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HPT axis, CSF monoamine metabolites, suicide intent and depression severity in male suicide attempters
Journal of Affective Disorders 111 (2008) 119 – 124 www.elsevier.com/locate/jad
Brief report
HPT axis, CSF monoamine metabolites, suicide intent and depression severity in male suicide attempters Jussi Jokinen ⁎, Mats Samuelsson, Anna-Lena Nordström, Peter Nordström Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden Received 16 July 2007; received in revised form 3 February 2008; accepted 4 February 2008 Available online 14 March 2008
Abstract A lower thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) in depressed women has been associated with violent suicide attempts, suicidal intent, higher lethality and suicide risk. The cerebrospinal fluid (CSF) 5hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) levels are related to suicidal behaviour. We studied the HPT axis function in twelve male suicide attempters and eight healthy volunteers submitted to lumbar puncture and to TRH test. Suicidal behaviour and depression severity were assessed. There was no association between deltamaxTSH and violent suicidality or subsequent suicide. The deltamaxTSH correlated with CSF HVA in suicide attempters. The plasma T3 showed a negative correlation with the Beck Suicide Intent Scale and the Montgomery Asberg Depression rating scale. Dopaminergic regulatory mechanisms on the thyroid hormone activity may be altered in male suicide attempters. © 2008 Elsevier B.V. All rights reserved. Keywords: TRH test; T3; CSF 5-HIAA; CSF HVA; Suicide intent; Depression severity
1. Introduction A reduced thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) in depressed patients was first reported by Prange et al. (1972) and Kastin et al. (1972). Approximately 25% to 30% of depressed patients have a blunted TSH response to TRH (Loosen and Prange, 1982; Loosen, 1985). Persistence of a blunted TSH response to TRH may predict relapse or poor response of the mood disorder to treatment (Targum, 1984) and hence greater risk of suicidal behaviour. ⁎ Corresponding author. Tel.: +46 8 51776759; fax: +46 8 303706. E-mail address: [email protected] (J. Jokinen). 0165-0327/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2008.02.001
Few studies have focused on associations between a blunted TSH response and suicidal behaviour, for review see Mann and Currier (2007). Linkowski et al. (1983) reported that depressed female patients with a history of violent suicide attempts had a reduced TSH response to TRH and patients with a blunted TSH response had a higher risk for suicide (Linkowski et al., 1984). Lower TSH response in depressed women was associated with suicidal intent, lethality, and agitation (Corrigan et al., 1992). Korner et al. (1987) followed 306 depressed patients for a mean of 5.8 years. The TSH response in 18 patients who committed suicide did not differ from the survivors. One study showed a higher mean TSH response in violent suicide attempters compared with non-attempters (Banki et al., 1984).
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Most of these studies have been performed in female patients (Linkowski et al., 1983, 1984; Corrigan et al., 1992; Banki et al., 1984). Serotoninergic and dopaminergic dysfunction are involved in the pathophysiology of suicidal behavior (Mann, 2003). Low 5-hydroxyindolacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) predicted suicide in male suicide attempters (Samuelsson et al., 2006) and CSF 5HIAA and homovanillic acid (HVA) levels were negatively correlated with the maximum lethality of suicide attempts (Sher et al., 2006). Few studies have focused on relationship between TSH response to TRH and CSF monoamine metabolites in suicidal patients. The maximal TSH response showed an inverse correlation with the CSF 5-HIAA, and it was lowest in the non-attempter group (Banki et al., 1984). The aim of this study was to explore the HPT axis function in male suicide attempters compared with healthy volunteers in relation to suicidal behaviour and to the CSF 5-HIAA and HVA levels. 2. Experimental procedures The study was approved by the ethics committee of the Karolinska University Hospital. 2.1. Patients Twelve male patients (age range: 20–49; mean 32 years) not receiving any antidepressant treatment admitted to the department of Psychiatry at the Karolinska Hospital after a suicide attempt were included after informed consent was obtained. Ten patients fulfilled criteria for mood disorders and two for psychotic disorder according to the DSM IV. All mood disorder patients were in the depressed phase. Five patients had comorbidity for alcohol abuse and six patients for a personality disorder. 2.2. Healthy volunteers Eight male healthy volunteers (HV) were recruited and screened carefully to exclude heredity for psychiatric disorder, previous psychiatric history or medical conditions. The mean age of HV was 24 years (age range: 21–28). 2.3. Assessment of suicidal behaviour and depression severity Suicide attempt method was defined violent according to the criteria of Traskman et al. (1981). The lethality of the index suicide attempt was evaluated with
