Citalopram Intervention for Hostility: Results of a Randomized Clinical Trial

A large body of evidence demonstrates an elevated risk for incident cardiovascular (CVD) events among individuals scoring high on measures of hostility (Miller, Smith, Turner, Guijarro, & Hallet, 1996), especially among initially healthy individuals (Everson-Rose & Lewis, 2005). In these studies, hostility is defined as a personality trait involving behavioral tendencies (i.e., aggressiveness), cognitive biases (i.e., tendency to interpret situations in a suspicious and mistrustful manner), and/or emotional or motivational characteristics (i.e., experience of frequent and intense anger, (Smith, 1992). Such studies have rarely included measures tapping all three domains (Suls & Bunde, 2005). Measures of hostility are also associated with other psychosocial traits implicated in cardiovascular health, such as impulsivity (Manuck, Flory, Ferrell, Mann, & Muldoon, 2000; Ramirez & Andreu, 2006), which is linked with smoking and alcohol use (Grano, Virtanen, Vahtera, Elovainio, & Kivimaki, 2004) and depression and low social support (Raynor, Pogue-Geile, Kamarck, McCaffery, & Manuck, 2002; Smith & Frohm, 1985) which are linked with CVD risk (Berkman, Leo-Summers, & Horwitz, 1992; Musselman, Evans, & Nemeroff, 1998). A common neurobiological mechanism which could potentially explain these diverse associations involves deficits in central serotonergic function (R. B. Williams, 1994a, , 1994b). Accumulating evidence suggests that central serotonergic systems may regulate a number of behavioral processes that may contribute to CVD risk (Malone et al., 2003; Muldoon et al., 2006; Muldoon et al., 2004). Diminished central serotonergic function can be indexed by low concentrations of the serotonergic metabolite 5-HIAA in the cerebrospinal fluid (CSF), or by blunted prolactin responses to the acute infusion of a serotonergic agonist. Using these two measures, reduced central serotonergic function has been shown to be associated with increased aggression in primates (Botchin, Kaplan, Manuck, & Mann, 1993; Higley, King et al., 1996; Higley, Mehlman et al., 1996) and with measures of hostility among humans, especially among men (Cleare & Bond, 1997; Coccaro, 1997; Manuck et al., 1998). In addition to aggression, reduced central serotonergic function, as indexed by blunted prolactin responses to fenfluramine challenge, has also been shown to be associated with impulsivity (Manuck et al., 1998) and with current and past depressive episodes in human samples (Flory, Mann, Manuck, & Muldoon, 1998; Mann, McBride, Malone, DeMeo, & Kelip, 1995). Finally, concentrations of CSF 5-HIAA have been shown to be positively related to affiliation (e.g., grooming) (Mehlman et al., 1995) and social dominance (Higley, King et al., 1996) in nonhuman primates, and to measures of social competence in humans (Kruesi et al., 1990), implicating central serotonergic systems in behaviors that contribute to social support as well as to individual variability in negative affect. Pharmacologic interventions that enhance central serotonergic activity, such as selective serotonin reuptake inhibitors (SSRIs) have been found to be effective in reducing aggression and hostile affect in psychiatric samples, such as those with personality disorders or clinically significant depression (Coccaro & Kavoussi, 1997; Fava et al., 1993; Salzman et al., 1995). Because other psychiatric symptoms (for example, anxiety and depression) are prevalent in such samples and may themselves be linked with irritability or aggression, it is difficult to know the extent to which reduced hostility in such studies may be simply a consequence of improvement in other aspects of one’s condition during treatment. Unfortunately, only a small number of controlled studies have examined the effects of serotonergic interventions on hostility in nonpsychiatric samples. In a trial of healthy volunteers, Knutson et al. (Knutson et al., 1998) showed that a four-week course of paroxetine was associated with significant reductions on the Assaultiveness subscale of the Buss-Durkee Hostility Inventory (a measure of physical aggression) relative to placebo controls, and marginally significant reductions in the Irritability subscale as well. In a small (n =12) study of men with a history of conduct disorder but no current Axis I diagnosis, those assigned to 3 weeks of paroxetine showed significant decreases in aggressive responding on a standard laboratory task relative to those assigned to placebo (Cherek, Lane, Pietras, & Steinberg, 2002). Finally, in two double-blind crossover studies of unselected (Moskowitz, Pinard, Zuroff, Annable, & Young, 2001) and high hostile individuals (aan het Rot, Moskowitz, Pinard, & Young, 2006), a 12–15 day course of tryptophan supplementation was shown to decrease self-reports of quarrelsome behavior during social interactions. Because there are few empirically validated interventions for hostility (Gidron, Davidson, & Bata, 1999), these are promising leads with potential clinical relevance for understanding, and potentially intervening with, a group of individuals who demonstrate increased health risk. Unfortunately, none of these existing studies have employed measures of hostility that are most widely represented in the literature examining cardiovascular health, none of them have measured hostility as a multidimensional construct, and only one of them (aan het Rot, Moskowitz, Pinard, & Young, 2006), a study of tryptophan supplementation, selected appropriate candidates for intervention based upon initial hostility scores, a problem that could potentially reduce the magnitude of observed effects. In addition to their impact on aggression or hostility, serotonergic interventions have also been examined with respect to their effects on depression, impulsivity, and sociability. The effects of SSRIs on ameliorating depressive symptomatology is well documented in clinically depressed samples (Nemeroff & Schatzberg, 2007). Only one study, to our knowledge, has examined the effects of serotonergic enhancement on impulsivity in a nonpsychiatric sample: In the study of men with a history of conduct disorder described earlier, paroxetine was shown to enhance delay of gratification, as assessed by a behavioral measure (Cherek, Lane, Pietras, & Steinberg, 2002). There are no published studies, to our knowledge, examining the effects of serotonergic manipulations on perceived social support, but there are a couple of findings suggesting that serotonergic interventions may increase prosocial behavior in the laboratory (Tse & Bond, 2002) or during daily life (aan het Rot, Moskowitz, Pinard, & Young, 2006) but see also (Moskowitz, Pinard, Zuroff, Annable, & Young, 2001). In sum, previous evidence shows a higher risk for cardiovascular disease among hostile individuals, and a greater prevalence of other behavioral characteristics potentially linked with CVD in this group as well. Reduced central serotonergic function among hostile individuals may be one of the mechanisms explaining this increased disease risk; pharmacologic manipulations designed to enhance central serotonergic activity have been shown to have beneficial effects on hostility as well as a number of other relevant psychosocial traits. This paper describes a placebo-controlled investigation examining the effects of a serotonergic agent on hostility among initially high hostile individuals with no current Axis I comorbidity. Citalopram was employed because of its high serotonin selectivity and relatively low affinity for other major neurotransmitter receptors (Scales & Doraiswamy, 1998). Unlike previous work in this area, our dependent measures in this study included measures of multiple dimensions of hostility, including those indices that have been most frequently shown to be associated with an elevated risk for CVD in previous reports. We hypothesize that a citalopram intervention will be associated with reduced hostility in this group, consistent with the possibility that reduced serotonergic function might explain, in part, the association between hostility and cardiovascular disease risk. We also propose that the intervention should have a salutary effect on other psychosocial characteristics (impulsivity, depression, and social support) that are associated with hostile traits or CVD risk.