Neurotransmitters, temperament and social functioning

European Neuropsychopharmacology 11 (2001) 261–274 www.elsevier.com / locate / euroneuro

Review

Neurotransmitters, temperament and social functioning Alyson J. Bond* Section of Clinical Psychopharmacology, Institute of Psychiatry, Kings College London, De Crespigny Park, London SE5 8 AF, UK Received 17 April 2001; accepted 26 April 2001

Abstract Dimensional models can be usefully employed to describe both normal and disordered personality. Studies in molecular genetics, receptor binding, peripheral monoamines and pharmacological challenges have investigated the neurochemical basis of personality. Substantial evidence now exists to support a psychobiological model but the specificity of Cloninger’s theory has not always been confirmed. Clinical studies have shown both temperament and character dimensions to improve with pharmacological treatment especially in treatment responders. Some personality changes are found to be independent of clinical effects and even to occur in normal subjects. Models of personality can help in predicting treatment outcome but individual dimensions may not be useful. It is hypothesised that social adaptation is related to the character dimensions and different sources of evidence link these to serotonergic actions. However, recent clinical studies have shown a specific effect of noradrenaline on self-perception and social motivation. Drugs with specific actions on different neurotransmitters may exert a distinctive pattern of effects on personality and social behaviour.  2001 Elsevier Science B.V. All rights reserved.

1. Introduction Social behaviour is fundamental to human society but the way in which people interact is dependent not only on the situation but also on the individuals concerned. Individual characteristics are formulated early on and are dependent on both genetic and environmental influences (Plomin et al., 1997; Silk, 1998). When an individual’s behaviour becomes profoundly asocial, then it tends to be labelled as symptomatic of a personality disorder. The field of personality research has been polarised into continuous dimensions along which all people differ and categories into which people who display extreme or unacceptable behaviour can be placed. However, people are only likely to be categorised as having a personality disorder (PD) when they have come to the attention of the medical authorities through a psychiatric consultation for an illness or because of criminal or antisocial behaviour. It has been shown that although many patients meet the criteria for a PD when depressed, this may resolve with remission of the *Tel.: 144-202-7848-0371; fax: 144-202-7252-5437. E-mail address: [email protected] (A.J. Bond).

illness (Joffe and Regan, 1988). Despite the desire of clinicians to be able to assign categories, the criteria for personality disorders are loose and reliable cut-offs are difficult to establish. The classification of PD has been described as one of the least satisfactory of all contemporary psychiatric diagnoses (Livesley, 1998). These difficulties have encouraged more widespread adoption of the dimensional view with no sharp distinction between normality and pathology (Parker and Barrett, 2000). This approach enables personality disorder to be described in terms of positions on a number of traits and also allows movement on traits accompanying clinical improvement to be assessed. Personality problems were thought to be intractable to treatment but recent research is showing both drug and psychological therapies may reduce them (Sanislow and McGlashan, 1998). Positive effects may not be confined to extreme problems but may even apply to personality traits within the normal population. 2. Classification of personality disorders Personality Disorders have until recently been assessed separately with no relation to normal or adaptive func-

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Table 1 Personality disorders according to Axis II of DSM-IV related to scores on the TCI dimensions

Personality disorder category

Cluster A

Cluster B

Cluster C

Paranoid Schizoid Scizotypal

Antisocial Borderline Histrionic

Avoidant Dependent Obsessive– compulsive

Narcissitic TCI dimension Temperament Character

Low reward dependence Low self-directedness Low cooperativeness

High novelty seeking Low self-directedness Low cooperativeness

tioning. Thus, DSM-IV (APA, 1994) separates Axis-I from Axis-II disorders. The psychiatric or psychological disorders are described under Axis-I and categories of personality disorder under Axis II. Personality disorders are divided into three clusters (Table 1) based on descriptive similarities. Cluster A represents an odd or eccentric pattern, B a dramatic, emotional or erratic pattern and C an anxious, fearful pattern. The major limitation is the categorical definition: a disorder has to be present or absent. In response to this, some PD inventories (e.g. Loranger et al., 1997) have been developed which include dimensional scoring of the personality disorders described in DSM-IV or ICD-10 (WHO, 1993) in addition to categorical division. In effect, this allows scores on each of the categories for one individual, irrespective of cluster and thus gives an indication of the degree to which the characteristics of each is present. A more comprehensive approach has been adopted by Livesley and colleagues (1998). They compiled a list of behaviours and traits that were representative of each DSM-III-R disorder (APA, 1987) and asked clinicians to rate the prototypicality of each behavioural act or trait for the target disorder. In addition they constructed self-report items and after analysis this resulted in 18 trait dimensions from 290 items:

High harm avoidance Low self-directedness Low cooperativeness

affective lability, anxiousness, callousness, cognitive dysregulation, compulsivity, conduct problems, identity problems, insecure attachment problems, intimacy problems, narcissism, oppositionality, rejection, restricted expression, self-harm, social avoidance, stimulus seeking, submissiveness and suspiciousness. Rather than three factors based on the DSM clusters, principal component analysis extracted four higher-order factors in both clinical and nonclinical samples (Table 2) which were not dissimilar to normal personality traits (Widiger, 1998). This then lends support to a dimensional rather than a categorical approach. However, this approach is still based on DSM diagnoses. Models which are based on normal personality dimensions may identify different combinations of traits which are important to the understanding of abnormal social behaviour.

