Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia: relationships with clinical phenotypes and cognitive deficits.

BACKGROUND: Schizophrenia patients have a higher prevalence of type 2 diabetes mellitus with impaired glucose tolerance (IGT) than normals. We examined the relationship between IGT and clinical phenotypes or cognitive deficits in first-episode, drug-naïve (FEDN) Han Chinese patients with schizophrenia. METHOD: A total of 175 in-patients were compared with 31 healthy controls on anthropometric measures and fasting plasma levels of glucose, insulin and lipids. They were also compared using a 75 g oral glucose tolerance test and the homeostasis model assessment of insulin resistance (HOMA-IR). Neurocognitive functioning was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). RESULTS: Of the patients, 24.5% had IGT compared with none of the controls, and they also had significantly higher levels of fasting blood glucose and 2-h glucose after an oral glucose load, and were more insulin resistant. Compared with those patients with normal glucose tolerance, the IGT patients were older, had a later age of onset, higher waist or hip circumference and body mass index, higher levels of low-density lipoprotein and triglycerides and higher insulin resistance. Furthermore, IGT patients had higher PANSS total and negative symptom subscale scores, but no greater cognitive impairment except on the emotional intelligence index of the MCCB. CONCLUSIONS: IGT occurs with greater frequency in FEDN schizophrenia, and shows association with demographic and anthropometric parameters, as well as with clinical symptoms but minimally with cognitive impairment during the early course of the disorder.

Val/Met BDNF as a genetic risk for a false sense of security in post-discharge suicide risk.

BACKGROUND: The time after discharge from psychiatric inpatient care is one of the most dangerous periods in terms of suicide risk. Predicting who is at higher risk could help with resource allocation to assure patients at high risk of suicide attempts are most closely followed. We previously showed that inpatients who improve their suicide ideation levels faster while in inpatient treatment are the ones with highest rates of post-discharge suicide. Here, we studied the possible genetic underpinnings associated with such risk. METHOD: We recorded the slope of suicide ideation recovery of 710 psychiatric inpatients from which we studied two genetic variants likely associated with suicide risk: The serotonin transporter variant 5-HTTLPR, and the BDNF gene variant Val66Met. RESULTS: We found that inpatients carrying the BDNF Met variant (hypothesized as conferring higher suicide risk) improved their suicide ideation scores faster than Val/Val carrying inpatients. No significant association was found for 5-HTTLPR. LIMITATIONS: The present sample was genetically homogenous, and future research should replicate these findings on a more diverse sample. CONCLUSIONS: In conclusion, we found a paradoxical result: Carrying the BDNF Met variant allows inpatients to improve faster, which was shown to confer higher risk at the post-discharge period. This may explain some inconsistencies in the literature in terms of the role of BDNF in suicide ideation and attempts.

Cigarette smoking, psychopathology and cognitive function in first-episode drug-naive patients with schizophrenia: a case-control study.

BACKGROUND: Although patients with chronic schizophrenia have substantially higher smoking rates than either the general population or patients with other mental illnesses, drug-naive patients with a first episode of schizophrenia have received little systemic study. This study examined smoking rates, the association between smoking and symptom severity and cognitive function in Chinese first-episode schizophrenia (FES) patients using cross-sectional and case-control designs. METHOD: Two hundred and forty-four drug-naive FES patients and 256 healthy controls matched for gender, age and education completed the Fagerström Test for Nicotine Dependence (FTND) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Patients were also rated on the Positive and Negative Symptom Scale (PANSS). RESULTS: The rate and quantity of smoking were not significantly higher among FES patients compared to the general population. Among patients, smokers scored higher than non-smokers on the total PANSS and the positive symptom subscale scores. There were no significant associations between cognitive function and smoking in either FES patients or healthy controls. CONCLUSIONS: In contrast to studies in patients with chronic schizophrenia, drug-naive FES patients did not smoke more frequently than the general population. Furthermore, patients with psychotic disorders who smoked did not exhibit significant cognitive differences compared with those who did not smoke. However, smoking may have other detrimental effects on physical and mental health, for example on positive symptoms.

Emotional self-regulation, impulsivity, 5-HTTLPR and tobacco use behavior among psychiatric inpatients.

