R.H. Belmaker

Major Depressive Disorder

Depression is related to the normal emotions of sadness and bereavement, but it does not remit when the external cause of these emotions dissipates, and it is disproportionate to their cause. Classic severe states of depression often have no external precipitating cause. It is difficult, however, to draw clear distinctions between depressions with and those without psychosocial precipitating events. 1 The diagnosis of major depressive disorder requires a distinct change of mood, characterized by sadness or irritability and accompanied by at least several psychophysiological changes, such as disturbances in sleep, appetite, or sexual desire; constipation; loss of the ability to experience pleasure in work or with friends; crying; suicidal thoughts; and slowing of speech and action. These changes must last a minimum of 2 weeks and interfere considerably with work and family relations. On the basis of this broad definition, the lifetime incidence of depression in the United States is more than 12% in men and 20% in women. 2 Some have advocated a much narrower definition of severe depression, which they call melancholia or vital depression. 3 A small percentage of patients with major depression have had or will have manic episodes consisting of hyperactivity, euphoria, and an increase in pleasure seeking. Although some pathogenetic mechanisms in these cases and in cases of major depressive disorder overlap, a history of mania defines a distinct illness termed bipolar disorder. 4 Depression is a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism. This review presents the major current approaches to understanding the biologic mechanisms of major depression.

World Psychiatric Association Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia

Data from two major government-funded studies of comparative antipsychotic effectiveness in schizophrenia contradict the widely prevalent belief that the newer second-generation medications are vastly superior to the older first-generation drugs. This has caused uncertainty among patients, clinicians and policy-makers about the relative utility of first- and second- generation antipsychotic agents in its treatment. To reduce confusion and provide a contextual understanding of the new data, the World Psychiatry Association Section on Pharmacopsychiatry comprehensively reviewed the literature on the comparative effectiveness of different antipsychotic treatments for schizophrenia and developed this update. Utilizing data from the approximately 1,600 randomized controlled trials of antipsychotic treatment in schizophrenia, we applied the two indirect and one direct method to comparing the effectiveness of 62 currently-available antipsychotic agents. The subclasses of 51 first-generation and 11 second-generation antipsychotics were both found to be very heterogeneous, with substantial differences in side-effect profiles among members. Second-generation antipsychotic agents were found to be inconsistently more effective than first-generation agents in alleviating negative, cognitive, and depressive symptoms and had a lower liability to cause tardive dyskinesia; these modest benefits were principally driven by the ability of second-generation antipsychotics to provide equivalent improvement in positive symptoms along with a lower risk of causing extrapyramidal side-effects. Clozapine was found to be more efficacious than other agents in treatment-refractory schizophrenia. There were no consistent differences in efficacy among other second-generation antipsychotic agents; if such differences exist, they are likely small in magnitude. Dosing was found to be a key variable in optimizing effectiveness of both first- and second- generation antipsychotic agents. There was enormous individual variability in antipsychotic response and vulnerability to various adverse effects. In contrast to their relatively similar efficacy in treating positive symptoms, there were substantial differences among both first- and second- generation antipsychotic agents with regard to their propensity to cause extrapyramidal, metabolic and other adverse effects; second-generation agents have a lower liability to cause acute extrapyramidal symptoms and tardive dyskinesia along with a tendency to cause greater metabolic side-effects than first-generation agents. Based on these data about the comparative effectiveness of different antipsychotic treatment options, we summarize elements of current best antipsychotic practice for the treatment of schizophrenia and discuss the role of government and the pharmaceutical industry in obtaining and disseminating information which can facilitate best practice.

Transcranial magnetic stimulation induces alterations in brain monoamines.

SummaryTranscranial magnetic stimulation has been suggested as a possible therapeutic tool in depression. In behavioral models of depression, magnetic stimulation induced similar effects to those of electroconvulsive shock. This study demonstrates the effect of a single session of rapid TMS on tissue monoamines in rat brain. Alterations in monoamines were selective and specific in relation to brain areas and type of monoamine. The results imply on a biochemical basis to the suggested ECT-like treatment potential of TMS.

No association between the serotonin transporter gene regulatory region polymorphism and the Tridimensional Personality Questionnaire (TPQ) temperament of harm avoidance

A functional polymorphism in the upstream regulatory region of the serotonin transporter gene has been recently reported to be associated with anxiety-related traits assessed by the NEO-PI-R. Individuals both hetero- and homozygous for the short form of a highly repetitive regulatory element in this gene have significantly higher neuroticism scores. We have attempted to replicate these findings in a normal cohort of 120 individuals, whom we have previously examined for association between personality dimensions and other serotonergic and dopaminergic receptor polymorphisms. The Tridimensional Personality Questionnaire (TPQ) was used to assess personality dimensions in this cohort. No association was observed in the present study between individuals grouped by the long and short form of the transporter gene and any of the personality dimensions measured by the TPQ including Harm Avoidance, which incorporates many aspects of anxiety and is correlated with NEO-PI-R Neuroticism.