the Medical Damage Rating Scale (MDS; Beck et al., 1975), an MDS score of ≥4 was cut-off for high lethality. The Suicide Intent Scale (SIS) is a 15-item instrument designed to measure the factual aspects of a suicide attempt: the total SIS can range between 0 (low intent) and 30 (high intent) (Beck et al., 1974). Depression severity was rated using the Montgomery Asberg Depression Rating Scale (Montgomery and Asberg, 1979). The MADRS consists of 10 items and each item is rated on a scale of 0 (no abnormality) to 6 (severe). A psychiatrist performed SIS and MADRS ratings within 48 h after admission. The patients who died within five years were identified and the causes of death were obtained from Statistics Sweden, which keeps the National Swedish Cause of death register. Four suicides were identified from the death certificates. 2.4. Lumbar punctures Lumbar punctures were performed in a standardized manner as described previously (Samuelsson et al., 2006). 2.5. Thyroid hormones and TRH test TRH test was performed after lumbar puncture (mean 8 days after). The baseline thyroid functioning was evaluated by measuring plasma TSH, T3 and T4 levels. On the examination day, the patients and HV fasted after 2400 h, at 0830 h; an intravenous line was secured by a drip infusion of physiological saline. At 0900 h, the baseline TSH level was measured. Then, 0.5 mg of TRH was slowly administered intravenously. Blood was obtained at 15, 30, 45, 60, 90 and 120 min for TSH measurement. TSH (microIU/mL) was measured by radioimmunoassay at the Hormone Laboratory in Huddinge hospital, the maximum response value was defined as maxTSH. The deltamaxTSH was defined as maxTSH minus baseline TSH. A blunted response to TRH was defined as a deltamax TSH less than 5 microIU/mL. 2.6. Statistical analysis The Statistical Package JMP V software, SAS Institute inc., Cary, NC, USA was used for parametric and nonparametric statistical analyses. For comparisons between two groups (patients/HV, suicide victims/survivors) or dichotomised groups for suicide or suicide attempt method (violent/non-violent, high/low medical damage, lethality), Student's t-test was used. For multiple comparisons, a
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one-way analysis of variance (ANOVA) was used; tests of correlations were performed using Pearson's r. The p value was set at b0.05. 3. Results 3.1. HPT axis and suicidality All subjects were clinically euthyroid with serum levels of TSH within the reference range. The mean TSH levels did not differ between the patients and HV (1.6 microU/L SD = 1 and 1.9 microU/L, SD = 0.8 respectively, NS). There was no significant difference in BMI between patients (mean 22.6) and controls (mean 21.4). As the patients were older than HV (age range: 20–49; mean 32 years and age range: 21–28; mean 24 years respectively) (p b 0.05 Student's t-test), age correlations were controlled. The thyroid hormone concentrations (TSH, T3, T4) were not age or BMI dependent either in patients or in HV. The deltamax TSH did not correlate with age in patients or in HV but showed a trend for correlation with BMI in patients (p b 0.08). The mean deltamax TSH for patients was 9.85 (SD 5.6) and for HV 9.15 (SD 4.1) (NS). When age and BMI were used as covariates in a regression analysis, the finding still remained non significant. Two patients and one HV were blunters (deltamax TSH b 5 microU/mL). A summary of the endocrine findings in TRH test in different groups (suicide completers, suicide attempters and HV) is shown in Fig. 1.
Index episode suicide attempt were 8 patients with a violent method and 4 with a non-violent method, four early suicides (all within two years) were identified. The Suicide Intent score for the total sample ranged from 10–27. DeltamaxTSH did not correlate with any variables of suicidal behaviour in this sample. Plasma T3 showed a significant negative correlation to the Beck Suicide Intent scale (r = − 0.67, p b 0.0167) and to the Montgomery Asberg Depression Rating scale (r = − 0.72, p b 0.008), Fig. 2.
Fig. 1. A summary of the endocrine findings in the TRH test: individual TSH response to TRH infusion in suicide completers (stars), suicide attempters (circles) and healthy controls (dots).
