We report on two substance misusers with depression resistant to tricyclic antidepressant treatment who responded to triiodothyronine augmentation. The management of resistant depression, augmentation strategies with particular reference to triiodothyronine, and the possible mechanism of action of triiodothyronine are discussed.published_or_final_versio

Ho, TP

Kan, CK

Hong Kong Medical Journal

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Title Triiodothyronine augmentation for the treatment of depressionin substance misusers unresponsive to tricyclic antidepressantsAuthor(s) Kan, CK; Ho, TPCitation Hong Kong Medical Journal, 2001, v. 7 n. 3, p. 299-302Issued Date 2001URL http://hdl.handle.net/10722/45320Rights Creative Commons: Attribution 3.0 Hong Kong LicenseHKMJ Vol 7 No 3 September 2001      299CASE REPORTKey words:Antidepressive agents, tricyclic;Depression;Triiodothyronine, drug effects;Triiodothyronine, therapeutic use ! !"#$% ! !"#$%&'( !"#$%&'()Triiodothyronine augmentation forthe treatment of depression insubstance misusers unresponsive totricyclic antidepressants○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○CK Kan  TP Ho  HKMJ 2001;7:299-302 !"#$%&'()*+),- ./01234 !"#$%Department of Psychiatry, Queen MaryHospital, 102 Pokfulam Road, Hong KongCK Kan, MB, BSTP Ho, MDCorrespondence to: Dr CK KanWe report on two substance misusers with depression resistant totricyclic antidepressant treatment who responded to triiodothyronineaugmentation. The management of resistant depression, augmentationstrategies with particular reference to triiodothyronine, and thepossible mechanism of action of triiodothyronine are discussed. !"#$%&'()*+,-./01234567&89:34 !"#$%&'()*+,-./0123456789:;,< !"#$%&'()*+,)-./012#3456789): !"#$%&'()*+,-!./01!234IntroductionDepression is a common condition—the National Comorbidity Survey inthe US found a lifetime prevalence of 17% for major depression.1 Annually,approximately 3% of the general population in the UK receive treat-ment for depression from their general practitioners.2 Despite the well-established efficacy of antidepressants in the treatment of depression,approximately 30% of patients fail to respond to tricyclic antidepressants(TCAs) or selective serotonin reuptake inhibitors.3Potentiation of antidepressant effects by L-triiodothyronine (T3)in tricyclic nonresponders was first reported by Prange et al in 1969.4L-triiodothyronine augmentation, however, has remained relativelyunderused locally and in other countries. A survey in the UK found thatthe T3 augmentation strategy has rarely been used among resistantdepression.5 A similar scenario exists locally, as revealed from thequestionnaire survey among Hong Kong psychiatric trainees.6 One ofthe reasons for the underutilisation of T3 augmentation is the lackof experience among psychiatrists. Thus, while reports in the literaturehave shown the usefulness of the strategy, it has rarely been applied inclinical practice.No reports of T3 augmentation were found in the Hong KongMedical Journal or the Hong Kong Journal of Psychiatry duringthe past 10 years. We report here two cases of depression resistantto TCA treatment—both patients were substance misusers whoresponded to T3 augmentation.300      HKMJ Vol 7 No 3 September 2001Kan et alCase reportsCase 1A 22-year-old Chinese single unemployed woman firstpresented in December 1995 with visual and audi-tory hallucination for 4 months. Her mood was notdepressed at that time. She drank a bottle of coughmixture a day and had been dependent on it since shewas 17 years old. She also used cannabis and benzodia-zepines occasionally. She was diagnosed with drug-induced psychosis. She was prescribed thioridazine50 mg/d for 3 months and her psychotic symptomsgradually subsided.The patient was admitted to Queen Mary Hospitalin September 1998 when she presented with restless-ness, agitation, disorientation, and irrelevant speechfor 2 days. She had been misusing methamphetamineintermittently since July 1997, when she graduallystopped using cough mixture. Urine toxicology onadmission showed amphetamine and a diagnosis ofamphetamine intoxication was made. She made aspontaneous recovery 3 days after admission, but, shebecame severely depressed with frequent weepingepisodes, loss of interest, insomnia, decreased appetite,sense of worthlessness, and guilt feelings with self-blame. Amitriptyline was started at an increased doseof 200 mg/d for 8 weeks. She failed to respond, how-ever, and haloperidol up to 8 mg/d was added for2 weeks but was stopped when there was no sign ofsignificant improvement. Investigation results wereunremarkable except for a persistent low free thyroxine(T4) of 0.9 pmol/L (normal range, 10-36 pmol/L) withnormal thyroid-stimulating hormone (TSH) level andelevated anti-thyroglobulin. She was clinically euthy-roid. While amitriptyline was maintained at 200 mg/d,T3 augmentation was started with an initial dose of20 µg for 5 weeks, and then increased to 40 µg. Hermood improved after 1 week of T3 augmentation andshe experienced complete remission 6 weeks later.At discharge, she was cheerful with no further depres-sive symptoms. L-triiodothyronine was maintained foranother 2 months before tapering of the dose.Case 2An 18-year-old Chinese single