebo, simvastatin 20 mg, or pravastatin 40 mg (equipotent LDL-cholesterol-lowering doses for drug arms with simvastatin and pravastatin chosen to represent the extremes of the lipophilicity spectrum) for 6 months of treatment followed by 2 months postcessation follow-up. Primary outcomes are cognition (cognitive battery), irritability/aggression (behavior measure), and serotonin (gauged by whole blood serotonin), assessed as the difference between baseline and 6 months, judging combined statin groups vs. placebo. Secondary outcomes include mood (CES-D and Wakefield depression inventory), quality of life (SF-12V), sleep (Leeds sleep scale, modified), and secondary aggression measures (Conflict Tactics Scale; Overt Aggression Scale, Modified). Cardiovascular reactivity will be examined in a 10% subset. As additional secondary endpoints, primary and selected secondary outcomes will be assessed by statin assignment (lipophilic simvastatin vs. hydrophilic pravastatin). "Reversibility" of changes, if any, at 2 months postcessation will be determined. If effects (favorable or unfavorable) are identified, we will seek to ascertain whether there are baseline variables that predict who will be most susceptible to these favorable or adverse noncardiac effects (i.e., effect modification). NIH Public Access BackgroundStatins are important and widely prescribed drugs, with well-documented and incontrovertible cardiac benefits. However, controversy remains regarding the existence and impact of noncardiac effects, including central nervous system (CNS) effects. The University of California-San Diego (UCSD) Statin Study, a National Institutes of Health/ National Heart Lung and Blood Institute-funded double-blind, placebo-controlled study, seeks to address these issues through a complex battery of tests assessing noncardiac outcomes pertaining to cognition, behavior, quality of life, and biochemistry, among other endpoints. This paper provides the general methodology employed and addresses certain theoretical issues in study design.Statin cholesterol-lowering drugs (HMG-CoA reductase inhibitors) are the most prescribed drugs in the United States and the world and contributed substantially to prescription drug cost increases in 200...

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“…However, others have found increased cortisol responses to ipsapirone, in association with aggression (Netter et al, 1999) and active mania (Yatham et al, 1999), and to meta-chlorophenylpiperazine (m-CPP, an agent with multiple serotonergic actions (Gatch, 2003)), in association with BPD (Hollander et al, 1994). A few studies have found no association of cortisol response to ipsapirone in relation to either trait anger (Klaasen et al, 2002), disinhibition (Netter et al, 1996), or levels of aggressive responding on a laboratory test of interpersonal antagonism (Moeller et al, 1998), although the first two of these studies may have used suboptimal doses of ipsapirone (Kahn et al, 1994). Overall, this literature suggests that various syndromes of impulsivity and aggressive behavior involve alterations in the function of 5-HT 1A and possibly D 2 receptors as well.…”

Section: -Ht 1a Receptor Function In Impulsive Aggressionmentioning

confidence: 99%

Blunted Hormone Responses to Ipsapirone are Associated with Trait Impulsivity in Personality Disorder Patients

Minzenberg

Grossman

New

et al. 2005

Neuropsychopharmacol

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Impulsive aggression is associated with central serotonergic dysfunction. Animal models particularly implicate the 5-HT 1A receptor in this behavior. We tested the hypothesis that central 5-HT 1A receptor function is impaired in impulsive aggressive personality disorder patients. A total of 52 individuals with DSM-III-R personality disorders, all medically healthy adult outpatients without concurrent psychiatric medication treatment, underwent serial plasma cortisol, prolactin, and temperature measurements before and after ipsapirone 20 mg oral administration. Subjects completed self-report measures of impulsivity, hostility, depression and anxiety, and childhood maltreatment. Stepwise regression analysis revealed impulsivity alone among symptom measures to be associated with significantly decreased peak cortisol and prolactin responses. Diagnoses of borderline personality disorder (BPD) and intermittent explosive disorderrevised (IED-R) were associated with significantly increased and decreased cortisol responses, respectively. However, post hoc analyses indicated that impulsivity was significantly negatively correlated with cortisol responses in the BPD group, and may mediate the association of both BPD and IED-R with altered cortisol responses. Temperature response was associated with neither diagnostic nor symptom measures. Neither diagnostic nor dimensional measures of depression or anxiety, nor severity of childhood maltreatment, were significantly associated with cortisol, prolactin, or temperature responses. Impulsivity is related to impaired function at (or downstream to) postsynaptic 5-HT 1A receptors, and this relationship may be partly responsible for the association of impaired serotonergic function with diagnoses such as BPD and IED-R. In addition, D 2 receptor dysfunction may play a role in impulsivity, whereas 5-HT 1A cell-body autoreceptor function may be spared in these disorders.

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Ipsapirone neuroendocrine challenge: relationship to aggression as measured in the human laboratory

Cited by 28 publications

References 34 publications

Differential Behavioral Effects of Plasma Tryptophan Depletion and Loading in Aggressive and Nonaggressive Men

Differential Behavioral Effects of Plasma Tryptophan Depletion and Loading in Aggressive and Nonaggressive Men

The UCSD Statin Study: a randomized controlled trial assessing the impact of statins on selected noncardiac outcomes

Blunted Hormone Responses to Ipsapirone are Associated with Trait Impulsivity in Personality Disorder Patients

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