Association between tridimensional personality questionnaire (TPQ) traits and three functional polymorphisms: dopamine receptor D4 (DRD4), serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT)

Dopamine D4 receptor (DRD4), serotonin transporter promoter regulatory region (5-HTTLPR) and catechol O-methyltransferase (COMT) polymorphisms were examined for association with TPQ personality factors in 455 subjects. Significant interactions were observed by multivariate analysis, (COMT × 5-HTTLPR: Hotellings Trace = 2.3, P = 0.02) and by subsequent univariate 3-way ANOVA when Novelty Seeking (NS) was the dependent variable: 5-HTTLPR × D4DR (F = 6.18, P = 0.03) and COMT × 5-HTTLPR (F = 4.42, P = 0.03). In the absence of the short 5-HTTLPR allele and in the presence of the high enzyme activity COMT val/val genotype, NS scores are higher in the presence of the DRD4 seven-repeat allele. The effect of these three polymorphisms on NS was also examined using a within-families design. Siblings who shared identical genotype groups for all three polymorphisms (COMT, DRD4 and 5-HTTLPR) had significantly correlated NS scores (intraclass coefficient = 0.39, F = 2.26, P = 0.008, n = 49) whereas sibs with dissimilar genotypes in at least one polymorphism showed no significant correlation for NS scores (intraclass coefficient = 0.177, F = 1.43, P = 0.09, n = 110). Similar interactions were also observed between these three polymorphisms and Novelty Seeking when the 150 independently recruited and non-related subjects were analyzed. The current results are consistent with two earlier reports in which we demonstrated an interaction between the 5-HTTLPR and DRD4 polymorphisms in 2-week-old neonates, in the same children assessed again at 2 months of age and in adults.

5-HT2C (HTR2C) serotonin receptor gene polymorphism associated with the human personality trait of reward dependence: interaction with dopamine D4 receptor (D4DR) and dopamine D3 receptor (D3DR) polymorphisms.

We recently reported an association between the long repeat allele of the dopamine D4 exon III receptor polymorphism and a human personality dimension, novelty seeking, as measured by the tridimensional personality questionnaire (TPQ), a personality instrument designed by Cloninger to reflect heritable facets of human temperament. The D4 receptor polymorphism (D4DR) accounts for only a small percent of the variance for this trait, suggesting that additional genes influence both novelty seeking as well as the other temperaments that are inventoried by the Cloninger TPQ. In the current investigation, we examined, in the original cohort of 120 normal volunteers, two additional coding region polymorphisms, a glycine to serine substitution in the dopamine D3 receptor (D3DR) and a cysteine to serine substitution in the 5-HT2C serotonin receptor (HTR2C). Three-way analysis of variance (TPQ score grouped by D4DR, D3DR and 5-HT2C) demonstrated that reward dependence and persistence scores were significantly reduced by the presence of the less common 5-HT2Cser polymorphism. The effect of the serine substitution in this X-linked serotonin receptor polymorphism on reward dependence was also observed when male and female subject groups were separately analyzed. There was also a significant interaction between the two dopamine receptor polymorphisms and the serotonin polymorphism on reward dependence. In particular, the effect of the 5-HT2C polymorphism on reward dependence was markedly accentuated in individuals who had the long version of the D4DR exon III repeat polymorphism. When present in the same individual, the 5-HT2C and dopamine receptor polymorphisms account for 30% of the observed variance for persistence (RD2) and 13% of the variance for reward dependence scores (RD134). However, the number of subjects with both less common D4DR and 5-HT2C polymorphisms is small, underscoring the importance of verifying this interaction in a larger cohort.

Monoamine oxidase in schizophrenia and other behavioral disorders

Publisher Summary This chapter discusses themonoamine oxidase (MAO) in schizophrenia and other behavioral disorders. Oxidative deamination by MAO represents a major degradative metabolic pathway for such biogenic amines as serotonin, norepinephrine, and dopamine. The concentration of these putative neurotransmitter amines within neurons and othercells is partially regulated by this enzyme. In addition, MAO functions in the intra and extra neuronal deactivation of other amines that accumulate in cells. The enzyme is widely distributed in the body, being present in most human tissues. It occurs in several molecular forms which possessdifferent substrate and inhibitor-related characteristics.