3. Main dimensions of personality No agreement has been reached on the number or content of dimensions needed to define personality but considerable overlap exists. Most consistency has been achieved on the two original dimensions of neuroticism

Table 2 Personality dimensions according to different systems Temperament and character inventory (Cloninger et al., 1993) Temperament Novelty seeking Harm avoidance Reward dependence Persistence

Character Self-directedness Cooperativeness Self-transcendence

NEO personality inventory (Costa and McCrae, 1992a)

Traits from DSM (Livesley et al., 1998)

Neuroticism Extraversion Openness to experience Agreeableness Conscientiousness

Emotional dysregulation Dissocial behaviour Inhibitedness Compulsivity

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and extraversion (Eysenck and Eysenck, 1964) which are included in most models. Both these and other personality traits measured by questionnaire have shown moderate heritability in twin and adoption studies (Loehlin, 1992). This work was confirmed by the results of a genome-wide scan (Cloninger et al., 1998). Significant linkage was found between a measure of anxiety proneness (harm avoidance) and a locus on chromosome 8p21-23 that explained 38% of the trait variance. Many models of personality have been developed but for the purposes of this review, I am going to concentrate on two models which have been developed quite separately and used widely in biobehavioural research: the psychobiological model (Cloninger, 1987) and the Five Factor Model (Costa and McCrae, 1992a). The original research for both models was carried out in the normal population but both have attempted to extend the boundaries of normal personality dimensions to cover the extremes of traits, known as personality disorder (PD). Cloninger (1987) originally described three dimensions relating to heritable tendencies to novelty, danger and reward. Novelty seeking (NS) is hypothesised to represent the tendency towards excitement in response to novel stimuli or cues for potential rewards. Harm avoidance (HA) is hypothesised to represent the tendency to respond intensely to signals of adverse stimuli leading to behavioural inhibition. Reward dependence (RD) is hypothesised to represent the tendency to respond intensely to signals of reward and to maintain behaviour previously associated with reward. These three dimensions all have four traits and are measured in the Tridimensional Personality Questionnaire (TPQ). Later, reward dependence was split into two factors as one of the traits, Persistence was found to represent a separate factor (Table 2) giving four temperament factors. In a later revision of the model (Cloninger et al., 1993) Three character factors, based on social and cognitive development, were added. Self-directedness (SD) represents the ability of the individual to regulate their behaviour and commit to chosen goals. Cooperativeness (C) represents the ability to identify with and accept other people. Both SD and C have five traits. Self-transcendence represents the ability to identify with being an integral part of the universe and has three traits. The authors claim that the seven-factor model, measured by the Temperament and Character Inventory (TCI), allows a better differentiation between individuals with extreme traits but normal adaptation and those with extreme traits and poor social adjustment. Low scores on the two character dimensions of self-directedness and cooperativeness predict a risk for a PD diagnosis and scores on the other dimensions indicate different subtypes (Svrakic et al., 1993). Thus, patients with cluster A, B and C diagnoses (Table 1) according to the DSM classifications were differentiated by low RD, high NS and high HA respectively. The differentiation between the clusters has been replicated (Mulder et al., 1999) and the association of

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low scores on SD and C with a diagnosis of PD has been established in several studies. Bayon et al. (1996) confirmed that low SD and C were essential features of all personality disorders. De la Rie et al. (1998) found SD to predict the presence or absence of a personality disorder in a Dutch sample. Casey and Joyce (1999) found strong negative correlations between SD and C and the total number of personality disorder symptoms assessed by the Structured Clinical Interview for DSM-III-R personality questionnaire and SD scores were found to predict the number of PD diagnoses. The TCI, therefore, represents an alternative and economical method of establishing the presence or absence of personality pathology and can be used as a diagnostic instrument. Costa and McCrae (1992a) describe five major personality factors (Table 2) which can be measured by the NEO personality inventory (NEO-PI) and both self-report and informant-generated inventories have been developed (Costa and McCrae, 1990). The close agreement shown between self and observer ratings (Bagby et al., 1998) challenges the view that current mood may affect selfrating of personality. Not only current depression but proneness to depression are associated with higher N scores and so the illness itself is unlikely to change the personality profile (Costa and McCrae, 1992b). The NEOPI measures 30 separate traits which load onto the five basic dimensions. There is evidence that all five have some biological foundation from heritability studies (Costa and McCrae, 1992a; Jang et al., 1996) and that facet-level traits do not just contribute to the main factors but have their own heritable basis (Jang et al., 1998). When the scores of the same individuals on the TPQ and the NEO are compared, then harm avoidance is highly correlated with neuroticism and novelty seeking is positively correlated with extroversion and negatively correlated with conscienciousness (Ebstein et al., 2000). The relationship between the NEO factors and diagnosis of PD has also been investigated (Svrakic et al., 1993; Ball et al., 1997). Svrakic et al. (1993) found that although both NEO-N and Agreeableness contributed to a prediction of number of personality disorder symptoms at interview, in contrast to the TCI dimensions, the results were not significant and contributed little to the variance. NEO-N is confounded by correlating highly with SD (r520.75) and HA (r50.71). It is not specific to Axis II disorders as it is also associated with many Axis I disorders such as major depression in the same way as HA. Ball et al. (1997) found that NEO-N was associated with many personality disorders and different patterns for Agreeableness, Conscientiousness and Extraversion emerged for different disorders. The TCI was also used in this study but in contrast to the results of Svrakic et al. (1993) the scales were not found to be as strongly associated with PD diagnoses as the NEO dimensions. However, normal personality dimensions were found to contribute significantly to the prediction of PD severity, confirming the dimensional approach.