Fig. 3. Deltamax TSH plotted against the CSF HVA concentration for the suicide attempters (circles) and suicide completers (stars). Correlation for suicide attempters (r = 0.71, p b 0.05).
Fig. 2. Plasma T3 plotted against the Beck Suicide Intent scale (SIS) scores in patients (r = − 0.67, p b 0.0167).
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3.2. HPT axis and monoamine metabolites 3.2.1. Patients Correlations between baseline TSH, T3, T4 and CSF 5-HIAA were not significant. Baseline TSH showed a significant positive correlation with CSF HVA (r = 0.68, p b 0.014) and T3 a trend with CSF HVA (p b 0.073). The deltamax TSH correlated with CSF HVA in suicide attempters (n = 8, r = 0.71, p b 0.05) but not in suicide completers (NS), Fig. 3. There was no significant association between CSF 5-HIAA and deltamax TSH. 3.2.2. Healthy volunteers Correlations between peripheral thyroid hormones, the deltamaxTSH and CSF monoamine metabolites were not significant. CSF monoamine metabolite levels did not differ between patients and HV. 4. Discussion Interestingly plasma T3 correlated both with the Beck Suicide Intent Scale and with the Montgomery Asberg Depression Rating Scale. There were negative correlations between plasma T3 levels and suicide intent and depression severity; the lower the levels of T3, the higher the suicide intent and depression severity. This is in line with a previous study reporting negative correlation of T3 and mood rating scores in bipolar patients (Larsen et al., 2004). A common pharmacological treatment strategy of refractory depression has been augmentation of antidepressants with thyroid hormone (Joffe and Sokolov, 2000). There is recent evidence that T3 accelerates the antidepressant response measured by MADRS in a placebo-controlled trial (Posternak et al., 2007). In this study neither deltamaxTSH nor a blunted TSH response to TRH, were associated with a suicidal behaviour, which has been reported, in earlier studies (Linkowski et al., 1983, 1984; Corrigan et al., 1992). Few clinical studies have assessed potential interactions between CNS monoaminergic systems and HPT axis function. In a recent study of healthy persons, CSF 5-HIAA and HVA concentrations were negatively correlated with plasma TSH and T3 (Strawn et al., 2004) indicating that CNS monoamine-thyroid interactions are of physiological significance in the euthyroid human. In a study of male violent offenders, positive correlation between the CSF HVA and the peripheral T3/T4 ratio was reported, indicating that increased activity in the dopaminergic system is associated with increased peripheral thyroid hormone activity (Yhede et al., 2003). Our finding of positive
correlation between CSF HVA and baseline TSH is in line with results of Yhede et al. but in contrast to the results from healthy humans who showed a negative correlation between the two systems. Our finding of positive correlation between deltamax TSH and CSF HVA in suicide attempters indicates that dopaminergic regulatory mechanisms on the thyroid hormone activity may be altered in male suicide attempters. In the present study there was no correlation between CSF 5-HIAA and the HPT axis functioning in male suicide attempters. Banki et al. (1984) reported that the deltamax TSH showed an inverse correlation with the CSF 5-HIAA in suicidal patients and Gold et al. (1977) observed a negative correlation between TSH response and CSF 5-HIAA in 6 patients with unipolar depression compared with healthy controls. Another study of patients with major depressive disorder found no correlation between TSH and CSF 5-HIAA or between TRH-stimulated deltamaxTSH and any of the monoamine metabolites (Peabody et al., 1987). Given the relationships between serotonin (5-HT) and HPT axis activity, it has been hypothesized that a reduced 5-HT input could increase TRH secretion (Loosen and Prange, 1982; Roy et al., 1988). There is evidence for that hypothyroidism reduces central 5-HT activity (Cleare et al., 1995). It has also been suggested that altered HPT axis activity in major depression is not related to central 5-HT dysfunction (Duval et al., 1999). Most TRH/TSH investigations have been made in depressed, rather than suicidal patients. Almost all of these early studies (Linkowski et al., 1983, 1984; Corrigan et al., 1992; Banki et al., 1984; Maes et al., 1989) have focused on female patients only. Even in a meta-analysis it has been proposed that augmentation strategy can improve time to treatment response particularly in women (Altshuler et al., 2001). All patients in this study were men and there may be a gender difference. To our knowledge, this is the first study to examine TSH response to TRH and the levels of monoamine metabolites in a sample of euthyroid male suicide attempters. The major limitations of this study are comorbidity and the small sample size. They formed a high-risk group concerning suicidality and we covered many aspects of suicidal behaviour. TRH test results did not correlate to any of these variables in a significant way indicating that the CNS thyroid system may not be directly involved in the biological vulnerability of suicidal behavior in male suicide attempters. However our results support the interpretation that there are indications of an altered dopaminergic regulation of thyroid hormone activity in male suicide attempters. The finding of an association between plasma
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T3 and suicide intent and depression severity is interesting and needs to be replicated. Role of funding source Funding for this study was provided by the Swedish Research Council (VR project no. 05454), Swedish Research Council (VR project no. 05454) had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Conflict of Interests No conflicts of interests to declare for any of the co authors.