BACKGROUND: While the serotonin transporter (SLC6A4) gene, 5-HTTLPR, interacts with the social environment to influence both emotional self-regulation and smoking behavior, less is known about interactions between emotional self-regulation and 5-HTTLPR or their joint influence on tobacco use. Here, we examined such interactions among psychiatric inpatients, the population with the highest rates of smoking. METHODS: Participants (506 adults) were psychiatric inpatients at The Menninger Clinic in Houston TX between 2012 and 16. Most were white (89%), male (55%), with a mean age of 32.3 years. Participants completed the Difficulties in Emotional Regulation Scale (DERS) at admission. We examined interactions with smoking among three DERS subscales and 5-HTTLPR, controlling for sex, race and age. RESULTS: Smoking rates were higher among those with the 5-HTTPLR L'L' genotype compared to peers carrying an S' allele (47.9% vs. 37.4%, respectively). Among S' allele carrying participants, impulse control difficulties (OR = 1.09; 95%CI: 1.03-1.14) and lack of emotion clarity (OR = 1.06; 95%CI: 1.00-1.11) increased risk for ever using tobacco, while accessing more ways to regulate emotion (OR = 0.95; 95%CI: 0.92-0.99) offered a protective effect against ever using tobacco. Neither demographic nor DERS covariates were associated with using tobacco among the L'L' group. LIMITATIONS: This ethnically homogenous sample limits generalizability and using a binary outcome can over-estimate a gene environment interaction effect. CONCLUSIONS: Emotional self-regulation exerts a stronger influence on using tobacco among carriers of an S' allele of 5-HTTLPR than peers with the L'L' genotype. Promoting emotional self-regulatory skills may have benefits for preventing tobacco use.

Animal Models and the Development of Vaccines to Treat Substance Use Disorders.

The development of pharmacotherapies for substance use disorders (SUDs) is a high priority in addiction research. At present, there are no approved pharmacotherapies for cocaine and methamphetamine use disorders, while treatments for nicotine and opioid use are moderately effective. Indeed, many of these treatments can cause adverse drug side effects and have poor medication compliance, which often results in increased drug relapse rates. An alternative to these traditional pharmacological interventions is immunotherapy or vaccines that can target substances associated with SUDs. In this chapter, we discuss the current knowledge on the efficacy of preclinical vaccines, particularly immunogens that target methamphetamine, cocaine, nicotine, or opioids to attenuate drug-induced behaviors in animal models of SUDs. We also review vaccines (and antibodies) against cocaine, nicotine, and methamphetamine that have been assessed in human clinical trials. While preclinical studies indicate that several vaccines show promise, these findings have not necessarily translated to the clinical population. Thus, continued effort to design more effective vaccine immunogens using SUD animal models is necessary in order to support the use of immunotherapy as a viable option for individuals with SUDs.

A 2.5-year follow-up of cocaine use among treated opioid addicts. Have our treatments helped?

During a 2.5-year follow-up study of opioid addicts, we found that cocaine abuse had become an increasing and major problem through 1983. Cocaine abuse had only minimally declined during the follow-up period despite treatment, and the number of opioid addicts with at least weekly cocaine abuse had doubled. The clear effect of methadone maintenance treatment in reducing opioid abuse was not evident for cocaine abuse. During the follow-up period, more cocaine use was reported by the methadone-treated subjects than by those undergoing detoxification only. Prognostically, cocaine users were more likely to be nonwhites and men. Subjects who increased their cocaine use during the follow-up period were more likely to have depressive disorders and more likely to be found among methadone- and "drug-free"-treated subjects than among detoxification subjects. Thus, among methadone- and drug-free-treated subjects, depression appeared to be a risk factor for escalating cocaine abuse; this risk factor may benefit from specific interventions.

Pharmacotherapy for cocaine-abusing methadone-maintained patients using amantadine or desipramine.

In a double-blind, placebo-controlled 12-week randomized clinical trial, we compared amantadine hydrochloride (300 mg/d; n = 33), desipramine hydrochloride (150 mg/d; n = 30), and placebo (n = 31) in the treatment of cocaine-abusing methadone-maintained patients. Treatment retention and medication compliance were excellent, with more than 75% of the patients completing the full 12-week trial. Although reported cocaine abuse was significantly lower in the medicated groups compared with the placebo group at week 4, this difference became nonsignificant at week 8, and no difference was found in cocaine-free urine samples. Future studies of amantadine and desipramine treatment in these patients should consider alternatives to methadone hydrochloride, such as buprenorphine hydrochloride, and the selection of more homogeneous patient subgroups, such as depressed cocaine abusers.