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4. Neurotransmitter involvement The temperament dimensions of the TPQ or TCI are considered to be heritable factors, manifest early in life and involving unconscious learning. Cloninger (1987) proposed that the three factors, novelty seeking (NS), harm avoidance (HA) and reward dependence (RD) were strongly influenced by different neurotransmitter systems such as the dopaminergic, serotonergic and noradrenalinergic systems respectively. In contrast, the character dimensions are posited to be based on insightful learning and thus related to psychological processes. Some support for this proposal comes from findings that the character dimensions of the TCI have been shown to relate to both perceived parental attitudes and to adult defence styles according to a psychoanalytical model. SD correlated with high scores on both Maternal and Paternal Care and low scores on Maternal Overprotection on the Parental Bonding Instrument (Ono et al., 1999) and both C and SD related strongly to immature defences on the Defense Style Questionnaire (Mulder et al., 1999). Evidence to support the neurochemical basis of personality dimensions has been sought from many different sources: molecular genetics, receptor binding, peripheral levels of monoamines and pharmacological challenge studies.

4.1. Molecular genetics Extensive work has been carried out with particular candidate genes, including polymorphisms related to the serotonin transporter, serotonin 1b receptor, serotonin 2c receptor, dopamine transporter, dopamine D3 receptor (D3DR), dopamine D4 receptor (D4DR), catechol-omethyltransferase (COMT) and tyrosine hydroxylase, the basis for which has been well described elsewhere (Benjamin et al., 1998). A link between the serotonin transporter and anxiety-related traits, measured by the NEO-N, anxiety on the 16 PF and a derived measure similar to HA, was first reported in 1996 (Lesch et al., 1996). This work has continued and several recent studies have confirmed an association between the short allele of 5-HTTLPR and higher scores on both the TPQ-HA (Ricketts et al., 1998; Katsuragi et al., 1999) and NEO-neuroticism (Greenberg et al., 2000; Osher et al., 2000). However, negative findings have also been reported (Deary et al., 1999; Flory et al., 1999; Herbst et al., 2000). The situation is, therefore, likely to be more complex with interactions among genes (Mazzanti et al., 1998) or possibly with facet-level traits showing independent relationships. Recent evidence has also shown that the TCI character traits of Self-directedness and Cooperativeness are both associated with 5HTTLPR and these results revealed the associations to be stronger than for either HA or Neuroticism (Hamer et al., 1999; Kumakiri et al., 1999). This evidence suggests that the distinction made by Cloninger et al. (1993) between the temperament and character traits of the TCI may be

artificial but this work may help to identify the biological basis of yet more traits. An association between TPQ-NS and the D4DR polymorphism was shown at a similar time to the first report for the serotonin transporter (Ebstein et al., 1996). Although there is no direct equivalent of NS in the NEO-PI, a positive loading on Extraversion together with a negative loading on Conscientiousness seems to show good correspondence with NS (70%) and NS has been estimated from the NEO (McCrae and Costa, 1990). The finding that this combination (high E together with low C scores) is associated with the long allele of D4DR was, therefore, confirmatory of the relationship found with NS (Benjamin et al., 1996). Several recent studies have also confirmed the association between the D4DR gene and NS in different populations (Ono et al., 1997; Ekelund et al., 1999; Strobel et al., 1999; Tomitaka et al., 1999; Benjamin et al., 2000a; Okuyama et al., 2000) but there have also been negative reports (Vandenbergh et al., 1997; Herbst et al., 2000). It is possible that additional genes or interactions between them influence the various personality dimensions. Ebstein et al. (1997) examined three polymorphisms, D4DR, D3DR and 2-HT2C, and found a significant interaction between the two dopamine receptor polymorphisms and the serotonin polymorphism on TPQRD. Both RD and persistence scores were reduced by the presence of the rare 5-HT2C allele and this effect was accentuated by the combination with the long D4DR allele. A similar interaction between D4DR and 5-HT2C and RD has since been confirmed (Kuhn et al., 1999). The relationship between COMT and 5-HTTLPR and persistence has also been examined (Benjamin et al., 2000b). In the presence of COMT homozygosity and the short 5HTTLPR allele, higher persistence scores were found. Recently an association has been found between the tyrosine hydroxylase repeat polymorphism and NEO traits (Persson et al., 2000). Higher mean scores on N scales were found among T8 allele carriers and the T6 / T10 genotype was related to higher scores on some C facets. This field is rapidly expanding. It has been suggested that failure to replicate some of the major findings may be due to demographic factors such as the age and gender composition of the samples (Vandenbergh et al., 1997). Care is also needed in interpreting some of the results based on small clinical samples. Similarly, findings with less common polymorphisms need verifying with larger samples. However, the associations found between both dopamine and serotonin receptor and transporter polymorphisms and major personality traits not only contributes to our knowledge of the biological basis of personality but may have implications for existing and new pharmacological interventions.

4.2. Receptor binding Studies using positron emission tomography (PET) have

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examined the relationship between personality traits and receptor binding. Most studies have used categorical diagnoses in small patient groups, which are beyond the remit of this article but a few have used questionnaires to measure traits. Low striatal dopamine D 2 receptor binding has been found to relate to personal detachment on the Karolinska Scales of Personality (KSP) (Farde et al., 1997). A later study confirmed this association but failed to find any association with attachment scores on the TPQ (Breier et al., 1998) although a further exploratory analysis did link the binding to the sentimentality sub-scale of the TPQ. Both attachment and sentimentality are sub-scales of TPQ-RD so that although this result offers some evidence of a biological foundation to the TPQ dimensions, it does not support the hypothesised relationship between dopamine and NS (Cloninger, 1987). Cloninger (2000) has stated that KSP-detachment resembles low TCI-NS and RD but no relationship with NS was shown in the previous study. The relationship between D 2 binding and the NEO PI-R dimensions has also been examined (Kestler et al., 2000). An association was found between the binding and NEO-depression but not with detachment-like traits. The relationship between personal detachment and striatal D 2 binding led another group to investigate a possible association with striatal dopamine transporter binding (Laakso et al., 2000). They found that age-corrected dopamine transporter binding in the putamen correlated negatively with KSP-detachment scores, confirming that low dopaminergic neurotransmission is associated with characteristics of a detached personality. A problem with neuroimaging studies is that constraints on sample size tend to make the sample non-representative and it is therefore difficult to replicate results. Three studies have now found a relationship between dopamine binding and personal detachment measured by the Karolinska Scale but this trait seems to be independent from the forms of detachment measured by the TPQ and NEO. More studies are needed to elucidate if other personality traits show relationships to serotonergic or noradrenergic neurotransmission.