Acknowledgements We wish to thank professor Marie Åsberg and professor Lil Träskman-Benz for inspiring us to study suicide and biological vulnerability, professor Leif Bertilsson for analysing the monoamine metabolites and professor Peter Eneroth for analysing the hormone data. References Altshuler, L.L., Bauer, M., Frye, M.A., Gitlin, M.J., Mintz, J., Szuba, M.P., Leight, K.L., Whybrow, P.C., 2001. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am. J. Psychiatry 158, 1617–1622. Banki, C.M., Arato, M., Papp, Z., Kurcz, M., 1984. Biochemical markers in suicidal patients. Investigations with cerebrospinal fluid amine metabolites and neuroendocrine test. J. Affect. Disord 6, 341–350. Beck, A.T., Schuyler, D., Herman, I., 1974. Development of suicidal intent scales, in the prediction of suicide. In: Beck, A.T., Resnik, H.L., Lettieri, D.J. (Eds.), The prediction of suicide. Charles Press, Bowie, MD, pp. 45–56. Beck, A.T., Beck, R., Kovacs, M., 1975. Classification of suicidal behaviors: I. Quantifying intent and medical lethality. Am. J. Psychiatry 132 (3), 285–287. Cleare, A.J., McGregor, A., O'Keane, V., 1995. Neuroendocrine evidence for an association between hypothyroidism, reduced central 5-HT activity and depression. Clin. Endocrinology (Oxf) 43, 713–719. Corrigan, M.H., Gillette, G.M., Quade, D., Garbutt, J.C., 1992. Panic, suicide, and agitation: Independent correlates of the TSH response to TRH in depression. Biol. Psychiatry 31, 984–992. Duval, F., Mokrani, M.C., Bailey, P., Correa, H., Diep, T.S., Crocq, M. A., Macher, J.P., 1999. Thyroid axis activity and serotonin function in major depressive episode. Psychoneuroendocrinology 24, 695–712. Gold, P.W., Goodwin, F.K., Wehr, T., Rebar, R., 1977. Pituitary thyrotropin response to thyrotropin-releasing hormone in affective illness: relationship to spinal fluid amine metabolites. Am. J. Psychiatry 134, 1028–1031. Joffe, R.T., Sokolov, S.T., 2000. Thyroid hormone treatment of primary unipolar depression: a review. Int. J. Neuropsychopharmacol. 3, 143–147.