A 2.5-year follow-up of depression, life crises, and treatment effects on abstinence among opioid addicts.

Follow-up studies have suggested that treatment increases addicts' likelihood of remaining abstinent and that depression and life crises are associated with decreased abstinence. An important issue is to what extent receiving treatment can ameliorate psychosocial risk factors such as life crises and depression and decrease ex-addicts' vulnerability to continued drug abuse. In our 2.5-year follow-up of 268 opiate addicts, drug abuse treatment was generally associated with increased abstinence, and life crises and depression were significant risk factors for continued drug abuse. The impact of these risk factors, however, was ameliorated by drug abuse treatment. Although life crises had a greater impact than depression, these two risk factors had additive effects in increasing the risk for continued drug abuse. Among the types of life crises, arguments and losses ("exits") had very strong additive effects with depression as predictors of drug abuse.

Buprenorphine vs methadone maintenance treatment for concurrent opioid dependence and cocaine abuse.

BACKGROUND: Buprenorphine, a partial mu-agonist and kappa-antagonist, has been proposed as an alternative to methadone for maintenance treatment of opioid dependence, especially for patients with concurrent cocaine dependence or abuse. This study evaluated whether higher maintenance doses of buprenorphine and methadone are superior to lower doses for reducing illicit opioid use and whether buprenorphine is superior to methadone for reducing cocaine use. METHODS: A total of 116 subjects were randomly assigned to 1 of 4 maintenance treatment groups involving higher or lower daily doses of sublingual buprenorphine (12 or 4 mg) or methadone (65 or 20 mg) in a double-blind, 24-week clinical trial. Outcome measures included retention in treatment and illicit opioid and cocaine use as determined by urine toxicology testing and self-report. RESULTS: There were significant effects of maintenance treatment on rates of illicit opioid use, but no significant differences in treatment retention or the rates of cocaine use. The rates of opioid-positive toxicology tests were lowest for treatment with 65 mg of methadone (45%), followed by 12 mg of buprenorphine (58%), 20 mg of methadone (72%), and 4 mg of buprenorphine (77%), with significant contrasts found between 65 mg of methadone and both lower-dose treatments and between 12 mg of buprenorphine and both lower-dose treatments. CONCLUSIONS: The results support the superiority of higher daily buprenorphine and methadone maintenance doses vs lower doses for reducing illicit opioid use, but the results do not support the superiority of buprenorphine compared with methadone for reducing cocaine use.

Prognostic significance of psychopathology in treated opiate addicts. A 2.5-year follow-up study.

Two different methods for assessing psychopathology in opiate addicts were compared as predictors of long-term treatment outcome: (1) categorical psychiatric diagnosis using the Schedule for Affective Disorders and Schizophrenia--Lifetime Version and the Research Diagnostic Criteria and (2) global rating of psychiatric impairment using the Psychiatric Severity scale of the Addiction Severity Index (ASI). Follow-up interviews were completed 2.5 years after treatment seeking in 76% of a sample of 361 opiate addicts. Five dimensions of treatment outcome were assessed, including current functioning, psychosocial adjustment, substance use impairment, legal problems, and medical disability. Most lifetime psychiatric disorders with a prevalence of greater than 10% were significantly related to the outcome dimensions of current functioning and/or psychosocial adjustment and were unrelated to substance use impairment, legal problems, and medical disability. The ASI Psychiatric Severity rating more robustly predicted poorer functioning in the same two areas and less severe legal problems. While controlling for ASI Psychiatric Severity, the only Research Diagnostic Criteria diagnosis that remained significantly related to treatment outcome was major depression, suggesting that, as regards their prognostic characteristics, the other diagnoses are accounted for by a global underlying severity dimension.

Desipramine in opioid-dependent cocaine abusers maintained on buprenorphine vs methadone.