4.3. Peripheral measures of monoamines Interest has been shown in the relationship between monoamines measured in urine, plasma and platelets and personality dimensions. The predicted relationship between noradrenaline and TPQ-RD has been tested. Urinary levels of the noradrenaline metabolite, 3-methoxy-4-hydroxyphenylglygol (MHPG), were measured in healthy male subjects who also completed the TPQ (Garvey et al., 1996). A significant inverse correlation was found between levels of MHPG and TPQ-RD (r520.412) but no relationship was found with NS or HA, lending support to the hypothesis that high RD traits are associated with low noradrenergic activity. Curtin et al. (1997) measured urinary levels of catecholamines, catecholamine metabo-

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lites and 5-HIAA in healthy male subjects and correlated these with the TPQ dimensions. They found a positive relationship between TPQ-RD and MHPG (r50.51) and also found a relationship between RD and adrenaline (r50.50) but no relationships were found with the other temperament dimensions. Cluster analysis on urinary monoamine measures identified three mutually exclusive clusters and the TPQ scores were found to discriminate among subjects belonging to these clusters e.g. the highest scores on RD were found in subjects who excreted high amounts of monoamines whereas high scores on HA tended to be associated with subjects who had the lowest catecholamine values. These results suggest that RD is associated with both increased noradrenergic and adrenergic turnover. Plasma concentrations of different monoamines have also been measured to test the relationship with both sensation seeking and the TPQ dimensions (Gerra et al., 1999). Sensation seeking has been shown to correlate significantly with high NS and low HA on the TPQ (Earlywine et al., 1992). Noradrenaline (NA) and prolactin showed significant correlations with NS and NA-dependent testosterone showed significant correlations with both NS and RD but no significant relationships were shown for HA or for cortisol or adrenaline. This result suggests that the noradrenergic, as well as the dopaminergic, system is involved in NS. The relationship between serotonergic function and HA has been tested by correlating two platelet markers of 5-HT function, the maximum number of binding sites (Bmax ) for 125 I-lysergic acid diethylamide ( 125 I-LSD) and 3 H-paroxetine binding with TPQ scores in a group of 18 patients with MDD, some of whom were comorbid for OCD (Nelson et al., 1996). A significant inverse correlation was found between HA and 125 I-LSD Bmax values but not with 3 H-paroxetine binding Bmax values. This offers some support for Cloninger’s hypothesis. However, there have also been negative findings. Chatterjee et al. (1997) found no relationship between any of the TCI traits and platelet 5-HT 2 receptor binding in 20 social phobics and 20 healthy controls. Tryptophan is the precursor for serotonin and reducing tryptophan acutely has been shown to increase aggression, especially in those with higher trait scores on the dimension of hostility (Bond and Wingrove, 2001). Swann et al. (1999) therefore examined the relationship between the ratio of plasma tryptophan to large neutral amino acids (TRYP/ LNAA ratio) and personality characteristics in a group of 58 alcoholics. A negative correlation was found between the TRYP/ LNAA ratio and HA. In addition, a positive correlation was shown between the ratio and Self-directedness (SD) on the TCI. Low tryptophan availability was therefore associated with susceptibility to anxiety and low self-determination, possibly indicating a risk of personality disorder in this group of alcohol-dependent patients. Although this result provides additional support for the large literature linking abnor-

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malities in serotonin functioning with indices of aggression (Oquendo and Mann, 2000), it is important to recognise that results found in psychiatric patients may be confounded by clinical state or behaviour (abuse of alcohol) and thus relationships found in vulnerable groups may not pertain to the general population. This may also apply to those with a family history of psychiatric disorder, as illustrated by a study in which a significant relationship between platelet MAO activity and TPQ-NS was found in sons of alcoholics but not in sons of nonalcoholics (Howard et al., 1996). This was despite the groups showing no significant differences on any of the measures. Some independent support has been found for the relationship between serotonergic function and HA in a normal population of undergraduate students (Peirson et al., 1999). A significant inverse correlation was found between EC50 serotonin concentration and HA, indicating that increased 5-HT 2 receptor sensitivity is implicated in high HA. Interestingly, TCI-SD showed an opposite but significant relationship.

4.4. Pharmacological challenges Neuroendocrine challenges have a distinct advantage over strategies employing peripheral measurements of neurotransmitters or their metabolites as they provide an index of brain function. They have mostly been used to discriminate between responses to a particular agent, indicative of neurotransmitter function, in clinical groups but some studies have looked at the relationship of the responses to measures of personality. Apomorphine, a dopamine receptor agonist, has been used to examine the hypothesised relationship between dopamine and TPQ-NS (Wiesbeck et al., 1995). A significant correlation was found between the growth hormone response and NS in a group of abstinent alcohol-dependent men. No relationship was shown with the other dimensions. Several 5-HT agents have been used in challenge studies. Fenfluramine, a 5-HT releaser and uptake inhibitor, and its d-isomer have been used as a challenge agent to measure serotonergic activity in many different disorders (Newman et al., 1998) but there are fewer studies relating the hormone responses such as cortisol and prolactin to personality. However, the large body of work linking abnormalities in serotonin with impulsive aggressive behaviour has led some researchers to study such traits in the normal population (Cleare and Bond, 1997; Manuck et al., 1998; Evans et al., 2000). Some of these studies examined a single trait such as hostility (Cleare and Bond, 1997) and positive findings confirmed the value of the dimensional approach. Some later studies have included a general measure of personality. Evans et al. (2000) administered a 30-mg d-fenfluramine challenge to normal subjects who had been divided into those scoring