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Kastin, A.J., Ehrensing, R.H., Schalch, D.S., Anderson, M.S., 1972. Improvement in mental depression with decreased thyrotropin response after administration of thyrotropin-releasing hormone. Lancet 2 (7780), 740–742. Korner, A., Kirkegaard, C., Larsen, J.K., 1987. The thyrotropin response to thyrotropin-releasing hormone as a biological marker of suicidal risk in depressive patients. Acta Psychiatr. Scand. 76, 355–358. Larsen, J.K., Faber, J., Christensen, E.M., Bendsen, B.B., Solstad, K., Gjerris, A., Siersbaek-Nielsen, K., 2004. Relationship between mood and TSH response to TRH stimulation in bipolar affective disorder. Psychoneuroendocrinology 29 (7), 917–924. Linkowski, P., Van Wettere, J.P., Kerkhofs, M., Brauman, H., Mendlewicz, J., 1983. Thyrotrophin response to thyreostimulin in affectively ill women relationship to suicidal behaviour. Br. J. Psychiatry 143, 401–405. Linkowski, P., Van Wettere, J.P., Kerkhofs, M., Gregoire, F., Brauman, H., Mendlewicz, J., 1984. Violent suicidal behavior and the thyrotropin-releasing hormone-thyroid-stimulating hormone test: a clinical outcome study. Neuropsychobiology 12, 19–22. Loosen, P.T., Prange Jr., A.J., 1982. Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: a review. Am. J. Psychiatry 139, 405–416. Loosen, P.T., 1985. The TRH-induced TSH response in psychiatric patients: a possible neuroendocrine marker. Psychoneuroendocrinology 10, 237–260. Maes, M., Vandewoude, M., Schotte, C., Martin, M., Blockx, P., Scharpe, S., Cosyns, P., 1989. Hypothalamic-pituitary-adrenal and -thyroid axis dysfunctions and decrements in the availability of L-tryptophan as biological markers of suicidal ideation in major depressed females. Acta Psychiatr. Scand. 80, 13–17. Mann, J.J., 2003. Neurobiology of suicidal behaviour. Nat. Rev. Neurosci. 4, 819–828. Mann, J.J., Currier, D., 2007. A review of prospective studies of biologic predictors of suicidal behavior in mood disorders. Arch. Suicide Res. 11 (1), 3–16. Montgomery, S.A., Asberg, M., 1979. A new depression scale designed to be sensitive to change. Br. J. Psychiatry 134, 382–389. Peabody, C.A., Whiteford, H.A., Warner, M.D., Faull, K.F., Barchas, J.D., Berger, P.A., 1987. TRH stimulation test and depression. Psychiatry Res. 22 (1), 21–28. Posternak, M., Novak, S., Stern, R., Hennessey, J., Joffe, R., Prange, A., Zimmerman, M., 2007. A pilot effectiveness study: placebocontrolled trial of adjunctive L-triiodothyronine (T3) used to accelerate and potentiate the antidepressant response. Int. J. Neuropsychopharmacol. 13, 1–11. Prange Jr., A.J., Lara, P.P., Wilson, I.C., Alltop, L.B., Breese, G.R., 1972. Effects of thyrotropin-releasing hormone in depression. Lancet 2 (7785), 999–1002. Roy, A., Karoum, F., Linnoila, M., Pickard, D., 1988. Thyrotropin releasing hormone test in unipolar depressed patients and controls: relationship to clinical and biological variables. Acta Psychiatr. Scand. 77, 151–159. Samuelsson, M., Jokinen, J., Nordstrom, A.L., Nordstrom, P., 2006. CSF 5-HIAA, suicide intent and hopelessness in the prediction of early suicide in male high-risk suicide attempters. Acta Psychiatr. Scand. 113, 44–47. Sher, L., Carballo, J.J., Grunebaum, M.F., Burke, A.K., Zalsman, G., Huang, Y.Y., Mann, J.J., Oquendo, M.A., 2006. A prospective study of the association of cerebrospinal fluid monoamine metabolite levels with lethality of suicide attempts in patients with bipolar disorder. Bipolar Disord. 8, 543–550.
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Strawn, J.R., Ekhator, N.N., D'Souza, B.B., Geracioti Jr., T.D., 2004. Pituitary-thyroid state correlates with central dopaminergic and serotonergic activity in healthy humans. Neuropsychobiology 49, 84–87. Targum, S.D., 1984. Persistent neuroendocrine dysregulation in major depressive disorder: a marker for early relapse. Biol. Psychiatry 19 (3), 305–318.
Traskman, L., Asberg, M., Bertilsson, L., Sjostrand, L., 1981. Monoamine metabolites in CSF and suicidal behaviour. Arch. Gen. Psychiatry 38, 631–636. Yhede, R., Blennow, K., Forsman, A., Soderstrom, H., 2003. The activity in the CNS catecholaminergic systems covaries with thyroid hormone metabolism in humans. J. Neural. Transm. 110 (12), 1369–1373.
