Citalopram neuropharmacological challenge in alcohol-dependent patients and controls: pharmacogenetic, endocrine and psychobehavioral results.
OBJECTIVE
Alcoholism has been associated with long-lasting alterations in LHPA (limbic-hypothalamus-pituitary-adrenal) axis function, related to a dysfunction of the serotonergic neurotransmission. Functional polymorphisms of the serotonin system were previously reported to have significant influence on serotonin-induced neuroendocrine response. The aim of the study is to investigate in a double-blind, placebo-controlled approach, whether citalopram (a selective serotonin reuptake inhibitor, SSRI) would affect LHPA axis function as measured with ACTH (adrenocorticotrophic hormone) levels representing endocrine responsivity in 11 alcohol-dependent individuals compared to 12 controls. Furthermore we wanted to know whether functional polymorphisms (5-HTTLPR and 5HT2C Ser23Cys), have any influence on this responsivity.


METHODS
Alcohol-dependent inpatients aged 36.45+/-7.7 years who were detoxified, without comorbid psychiatric/medical disorders or concurrent psychotropic medications, and 12 age-matched healthy controls aged 32.50+/-6.4 years were enrolled. Subjects also reported their subjective experiences like anxiety, craving and intoxication using visual analogue scales (VAS), side-effects were assessed by the serotonin syndrome scale (SSS). Measurements were taken at 8 timepoints at 30 mins interval, from -2 (60 mins pre-application) to +6 (180 mins post-application). Patients had a mean duration of illness of 8.91+/-3.4 years, consumed a mean of 326.36+/-220.8 g alcohol/day whereas control subjects consumed a mean of 32.50+/-41.4 g alcohol/day. A 0.4 mg citalopram/kg body weight dose was administered intravenously to patients (31.96+/-4.45 mg), and to controls (34.22+/-7.65 mg).


RESULTS
ACTH levels were higher for both groups in the verum compared to placebo administrations across timepoints. 5HT2C Ser23 alleles effected significantly higher ACTH responses under placebo administration but attenuated the responses under citalopram administration. Considering both groups together, no influence of 5-HTTLPR alleles was found on ACTH levels in either group under either regimen. While citalopram administration did not reduce craving in alcohol-dependent patients, it increased anxiety in patients and controls compared to placebo administration.


CONCLUSIONS
Despite the small differences in endocrine and subjective responses between alcoholic patients and controls, the effect of SSRI on endocrine response with respect to 5HT2C functional alleles deserves further investigation in larger samples to clarify whether this genetic variant constitutes a potential risk factor for changes in neuroendocrine functioning and subsequent psychiatric disorders.
Wong
W M
WM
Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany.
Hasemann
S
S
Schwarz
M
M
Zill
P
P
Koller
G
G
Soyka
M
M
Preuss
U W
UW
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000437:Alcoholism / Q000097:blood / Q000235:genetics* / Q000523:psychology*; D000483:Alleles; D000928:Antidepressive Agents; D001007:Anxiety / Q000209:etiology / Q000523:psychology; D001519:Behavior; D015283:Citalopram; D004311:Double-Blind Method; D005787:Gene Frequency; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008032:Limbic System / Q000187:drug effects; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects; D011110:Polymorphism, Genetic / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D044405:Receptor, Serotonin, 5-HT2C / Q000097:blood; D050486:Serotonin Plasma Membrane Transport Proteins / Q000097:blood; D020230:Serotonin Syndrome / Q000523:psychology
D000928:Antidepressive Agents; D044405:Receptor, Serotonin, 5-HT2C; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D015283:Citalopram; D000324:Adrenocorticotropic Hormone