high or low on impulsiveness (measured by the I7 scale) and correlated the prolactin response with scores on the TPQ-HA dimension. Although they found the high impulsive group to have a reduced prolactin response compared to the low impulsive group, there was no significant association with HA. In contrast, blunted prolactin responses to a challenge with a low dose of d-fenfluramine (15 mg) have been found to be associated with high HA (Hennig et al., 2000). Manuck et al. (1998) included the NEO-PI in a range of measures. They administered fenfluramine 30–60 mg (dose adjusted for body weight) and correlated the prolactin response with all the measures including the NEO dimensions. Previously found relationships between blunted hormone responses and measures of aggression and impulsivity were confirmed (Coccaro et al., 1996). In addition, they found a significant inverse correlation between the prolactin response and Neuroticism (r52 0.31), in particular the subscale of Angry Hostility (r52 0.35), and a positive correlation with Conscientiousness (r50.30) in men. There were no significant correlations in the general sample of woman but in a small subgroup of postmenopausal women, the significant positive relationship between the prolactin response and Conscientiousness (r50.69) was confirmed. This relationship between a normally functioning 5-HT system and positive traits such as resourcefulness, persistence and self-discipline is a new finding as most previous work has concentrated on deficits in functioning in clinical groups but it supports the hypothesised role of serotonin as an inhibitory neurotransmitter involved in constraint and delay (Depue and Spoont, 1986) and has implications for the possible treatment of personality disorders. Although SSRIs do not provoke reliable hormone responses, I.V. clomipramine can be used. A clomipramine challenge (12.5 mg I.V.) was administered to 32 healthy subjects who had completed the TPQ (Ruegg et al., 1997). The predicted relationship between cortisol and HA was positive (r50.33) but just failed to reach significance (P50.08) but there was a significant correlation between baseline plasma prolactin levels and HA (r50.36), which the authors explain as an indication of serotonergic activity. There was also a significant inverse correlation between the prolactin response and NS (r520.40). These results reflect the possibility that although baseline hormonal levels and the cortisol response are a reflection of the serotonergic activity of clomipramine, the prolactin response may also be related to its dopaminergic activity. In addition, challenges with various 5-HT1A agonists, such as flesinoxan and ipsapirone have been used to test Cloninger’s hypothesis. The prolactin response to I.V. flesinoxan (1 mg) was measured in 21 depressed inpatients who completed the TPQ and was found to correlate significantly with HA (r50.47) but not the other two dimensions (Hansenne et al., 1997). However, HA was strongly influenced by clinical state in this study, as shown by the highly significant correlation with severity of

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depression (r50.77) measured by the Hamilton Depression Scale (HDRS: Hamilton, 1960). The wider relationship between HA and serotonergic activity could not therefore be established. Hansenne and Ansseau (1999) went on to examine this. They administered I.V. flesinoxan (1 mg / 70 kg) to 23 normal subjects who had completed the TPQ. As would be expected, the mean scores for these subjects on HA (17.764.3) were lower than for the previous depressed sample (24.764.5) but the significant relationship between HA and the prolactin response (r50.46) was confirmed. A study examining a low dose of ipsapirone (10 mg) found no significant relationship between the cortisol response and HA in healthy volunteers (Hennig et al., 2000). However, this study also investigated the prolactin response to d-fenfluramine in the same subjects (see above) and when the combined response was examined, a blunted prolactin response to d-fenfluramine combined with a blunted cortisol response to ipsapirone was associated with significantly higher levels of the HA sub-scales fatigability and asthenia. The doses used in this study were much lower than usual which may account for the negative finding with ipsapirone alone. However, the novel approach demonstrates that combined challenge tests may be a productive way of examining the biological basis of different personality traits. In an ambitious study by Tancer et al. (1994), a triple drug challenge (levodopa, fenfluramine and clonidine) was administered to cover the dopaminergic, serotonergic and noradrenergic neurotransmitter systems. The challenges were administered to both social phobia patients and normal controls. No relationships were found in the patients but a significant correlation was found between the growth hormone response to clonidine and RD in the controls, providing some support for Cloninger’s theory. The relationship between temperament and dopamine activity has also been assessed by the administration of d-amphetamine, an indirect dopamine agonist. Rather than measuring the hormone responses in these studies, the response to the drug on cognitive, psychophysiological, behavioural and subjective measures has been correlated with the TPQ dimensions. Higher scores on NS were associated with decreased performance on a verbal memory task after d-amphetamine (0.25 mg / kg) while lower scores were associated with improvement (Fleming et al., 1995). Higher scores on NS also corresponded to heightened sensitivity to drug effects on pre pulse inhibition and a subjective measure of stimulation (Hutchison et al., 1999). No relationship between response and any of the TPQ dimensions was found in a study using lower doses (5 and 10 mg) of d-amphetamine (Corr and Kumari, 2000) but the effects were moderated by EPQ-psychoticism (Eysenck and Eysenck, 1975). In low-P individuals, damphetamine increased energetic arousal and hedonic tone and reduced tense arousal, whereas in high-P individuals, it had the reverse effect. Repeated intermittent administration of d-amphetamine has been shown to lead to behavioural

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sensitization i.e. a progressively increasing and enduring enhancement in the behavioural response (Strakowski and Sax, 1998). There are individual differences in the magnitude of this effect which may be partly explained by temperament and so this relationship has been examined. In a study looking at repeated administration of d-amphetamine (0.25 mg / kg), a greater magnitude of change in elevated mood over the three administrations significantly correlated with ratings of NS (Sax and Strakowski, 1998). These results do offer support for the hypothesised relationship between NS and dopamine.