Dopamine D4 receptor (D4DR) and serotonin transporter promoter (5-HTTLPR) polymorphisms in the determination of temperament in 2-month-old infants

We and others have previously shown that the dopamine D4 exon III repeat (D4DR) and the serotonin-transporter promoter region (5-HTTLPR) polymorphisms are not only associated with adult personality traits1–7 but also with temperament in 2-week-old neonates.8 We now report the results of a second study of these infants and their temperament at 2 months using Rothbarts Infant Behavior Questionnaire (IBQ).9 There were significant negative correlations between neonatal orientation and motor organization as measured by the Neonatal Behavioral Assessment Scale (NBAS)10 at 2 weeks and negative emotionality, especially distress in daily situations, at 2 months of age. There were significant main effects for negative emotionality and distress when the infants were grouped by the D4DR and the 5-HTTLPR polymorphisms. Infants with long D4DR alleles had significantly lower scores on Negative Emotionality (F[1,72;[thinsp;= 8.50, P = 0.005) and Distress to Limitations (F[1,72;[thinsp;= 4.93, P = 0.03) than infants with short D4DR alleles. In contrast, infants with the short homozygous (s/s) 5-HTTLPR genotype had higher scores on Negative Emotionality (F[1,72;[thinsp;= 3.88, P = 0.053) and Distress to Limitations (F[1,72;[thinsp;= 4.94, P = 0.029) than infants with the I/s or I/I genotypes. The strongest effects occurred in those infants with the s/s 5-HTTLPR polymorphism who also were lacking long D4DR alleles which in some studies has been linked to adult novelty seeking.1,6 These infants showed most negative emotionality and most distress to daily situations, temperament traits that are perhaps the underpinning of adult neuroticism.

Dopamine D4 receptor and serotonin transporter promoter in the determination of neonatal temperament.

Genetic effects on behavior were evaluated at a time in early development when we hypothesized that environmental influences are minimal and least likely to confound associations between temperament and genes. The behavioral effects of two common polymorphisms linked respectively in some, but not all, studies to novelty seeking (dopamine D4 receptor – D4DR) and neuroticism and harm avoidance (serotonin transporter promoter region – STPR) were examined in a group of 81 two-week-old neonates. Neonate temperament was evaluated using the Brazelton neonatal assessment scale (NBAS). Multivariate tests of significance showed a significant association of D4DR across four behavioral clusters pertinent to temperament including orientation, motor organization, range of state and regulation of state. A significant multivariate interaction was also observed between D4DR and STPR. The effect of the homozygous short STPR genotype (s/s) was to lower the orientation score for the group of neonates lacking the long form (L) of D4DR. When adult subjects were grouped by the STPR polymorphism there is no significant effect of L-D4DR in those subjects homozygous for the STPR short form (s/s) whereas in the group without the homozygous genotype the effect of L-D4DR is significant and accounts for 13% of the variance in novelty seeking scores between groups.

Additional evidence for an association between the dopamine D4 receptor (D4DR) exon III repeat polymorphism and the human personality trait of Novelty Seeking.

The long alleles (≥6 repeats) of the dopamine D4 dopamine receptor exon III polymorphism have been linked in some, but not all, studies to Novelty Seeking (NS), one of four personality traits defined by Cloningers tridimensional personality questionnarie (TPQ). In order to further examine the robustness of our original observation we have recruited an additional cohort similar in demographic structure to the original cohort. Although no significant difference in mean NS scores was observed when the new subjects (n = 94) were grouped by presence (NS = 17.83 ± 1.16) or absence (NS = 16.45 ± 0.65) of the 7 repeat allele, a significant difference in range of NS scores was observed (non-parametric Moses range test, P = 0.01). The effect of the seven allele was also significant in those individuals scoring highest on NS (>1 standard deviation from the mean; t-test, t = 5.13, P = 0.002). In the expanded cohort (n = 218) a significant effect of the seven allele on NS is demonstrated by both parametric (t = 2.26, P = 0.01) and non-parametric (range test, P = 0.004) statistical tests. The effect is also observed in both principal ethnic groups (Ashkenazi and non-Ashkenazi Jews). In the expanded cohort the effect is significant in female (t = 2.2, P = 0.03, n = 98) but not in male subjects (t = 1.12, P > 0.1, n = 116). We discuss both direct and indirect evidence that in our opinion continues to support a modest role for the long alleles of the dopamine D4 receptor repeat polymorphism in the determination of NS behavior at least in some population groups.