unemployed man hadbeen a polysubstance misuser since the age of 13 years.He first experimented with cannabis, then quicklygraduated to daily use of methamphetamine by fumeinhalation. At the age of 15 years, he stopped usingmethamphetamine and started taking heroin. He becamedependent on heroin and used up to one tablet per day.The diagnosis of depression was first made at theage of 16 years when he presented with loss of interest,decreased energy, loss of confidence, poor concen-tration, recurrent suicidal ideas, insomnia, and lossof appetite for the previous 2 months. At that time hewas misusing heroin only and the pattern of its useapparently had no relationship to his depressed mood.He was admitted twice for detoxification and treat-ment of depression in November 1998 and June 1999.His depression responded partially to dothiepin150 mg/d and he had mild depressive symptoms inbetween treatment episodes. His drug compliance wasgood.His mood deteriorated again in September 1999.This mood change was apparently precipitated bythe tense family relationship he experienced as a resultof his continued use of heroin. An attempt was madeto further increase the dose of dothiepin but he couldnot tolerate the feelings of sedation and dizziness.After detoxification with methadone replacement, heremained depressed with similar symptoms to thosehe previously experienced. All investigations includ-ing thyroid function test were normal. Subsequently,T3 augmentation was started with T3 20 µg/d andincreasing to 40 µg/d for 10 days. The dothiepin doseremained at 150 mg/d. Some improvement in moodwas noted 3 days after T3 augmentation. After 2weeks, he had no more episodes of crying and hisenergy and interest recovered. He participated activelyin ward activities and began to plan his future. L-triiodothyronine was reduced 2 months later and heremained euthymic and abstained from heroin.DiscussionWhen patients do not respond to an adequate trialof a TCA, drug compliance should be checked, thediagnosis reviewed, and any perpetuating factors,such as important stressors should not be overlooked.For the true nonresponders, treatment options includeswitching to another antidepressant, electroconvulsivetherapy, or using an augmentation strategy. Whetherto switch antidepressants or to augment depends onthe severity of illness and the side-effects of the currentmedication. Switching to another antidepressanthas the advantage of keeping the treatment simple andthus helps to improve compliance. Augmentation oftenproduces a more rapid onset of action, however. Thisapproach may also help to improve the initial responseof the first agent or add other beneficial effects to theoriginal regimen.7Of all the augmentation strategies, lithiumaugmentation has received the most attention. Therehas been increasing evidence of the effectiveness ofHKMJ Vol 7 No 3 September 2001      301Triiodothyronine augmentation for depressionT3 augmentation, however. In 1982, Goodwin et al8performed the first double-blind study reporting theefficacy of T3 in converting TCA nonresponders toresponders. A recent meta-analysis has reported thatdepressed patients resistant to treatment given T3augmentation were two-fold more likely to respondthan non-augmented controls.9 Systematic comparisonof T3 and lithium found that each was effective inapproximately two thirds of TCA nonresponders. Itremains impossible, however, to predict which patientswill respond better to T3 or lithium augmentation.Joffe10 reported that patients who did respond tothe addition of T3 were less likely to benefit fromadjunctive lithium and vice versa.The usual dose of T3 in augmentation therapy is25 µg/d to 50 µg/d. A starting dose of 20 µg increas-ing to 40 µg was given to the patients in this study.Initial improvement in mood is usually apparent withinseveral days. Goodwin et al8 reported that there wasimprovement in all aspects of the depressive syndromewithin 1 to 3 days. For the two patients in this study,initial responses were noted after 3 and 7 days. Anadequate trial of T3 augmentation should last for 7to 14 days to reach its full effect. If T3 augmentationis effective, most studies recommend a maintenanceperiod of 2 months before gradually reducing the doseat the rate of 10 µg every 3 to 7 days.L-triiodothyronine augmentation therapy should notbe used in the presence of endocrine disorders such ashyperthyroidism, uncorrected adrenal insufficiency,and phaeochromocytoma. It is also contraindicated forpatients with cardiac disease, angina, acute myocardialinfarction, or hypertension. Adverse reactions areuncommon if daily doses do not exceed 50 µg. Thetwo patients reported here did not have any side-effects.While receiving treatment, patients should be moni-tored for signs and symptoms of thyrotoxicosis.The two cases illustrated here show a commonfeature. Both subjects were substance misusers and yetthey responded to T3 augmentation. This suggests thatT3 augmentation can be helpful in resistant depressionregardless of the aetiology of the illness. We are notaware of any study specifically conducted on theefficacy of T3 augmentation among substance misusers.Mood disturbances, in particular depression, however,are common among substance misusers, especially forthose who