5. Relationship of personality dimensions to drug treatment Although personality dimensions have traditionally been thought to be stable over time, the hypothesised relationship to neurotransmitter systems (Cloninger, 1987) means abnormalities in these systems might lead to higher or lower scores on the dimensions and this has implications for treatments which affect the systems. Apart from moderately elevated scores on HA or N, the temperament dimensions have been found to be relatively stable during the course of major depression (Brown et al., 1992; Joffe et al., 1993; Strakowski et al., 1995; Richter et al., 2000). Support for the biological basis of the personality dimensions of the TPQ and the NEO has also been sought in treatment studies. The strongest evidence has been found for the relationship between HA and the serotonergic system. Consistent with the hypothesis, a reduction in the HA factor has been consistently observed in depressed patients after receiving antidepressant treatment targeting the serotonergic system. In a study comparing treatment with fluoxetine with cognitive therapy, both treatments showed improvement from baseline but HA only decreased after fluoxetine (Dunner et al., 1996). The TPQ was administered to patients taking part in double-blind trials of serotonergic antidepressants (paroxetine, fluoxetine or amesergide) both at baseline and after 12 weeks (Chien and Dunner, 1996). HA scores were found to be significantly reduced in patients whose depression improved whereas nonresponders showed no decrease. The subscale NS2, impulsiveness, was also significantly reduced in responders but the global dimensions of NS and RD were not affected. These changes do not appear to be specific to the serotonergic system, however, as similar changes have been shown with non-serotonergic compounds. Scores on HA but not NS or RD were found to decrease significantly in those who responded to treatment with either desipramine or imipramine (Joffe et al., 1993). Bagby et al. (1999) tested the neurotransmitter specificity of the hypothesis by comparing a noradrenergic antidepressant, desipramine, with two SSRIs, paroxetine and sertraline. They found decreases in N and the subscale Anger-hos-

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tility and increases in E and the subscale Gregariouness following treatment with desipramine as well as paroxetine and sertraline. Changes in N and E were significantly correlated with change in depression severity but changes in Anger and Gregariouness were not so. Although some personality changes were therefore independent of illness status, they were not related to a particular neurotransmitter in this study. In a much larger study, TPQ scores of dysthymic patients have also been reported to be changed after 12 weeks’ treatment with sertraline, imipramine or placebo compared to baseline (Hellerstein et al., 2000). HA scores were decreased and RD increased and significantly more change was shown for those who remitted. A further analysis showed that significant changes were confined to women patients. The greatest change in HA was shown after sertraline and the greatest change in RD after imipramine which does offer support for the predictions of the psychobiological model. This result indicates that much larger patient numbers are required to test Cloninger’s hypotheses. Taken together, these results suggest that although some personality change, especially that related to HA or N, is related to clinical improvement, remission does not account for all the change. Antidepressant drugs may therefore exert direct effects on neurochemical pathways which are independent of their clinical effects. The character factors of the TCI are said to result from social learning and are thus predicted to respond to psychological rather than pharmacological interventions (Cloninger et al., 1993; Cloninger and Svrakic, 1997). In contrast to this prediction, some studies have found that antidepressant treatment can affect the character as well as the temperament factors of the TCI, especially the SD and C factors. For example, Allugulander et al. (1998) reported that symptomatic volunteers diagnosed with generalised anxiety disorder showed not only decreased HA and increased NS but also increases in SD and C after paroxetine treatment for 4–6 months. Similar results were found in patients with unipolar depression who received treatment with a serotonergic antidepressant (paroxetine, fluoxetine, fluvoxamine or amesergide) (Black and Sheline, 1997). These patients not only had increased SD and C scores but were also less likely to meet the criteria for a PD after 6–10 weeks’ treatment. This change paralleled the improvement in depressed mood. Richter et al. (2000) administered the TCI to inpatients pre- and post-discharge. Inpatient treatment was uncontrolled but comprised a combination of antidepressant and psychological therapy. Matched healthy controls also completed the TCI but only on one occasion. Changes in personality after treatment were found on both temperament and character dimensions but the patients could still be distinguished from the healthy controls. Apart from the last study, in which psychotherapy may also have influenced the character dimensions, these findings seem to be inconsistent with