Brief report
HPT axis, CSF monoamine metabolites, suicide intent and depression severity in male suicide attempters Jussi Jokinen ⁎, Mats Samuelsson, Anna-Lena Nordström, Peter Nordström Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden Received 16 July 2007; received in revised form 3 February 2008; accepted 4 February 2008 Available online 14 March 2008
Abstract A lower thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) in depressed women has been associated with violent suicide attempts, suicidal intent, higher lethality and suicide risk. The cerebrospinal fluid (CSF) 5hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) levels are related to suicidal behaviour. We studied the HPT axis function in twelve male suicide attempters and eight healthy volunteers submitted to lumbar puncture and to TRH test. Suicidal behaviour and depression severity were assessed. There was no association between deltamaxTSH and violent suicidality or subsequent suicide. The deltamaxTSH correlated with CSF HVA in suicide attempters. The plasma T3 showed a negative correlation with the Beck Suicide Intent Scale and the Montgomery Asberg Depression rating scale. Dopaminergic regulatory mechanisms on the thyroid hormone activity may be altered in male suicide attempters. © 2008 Elsevier B.V. All rights reserved. Keywords: TRH test; T3; CSF 5-HIAA; CSF HVA; Suicide intent; Depression severity
1. Introduction A reduced thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) in depressed patients was first reported by Prange et al. (1972) and Kastin et al. (1972). Approximately 25% to 30% of depressed patients have a blunted TSH response to TRH (Loosen and Prange, 1982; Loosen, 1985). Persistence of a blunted TSH response to TRH may predict relapse or poor response of the mood disorder to treatment (Targum, 1984) and hence greater risk of suicidal behaviour. ⁎ Corresponding author. Tel.: +46 8 51776759; fax: +46 8 303706. E-mail address: [email protected] (J. Jokinen). 0165-0327/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2008.02.001
Few studies have focused on associations between a blunted TSH response and suicidal behaviour, for review see Mann and Currier (2007). Linkowski et al. (1983) reported that depressed female patients with a history of violent suicide attempts had a reduced TSH response to TRH and patients with a blunted TSH response had a higher risk for suicide (Linkowski et al., 1984). Lower TSH response in depressed women was associated with suicidal intent, lethality, and agitation (Corrigan et al., 1992). Korner et al. (1987) followed 306 depressed patients for a mean of 5.8 years. The TSH response in 18 patients who committed suicide did not differ from the survivors. One study showed a higher mean TSH response in violent suicide attempters compared with non-attempters (Banki et al., 1984).
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Most of these studies have been performed in female patients (Linkowski et al., 1983, 1984; Corrigan et al., 1992; Banki et al., 1984). Serotoninergic and dopaminergic dysfunction are involved in the pathophysiology of suicidal behavior (Mann, 2003). Low 5-hydroxyindolacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) predicted suicide in male suicide attempters (Samuelsson et al., 2006) and CSF 5HIAA and homovanillic acid (HVA) levels were negatively correlated with the maximum lethality of suicide attempts (Sher et al., 2006). Few studies have focused on relationship between TSH response to TRH and CSF monoamine metabolites in suicidal patients. The maximal TSH response showed an inverse correlation with the CSF 5-HIAA, and it was lowest in the non-attempter group (Banki et al., 1984). The aim of this study was to explore the HPT axis function in male suicide attempters compared with healthy volunteers in relation to suicidal behaviour and to the CSF 5-HIAA and HVA levels. 2. Experimental procedures The study was approved by the ethics committee of the Karolinska University Hospital. 2.1. Patients Twelve male patients (age range: 20–49; mean 32 years) not receiving any antidepressant treatment admitted to the department of Psychiatry at the Karolinska Hospital after a suicide attempt were included after informed consent was obtained. Ten patients fulfilled criteria for mood disorders and two for psychotic disorder according to the DSM IV. All mood disorder patients were in the depressed phase. Five patients had comorbidity for alcohol abuse and six patients for a personality disorder. 2.2. Healthy volunteers Eight male healthy volunteers (HV) were recruited and screened carefully to exclude heredity for psychiatric disorder, previous psychiatric history or medical conditions. The mean age of HV was 24 years (age range: 21–28). 2.3. Assessment of suicidal behaviour and depression severity Suicide attempt method was defined violent according to the criteria of Traskman et al. (1981). The lethality of the index suicide attempt was evaluated with