BACKGROUND: Cocaine abuse occurs in 40% to 60% of patients entering opioid maintenance treatment, and effective pharmacotherapies are needed for this combined dependence. METHODS: This 13-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy of desipramine hydrochloride (0 or 150 mg/d) plus buprenorphine hydrochloride (12 mg/d) or methadone hydrochloride (65 mg/d) in 180 opioid-dependent cocaine abusers (124 men, 56 women). Supervised urine samples were obtained thrice weekly, and self-reported cocaine and heroin use was reported once weekly. Desipramine plasma levels were determined at weeks 4 and 10. RESULTS: In men, opioid abstinence was increased more rapidly over time when treated with methadone than with buprenorphine, whereas cocaine abstinence was increased more with buprenorphine than with methadone. In women, opioid abstinence was increased the least rapidly when treated with buprenorphine plus placebo, while cocaine abstinence was increased more rapidly over time when treated with methadone than with buprenorphine. Regardless of sex or opioid medication, desipramine increased opioid and cocaine abstinence more rapidly over time than placebo. Self-reported opioid use confirmed these findings. Desipramine plasma levels were higher in women than in men, particularly those on buprenorphine maintenance. Higher desipramine plasma levels were associated with greater opioid, but not cocaine, abstinence. CONCLUSIONS: Desipramine may be a useful adjunctive medication in facilitating opioid and cocaine abstinence in opioid-maintained patients. The efficacy of opioid medications to treat opioid or cocaine dependence may differ by sex. These findings highlight the importance of including sex as a factor when examining treatment outcome in these types of trials.

Desipramine facilitation of initial cocaine abstinence.

We conducted a double-blind, random assignment, six-week comparison of desipramine hydrochloride (n = 24), lithium carbonate (n = 24), and placebo (n = 24) treatments for cocaine dependence. Subjects were 72 outpatient cocaine abusers who met DSM-III-R dependence criteria for cocaine but not for other substance abuse. Subjects in each treatment group were similar in history of cocaine and other substance abuse, cocaine craving, sociodemographics, and other psychiatric comorbidity. Desipramine, compared with both other treatments, substantially decreased cocaine use. Lithium treatment outcome did not differ from that of placebo. Desipramine-treated subjects attained contiguous periods of abstinence substantially more frequently than subjects receiving lithium or placebo. Fifty-nine percent of the desipramine-treated subjects were abstinent for at least three to four consecutive weeks during the six-week study period, compared with 17% for placebo and 25% for lithium. Cocaine craving reductions were also substantially greater in the desipramine-treated subjects. Establishment of initial abstinence is the first stage in recovery from cocaine dependence. Our findings indicate that desipramine is an effective general treatment, for this first treatment stage, in actively cocaine-dependent outpatients.

Noradrenergic dysregulation during discontinuation of cocaine use in addicts.

BACKGROUND: The primary objective of the study was to prospectively determine possible noradrenergic dysregulation in cocaine addicts by assessing biochemical, behavioral, and cardiovascular responses to intravenous yohimbine hydrochloride during early and late discontinuation of cocaine use. METHODS: Twelve male and two female hospitalized cocaine-dependent subjects (mean +/- SD age, 30.9 +/- 7.3 years) who were not seeking primary treatment for addiction participated voluntarily for monetary remuneration. Following an initial test dose of intranasal cocaine, 2 mg/kg, cocaine addicts received single-blind, monitored cocaine insufflation, 2 mg/kg three times each day, for 3 consecutive days. One to two days (early discontinuation) and 15 to 16 days (late discontinuation) after the last dose of cocaine, subjects received double-blind, randomized intravenous infusions of yohimbine hydrochloride, 0.4 mg/kg, or placebo. Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and plasma cortisol levels, anxiety-related symptoms on clinician- and subject-rated scales, blood pressure, and heart rate were measured throughout each test day. Ten of 14 subjects completed the entire study. RESULTS: Subjects had a significantly greater placebo-corrected MHPG response to yohimbine during early compared with late discontinuation. Subjects rated themselves significantly more nervous following yohimbine administration during early compared with late discontinuation. Seventy-one percent of subjects experienced a yohimbine-induced panic attack during early discontinuation compared with none during late discontinuation. CONCLUSIONS: The results of this study provide evidence of an underlying dysregulation in noradrenergic function and a vulnerability to panic anxiety during early discontinuation of cocaine use in addicts. Additional investigations of noradrenergic function appear warranted to further clarify derangements associated with cocaine addiction.