Cloninger’s proposal that neurobiological factors are less influential on the character dimensions. These studies were all conducted in clinical populations. It is possible that because depressed patients are reported to have lower SD and C scores generally (Hansenne and Ansseau, 1999; Richter et al., 2000), these dimensions might be related to illness as well as personality variables and, therefore, might be responsive to antidepressant treatment. To test whether antidepressant drugs have independent effects on personality, it is possible to use healthy controls in whom personality variables such as SD and C would be expected to be stable and not to change after drug administration. Very few studies have examined the effects of drug treatment on the personality of healthy volunteers although subthreshold symptoms of irritability and anxiety have been shown to improve after 5 weeks of low dose clomipramine compared to active placebo (Gorenstein et al., 1998). In a novel study, Knutson et al. (1998) administered paroxetine or placebo to 46 healthy volunteers for 4 weeks. They did not use the TPQ / TCI but assessed the effects on a rating scale of hostility and aggression and on a collaborative behavioural task. They found decreased ratings of aggression and negative affect and an increase in cooperative behaviour on the task after 1 week. In a very recent study, Tse and Bond (2001) administered the TCI to 20 healthy male volunteers preand post-2 weeks of citalopram or placebo. No changes were shown on the temperament factors but an increase in SD was found after citalopram compared to placebo. These preliminary results indicate that the effects of serotonergic manipulation are not confined to psychiatric illness. Positive character changes may also occur in normal healthy volunteers which confirms the findings previously described in patients that pharmacological treatment may induce changes in personality traits which are independent of effects on depression. Positive effects have also been found on other measures of personality after SSRI treatment. The Karolinska Scales of Personality were used to measure personality traits in patients with MDD before and after 24 weeks’ treatment with sertraline or citalopram (Ekselius and Von Knorring, 1999). Significant changes were seen on all except one scale and these effects represented ‘normalisation’ e.g. decreased anxiety and increased socialisation. The Cattell 16 Personality Factor Inventory (16 PF) was used in a study of patients with MDD or OCD before and after 8–12 weeks’ treatment with paroxetine (Brody et al., 2000). Six of the seven 16 PF factors changed in the predicted direction after treatment. Two of the factors related to HA showed greater change in responders and correlated with clinical measures, confirming previous findings (Chien and Dunner, 1996). The two social dominance factors and one of the two social affiliation factors showed change which was independent of clinical improvement. These factors may then be more like the TCI character factors.

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6. Personality factors in predicting response to drug treatment The temperament factors have been found to be predictive of treatment outcome. Joyce et al. (1994) examined the ability of the TPQ dimensions to predict outcome in 84 patients with major depressive disorder (MDD) who were treated with clomipramine or desipramine. They dichotomised each of the three original TPQ scales and divided the patients into eight temperament types. Using this model, temperament explained more of the variance than any of the clinical variables. In the total sample, temperament type explained 25% of the variance and confining the results to the more severely depressed patients increased this to 40%. Patients with high scores on both HA and RD had a favourable response to treatment with either clomipramine or desipramine. In addition, women showed a differential response to the drugs: those with high HA were more likely to respond to desipramine and those with high RD to clomipramine. This result is not supportive of Cloninger’s specific predictions but it does uphold a neurobiological basis to personality. The contribution of temperament to response to treatment with nefazodone has also been examined. In a small study, Nelson and Cloninger (1995) reported that a model involving RD and HA scores had significant predictive value and high scores on RD alone significantly separated responders from nonresponders. However, in a later review of the data, the analysis was found to be flawed and the relationship was found not to be significant (published erratum). A model involving RD and HA scores also had significant predictive value in a later study (Nelson and Cloninger, 1997). In contrast to the other findings, higher RD was found to lead to a lower response rate but the model explained very little of the variance (1.1%). The combination of high RD and low HA led to a better outcome in patients with major depression after 6 weeks of treatment with paroxetine with or without supplementary pindolol (Tome et al., 1997). When paroxetine treatment was augmented with pindolol rather than placebo for 6 weeks and paroxetine then continued for 6 months, then the combination of high NS and low HA scores led to a better outcome at both 6 weeks and 6 months. When paroxetine was given with placebo, high SD scores predicted more clinical improvement at 6 weeks. Although these studies do indicate that the TCI dimensions can be useful in predicting treatment outcome, the results for individual factors are inconsistent. It may be necessary to use combinations of traits in a model as described by Joyce et al. (1994) as this was found to predict a substantial amount of the variance. One recent study has also examined the relationship of the character factors to treatment outcome (Sato et al., 1999). Patients (N586) with MDD were treated with maprotiline for 16 weeks. They filled in the TCI at baseline and treatment response was assessed on the HDRS at both

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8 and 16 weeks. The temperament dimensions were not significantly related to response but the character factors of SD and C were. Higher C scores predicted response at week 8 and higher SD scores predicted response at week 16. Low chronicity also predicted response at week 16. This result implies that patients with a shorter history of depression and probably less risk of comorbid personality disorder respond better to antidepressant treatment. The relationship between the two personality dimensions of sociotropy (interpersonal dependency) and autonomy (need for independence and control) proposed by Beck (1983) and response to antidepressant treatment has been studied in two studies. The relationship of these two dimensions to the NEO-PI has been studied (Cappeliez, 1993). It was found that sociotropy was positively related to NEO-N and negatively related to NEO-O whereas autonomy was positively related to NEO-C. It has also been suggested that sociotropy may be related to RD (Joyce, 1994). Autonomy has been found to relate to endogenous depression and sociotropy to non-endogenous depression (Peselow et al., 1992) and subjects with high autonomy–low sociotropy traits showed greater response to antidepressant treatment than those with high sociotropy–low autonomy traits. The sociotropy–autonomy distinction was, therefore, a predictor of response to drug treatment. Beck (1983) proposes that personality style sensitizes individuals to certain types of adverse events. An interaction between sociotropy and negative interpersonal events and between autonomy and negative achievement events has been linked to depression (Robins, 1990). A recent study, therefore, looked at the interaction between adverse life events, sociotropy and autonomy factors and response to antidepressant treatment (Mazure et al., 2000). In the context of the multivariate model that predicted outcome, interpersonal events were associated with better outcome and achievement events with worse outcome. However, congruency was found to be important for the interaction of personality style and event type. Better outcome was predicted when high sociotropy individuals experienced negative interpersonal events and high autonomy individuals experienced negative achievement events. In general, men had a better response than women to antidepressant treatment. It was not possible to look at type of antidepressant but the majority of patients were on SSRIs. More studies examining this question are needed. It might be expected that higher functioning patients with less personality pathology would respond better to a short antidepressant trial but other studies have demonstrated that these factors can also be improved by antidepressant treatment and that this change is not always correlated with clinical improvement. A series of larger studies in which clinical variables such as diagnosis, severity and chronicity are controlled and patients are assigned to treatment with antidepressants acting on different neurotransmitter sys-

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tems may help to elucidate the relationship between personality and treatment response.