the Medical Damage Rating Scale (MDS; Beck et al., 1975), an MDS score of ≥4 was cut-off for high lethality. The Suicide Intent Scale (SIS) is a 15-item instrument designed to measure the factual aspects of a suicide attempt: the total SIS can range between 0 (low intent) and 30 (high intent) (Beck et al., 1974). Depression severity was rated using the Montgomery Asberg Depression Rating Scale (Montgomery and Asberg, 1979). The MADRS consists of 10 items and each item is rated on a scale of 0 (no abnormality) to 6 (severe). A psychiatrist performed SIS and MADRS ratings within 48 h after admission. The patients who died within five years were identified and the causes of death were obtained from Statistics Sweden, which keeps the National Swedish Cause of death register. Four suicides were identified from the death certificates. 2.4. Lumbar punctures Lumbar punctures were performed in a standardized manner as described previously (Samuelsson et al., 2006). 2.5. Thyroid hormones and TRH test TRH test was performed after lumbar puncture (mean 8 days after). The baseline thyroid functioning was evaluated by measuring plasma TSH, T3 and T4 levels. On the examination day, the patients and HV fasted after 2400 h, at 0830 h; an intravenous line was secured by a drip infusion of physiological saline. At 0900 h, the baseline TSH level was measured. Then, 0.5 mg of TRH was slowly administered intravenously. Blood was obtained at 15, 30, 45, 60, 90 and 120 min for TSH measurement. TSH (microIU/mL) was measured by radioimmunoassay at the Hormone Laboratory in Huddinge hospital, the maximum response value was defined as maxTSH. The deltamaxTSH was defined as maxTSH minus baseline TSH. A blunted response to TRH was defined as a deltamax TSH less than 5 microIU/mL. 2.6. Statistical analysis The Statistical Package JMP V software, SAS Institute inc., Cary, NC, USA was used for parametric and nonparametric statistical analyses. For comparisons between two groups (patients/HV, suicide victims/survivors) or dichotomised groups for suicide or suicide attempt method (violent/non-violent, high/low medical damage, lethality), Student's t-test was used. For multiple comparisons, a
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one-way analysis of variance (ANOVA) was used; tests of correlations were performed using Pearson's r. The p value was set at b0.05. 3. Results 3.1. HPT axis and suicidality All subjects were clinically euthyroid with serum levels of TSH within the reference range. The mean TSH levels did not differ between the patients and HV (1.6 microU/L SD = 1 and 1.9 microU/L, SD = 0.8 respectively, NS). There was no significant difference in BMI between patients (mean 22.6) and controls (mean 21.4). As the patients were older than HV (age range: 20–49; mean 32 years and age range: 21–28; mean 24 years respectively) (p b 0.05 Student's t-test), age correlations were controlled. The thyroid hormone concentrations (TSH, T3, T4) were not age or BMI dependent either in patients or in HV. The deltamax TSH did not correlate with age in patients or in HV but showed a trend for correlation with BMI in patients (p b 0.08). The mean deltamax TSH for patients was 9.85 (SD 5.6) and for HV 9.15 (SD 4.1) (NS). When age and BMI were used as covariates in a regression analysis, the finding still remained non significant. Two patients and one HV were blunters (deltamax TSH b 5 microU/mL). A summary of the endocrine findings in TRH test in different groups (suicide completers, suicide attempters and HV) is shown in Fig. 1.
Index episode suicide attempt were 8 patients with a violent method and 4 with a non-violent method, four early suicides (all within two years) were identified. The Suicide Intent score for the total sample ranged from 10–27. DeltamaxTSH did not correlate with any variables of suicidal behaviour in this sample. Plasma T3 showed a significant negative correlation to the Beck Suicide Intent scale (r = − 0.67, p b 0.0167) and to the Montgomery Asberg Depression Rating scale (r = − 0.72, p b 0.008), Fig. 2.
Fig. 1. A summary of the endocrine findings in the TRH test: individual TSH response to TRH infusion in suicide completers (stars), suicide attempters (circles) and healthy controls (dots).
Fig. 3. Deltamax TSH plotted against the CSF HVA concentration for the suicide attempters (circles) and suicide completers (stars). Correlation for suicide attempters (r = 0.71, p b 0.05).
Fig. 2. Plasma T3 plotted against the Beck Suicide Intent scale (SIS) scores in patients (r = − 0.67, p b 0.0167).