misuse stimulants such as methamphetamineor cocaine. The two patients reported here had a historyof methamphetamine misuse. Although the psychiatricsymptomatology of most substance misusers tendsto fluctuate over time, the two patients were observedto have persistent depression in an in-patient setting,and the depressive symptoms mitigated with T3augmentation. The aetiology of depression in substancemisusers is complicated since both psychologicalreactions and physical consequences of illicit druguse may be important. Poor social support, familyrelationship problems, unemployment, delinquenthistory, and personality problems are common insubstance misusers, as shown for the two reportedpatients. As a result, depression in substance misusersdemands a diverse and aggressive treatment approach.Persistent depression is likely to create difficultiesfor rehabilitation among drug misusers. Although thisreport focuses on the drug treatment of these patients,psychosocial approaches should not be overlooked.The exact mechanism of action of T3 augmentationremains largely unknown. In depressed patients, thecirculating plasma levels of free T4 appear to be normal,but levels of free T3 may be decreased. Approximatelyone third of depressed patients show blunting ofthe TSH response to thyrotropin releasing hormone.Approximately 15% of depressed patients haveelevated basal TSH levels, probably indicating sub-clinical hypothyroidism, and thyroid autoantibodiesare found in a similar percentage of patients.11Thyroid abnormalities are found at a higher frequencyamong TCA nonresponders and this may link withthe underlying mechanism of T3 augmentation.In most case reports, patients had normal thyroidfunction, as in our second case. There seems to be norelationship between thyroid state and the efficacy ofT3 augmentation. In the first case, the patient had sickeuthyroid syndrome, which is sometimes seen indepressed patients. In this condition, peripheraldeiodination of T4 to T3 is reduced, although the TSHlevel is normal.One proposed mechanism of T3 augmentationis that T3 may raise peripheral thyroid hormoneconcentrations in patients with covert or borderlinehypothyroidism. Other authorities believe thatthere is no difference in the thyroid state of theresponders and nonresponders to T3 augmentation.12L-triiodothyronine may act in euthyroid patientsthrough augmentation of the β-adrenergic system.13Alternatively, T3 may also affect thyroid utilisationand local neuronal deiodination in the brain.ConclusionL-triiodothyronine augmentation is effective forsome TCA nonresponders and the evidence from the302      HKMJ Vol 7 No 3 September 2001Kan et altwo patients reported here seem to suggest that T3augmentation works equally well among substancemisusers. It should be remembered, however, that thisreport consists of only two patients. Although theauthors are impressed with the clinical improvement,there is no standardised measure for these changes.Nevertheless, we believed this treatment strategyshould be used more often in local practice.References1. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and12-month prevalence of DSM-III-R psychiatric disorders inthe United States. Results from the National ComorbiditySurvey. Arch Gen Psychiatry 1994;51:8-19.2. HMSO. Morbidity Statistic from General Practice: ThirdNational Study. London: HMSO; 1986.3. Roose SP, Glassman AH, Walsh BT, Woodring S. Tricyclicnonresponders: phenomenology and treatment. Am JPsychiatry 1986;143:345-8.4. Prange AJ Jr, Wilson IC, Rabon AM, Lipton MA. Enhancementof imipramine antidepressant activity by thyroid hormone.Am J Psychiatry 1969;126:457-69.5. Shergill SS, Katona CL. Pharmacological choices after oneantidepressant fails: a survey of UK psychiatrists. J AffectDisord 1997;43:19-25.6. Lui WC, Wing YK. Local experience of use of thyroidhormones therapy in psychiatric practice in Hong Kong.Proceedings of Hong Kong College of Psychiatrists AnnualScientific Symposium; 1998.7. Nelson JC. Overcoming treatment resistance in depression.J Clin Psychiatry 1998;59(Suppl):13S-9S.8. Goodwin FK, Prange AJ Jr, Post RM, Muscettola G,Lipton MA. Potentiation of antidepressant effects by L-triiodothyronine in tricyclic nonresponders. Am J Psychiatry1982;139:34-8.9. Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronineaugmentation in the treatment of refractory depression. Ameta-analysis. Arch Gen Psychiatry 1996;53:842-8.10. Joffe RT. T3 and lithium potentiation of tricyclic anti-depressants. Am J Psychiatry 1988;145:1317-8.11. Haggerty JJ Jr, Simon JS, Evans DL, Nemeroff CB. Relation-ship of serum TSH concentration and antithyroid anti-bodies to diagnosis and DST response in psychiatric inpatients.Am J Psychiatry 1987;144:1491-3.12. Schwarcz G, Halaris A, Baxter L, Escobar J, Thompson M,Young M. Normal thyroid function in desipramine non-responders converted to responders by the addition ofL-triiodothyronine. Am J Psychiatry 1984;141:1614-6.13. Howland RH. Thyroid dysfunction in refractory depression:implications for pathophysiology and treatment. J ClinPsychiatry 1993;54:47-54.

利用三碘甲狀腺氨酸強化療法治療對於三環抗抑鬱藥物無效的濫用藥物病人

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利用三碘甲狀腺氨酸強化療法治療對於三環抗抑鬱藥物無效的濫用藥物病人

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