7. Implications for social interaction Self-directedness, and to a lesser extent cooperativeness, have been associated with serotonergic activity in many of the different types of studies described. The finding that healthy people with no history of psychiatric disorder and presumably normally functioning neurotransmitter systems show positive changes after the administration of SSRIs (Knutson et al., 1998; Tse and Bond, 2001) has wideranging implications. It seems that these drugs do not simply control deficiencies but may aid normal social functioning possibly by allowing people to reflect before acting or making decisions in much the same way as is achieved by psychological therapies. Unlike Cognitive Therapy, however, the effects may be limited to the period of drug administration and may not persist. Therefore, although SSRIs may be helpful in the treatment of personality disorders, it seems likely that long-term administration would be necessary. There is a lack of evidence relating to the effects of non-serotonergic antidepressants on the TCI dimensions in healthy individuals. However, a new noradrenaline reuptake inhibitor, reboxetine, has been shown to improve social functioning in depressed patients (Dubini et al., 1997). Depression has profound effects on social functioning and these effects have been shown to persist (Tweed, 1993). The improvement of social functioning has, therefore, recently become a target for antidepressant medication. Although treatment with antidepressants can improve these social deficits, total resolution is difficult to achieve. Imipramine and phenelzine have been found to have positive effects on social functioning in small placebo controlled trials (Kocsis et al., 1988; Stewart et al., 1988; Agosti et al., 1991) and more recently some SSRIs have been evaluated. Sertraline showed similar effects to imipramine (Miller et al., 1998) but a study with fluoxetine in elderly patients had equivocal results (Heiligenstein et al., 1995). These studies were all short-term and in none did the patients reach normative levels of functioning. Fluoxetine has also been compared to reboxetine, a new noradrenaline reuptake inhibitor, in an 8-week placebo controlled trial (Dubini et al., 1997a). Both drugs improved social functioning on the Social Adaptation Self-evaluation Scale (Bosc et al., 1997) compared to placebo at 8 weeks but reboxetine achieved significantly more improvement than fluoxetine on scale items related to self-perception and active social behaviour (motivation). In addition, despite the short trial period, the reboxetine group reached normal levels of functioning on the scale. When only patients whose depression had remitted were examined, the fluoxetine group also showed scores in the normal range but these were still significantly lower than the reboxetine

remitted group. A smaller comparative study (Massana et al., 1999) has confirmed that reboxetine was more effective than fluoxetine in terms of social functioning in those patients who achieved remission. However, other SSRIs have not been compared to reboxetine and so it is currently unknown if the more selective compounds, like citalopram, would show a different profile of social effects. Unfortunately personality measures have not been used in these studies but other studies have shown the TPQ dimensions to be closely related to social functioning. Hellerstein et al. (2000) hypothesised that social adjustment would be related to HA both pre- and post-treatment. The correlation between Social Adjustment Scale (SAS: Weissman and Bothwell, 1976) and HA scores was found to be significant in the total sample at baseline (r50.46) and in both remitters (r50.46) and nonremitters (r50.54) after treatment. Joyce et al. (1994) reported that the percentage improvement on the HDRS correlated with improvement in social adjustment and with SAS scores at 6 weeks but they did not examine relationships between the SAS and the TPQ dimensions. The improvement reported for reboxetine on social motivation is consistent with Cloninger’s hypothesis of increased drive with noradrenaline relating to reward dependence. However, it seems likely that the character dimensions of SD and C are also involved in adaptive social functioning and, therefore, changes in these dimensions may be closely related to improvements on social functioning scales such as the SASS and SAS. Future studies examining the effects of serotonergic and noradrenergic antidepressants on these dimensions may help to establish the personality profile of patients who respond preferentially to a particular treatment.

8. Conclusions There is now a substantial amount of evidence supporting a neurobiological basis to personality. Broad associations between temperament factors and the predicted neurotransmitters were confirmed. An association between dopamine receptor and transporter polymorphisms and NS has been found in molecular genetic studies and people with higher scores on NS have shown increased sensitivity to the effects of d-amphetamine. Dopamine receptor and transporter binding have also been linked to a specific trait of personal detachment. Evidence from many different sources has linked serotonin to anxiety traits. The short allele of the serotonin transporter polymorphism has been associated with both HA and N. Both a platelet marker of 5-HT function and plasma concentrations of tryptophan were also related to levels of HA. Neuroendocrine challenges have revealed responses to 5-HT drugs to be associated with both N and HA. RD has been associated with urinary levels of MHPG and a challenge with

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clonidine also revealed a relationship with the growth hormone response. Treatment studies confirmed that HA scores were decreased by antidepressant treatment but revealed that this was not specific to serotonergic compounds. Some personality changes were independent of clinical effects. Models of personality may be able to predict response to drug treatment. Some very interesting findings concern the character dimensions which have been associated with serotonergic activity in different types of study. SD has been associated with a well functioning system and both increases in SD and in cooperative behaviour have been shown in healthy volunteers after SSRI treatment. This has implications for social functioning, which can be improved by serotonergic drugs. However, recent clinical studies have revealed the effectiveness of reboxetine, a noradrenaline reuptake inhibitor. Not all the studies cited in this review have shown significant relationships and some report conflicting findings. However, well controlled studies demonstrate the usefulness of this approach. The relationship between personality dimensions and different neurotransmitter actions is an area which warrants more investigation.

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