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3.2. HPT axis and monoamine metabolites 3.2.1. Patients Correlations between baseline TSH, T3, T4 and CSF 5-HIAA were not significant. Baseline TSH showed a significant positive correlation with CSF HVA (r = 0.68, p b 0.014) and T3 a trend with CSF HVA (p b 0.073). The deltamax TSH correlated with CSF HVA in suicide attempters (n = 8, r = 0.71, p b 0.05) but not in suicide completers (NS), Fig. 3. There was no significant association between CSF 5-HIAA and deltamax TSH. 3.2.2. Healthy volunteers Correlations between peripheral thyroid hormones, the deltamaxTSH and CSF monoamine metabolites were not significant. CSF monoamine metabolite levels did not differ between patients and HV. 4. Discussion Interestingly plasma T3 correlated both with the Beck Suicide Intent Scale and with the Montgomery Asberg Depression Rating Scale. There were negative correlations between plasma T3 levels and suicide intent and depression severity; the lower the levels of T3, the higher the suicide intent and depression severity. This is in line with a previous study reporting negative correlation of T3 and mood rating scores in bipolar patients (Larsen et al., 2004). A common pharmacological treatment strategy of refractory depression has been augmentation of antidepressants with thyroid hormone (Joffe and Sokolov, 2000). There is recent evidence that T3 accelerates the antidepressant response measured by MADRS in a placebo-controlled trial (Posternak et al., 2007). In this study neither deltamaxTSH nor a blunted TSH response to TRH, were associated with a suicidal behaviour, which has been reported, in earlier studies (Linkowski et al., 1983, 1984; Corrigan et al., 1992). Few clinical studies have assessed potential interactions between CNS monoaminergic systems and HPT axis function. In a recent study of healthy persons, CSF 5-HIAA and HVA concentrations were negatively correlated with plasma TSH and T3 (Strawn et al., 2004) indicating that CNS monoamine-thyroid interactions are of physiological significance in the euthyroid human. In a study of male violent offenders, positive correlation between the CSF HVA and the peripheral T3/T4 ratio was reported, indicating that increased activity in the dopaminergic system is associated with increased peripheral thyroid hormone activity (Yhede et al., 2003). Our finding of positive
correlation between CSF HVA and baseline TSH is in line with results of Yhede et al. but in contrast to the results from healthy humans who showed a negative correlation between the two systems. Our finding of positive correlation between deltamax TSH and CSF HVA in suicide attempters indicates that dopaminergic regulatory mechanisms on the thyroid hormone activity may be altered in male suicide attempters. In the present study there was no correlation between CSF 5-HIAA and the HPT axis functioning in male suicide attempters. Banki et al. (1984) reported that the deltamax TSH showed an inverse correlation with the CSF 5-HIAA in suicidal patients and Gold et al. (1977) observed a negative correlation between TSH response and CSF 5-HIAA in 6 patients with unipolar depression compared with healthy controls. Another study of patients with major depressive disorder found no correlation between TSH and CSF 5-HIAA or between TRH-stimulated deltamaxTSH and any of the monoamine metabolites (Peabody et al., 1987). Given the relationships between serotonin (5-HT) and HPT axis activity, it has been hypothesized that a reduced 5-HT input could increase TRH secretion (Loosen and Prange, 1982; Roy et al., 1988). There is evidence for that hypothyroidism reduces central 5-HT activity (Cleare et al., 1995). It has also been suggested that altered HPT axis activity in major depression is not related to central 5-HT dysfunction (Duval et al., 1999). Most TRH/TSH investigations have been made in depressed, rather than suicidal patients. Almost all of these early studies (Linkowski et al., 1983, 1984; Corrigan et al., 1992; Banki et al., 1984; Maes et al., 1989) have focused on female patients only. Even in a meta-analysis it has been proposed that augmentation strategy can improve time to treatment response particularly in women (Altshuler et al., 2001). All patients in this study were men and there may be a gender difference. To our knowledge, this is the first study to examine TSH response to TRH and the levels of monoamine metabolites in a sample of euthyroid male suicide attempters. The major limitations of this study are comorbidity and the small sample size. They formed a high-risk group concerning suicidality and we covered many aspects of suicidal behaviour. TRH test results did not correlate to any of these variables in a significant way indicating that the CNS thyroid system may not be directly involved in the biological vulnerability of suicidal behavior in male suicide attempters. However our results support the interpretation that there are indications of an altered dopaminergic regulation of thyroid hormone activity in male suicide attempters. The finding of an association between plasma
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T3 and suicide intent and depression severity is interesting and needs to be replicated. Role of funding source Funding for this study was provided by the Swedish Research Council (VR project no. 05454), Swedish Research Council (VR project no. 05454) had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Conflict of Interests No conflicts of interests to declare for any of the co authors.
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