Psychiatric disorders in relatives of probands with opiate addiction.

Previous research has documented high rates of major depression and antisocial personality in opiate addicts. This study was designed to investigate the relationship of dual diagnosis in opiate-addicted probands to family history of psychiatric disorders and substance use disorders in biological relatives. Psychiatric disorders and substance use disorders were evaluated using direct interview and family history in a sample of 877 first-degree relatives of 201 opiate addicts and 360 relatives of 82 normal controls. Results indicate that (1) compared with relatives of normal subjects, opiate addicts' relatives had substantially higher rates of alcoholism, drug abuse, depression, and antisocial personality; (2) relatives of depressed opiate-addicted probands had elevated rates of major depression and anxiety disorders but not of other disorders, suggesting the validity of subtyping opiate addicts by the presence or absence of major depression; and (3) in contrast, relatives of antisocial opiate addicts had rates of disorders that were not significantly different from those of relatives of opiate addicts without antisocial personality. Implications of these findings for the classification and treatment of substance abuse are discussed.

Clonidine in outpatient detoxification from methadone maintenance.

Inpatient narcotic detoxification with clonidine hydrochloride has been used since 1978. Outpatient withdrawal, potentially more useful, has not been adequately studied. This report describes a double-blind random assignment of 49 methadone hydrochloride-maintained patients whose dose had been lowered to 20 mg. Twenty-five were detoxified using methadone at 1-mg decrements, 24 by abrupt substitution with clonidine. Approximately 40% of both groups achieved successful detoxification, with one third maintaining abstinence over the subsequent six months. The groups were also largely equivalent on withdrawal symptoms, but the clonidine group experienced symptoms in the first half of the study and the methadone group in the second half. Clonidine appears to be a safe and efficacious outpatient treatment for opiate withdrawal, although the results were less favorable than those obtained in open or inpatient studies.

A randomized controlled trial of auricular acupuncture for cocaine dependence.

BACKGROUND: Partly because of a lack of a conventional, effective treatment for cocaine addiction, auricular acupuncture is used to treat this disorder in numerous drug treatment facilities across the country for both primary cocaine-dependent and opiate-dependent populations. OBJECTIVE: To evaluate the effectiveness of auricular acupuncture for the treatment of cocaine addiction. METHODS: Eighty-two cocaine-dependent, methadone-maintained patients were randomly assigned to 1 of 3 conditions: auricular acupuncture, a needle-insertion control condition, or a no-needle relaxation control. Treatment sessions were provided 5 times weekly for 8 weeks. The primary outcome was cocaine use assessed by 3-times-weekly urine toxicology screens. RESULTS: Longitudinal analysis of the urine data for the intent-to-treat sample showed that patients assigned to acupuncture were significantly more likely to provide cocaine-negative urine samples relative to both the relaxation control (odds ratio, 3.41; 95% confidence interval, 1.33-8.72; P =. 01) and the needle-insertion control (odds ratio, 2.40; 95% confidence interval, 1.00-5.75; P =.05). CONCLUSIONS: Findings from the current study suggest that acupuncture shows promise for the treatment of cocaine dependence. Further investigation of this treatment modality appears to be warranted.

[A double-blind randomized placebo-controlled study of the efficacy of the combined treatment with naltrexone and guanfacine for relapse prevention in opiate dependence].

OBJECTIVE: Authors studied the effect of α-2-adrenoreceptor agonist guanfacine on replace prevention in opiate addicts. MATERIAL AND METHODS: Three hundred and one recently detoxified opiate addicts were randomized under the double-blind double-dummy conditions into one of four treatment groups: naltrexone 50 mg/day+guanfacine 1 mg/day (N+G), naltrexone+guanfacine placebo (N+GP), naltrexone placebo+guanfacine (NP+G), and double placebo (NP+GP). The primary outcome was retention in treatment. The secondary outcomes were perceived stress (Perceived Stress Scale) and craving. RESULTS: At the end of six months, 20 (26.7%) patients in the N+G group and 15 (19.7%) (p=0.26 to N+G) in N+GP group were retained in treatment compared to 5 (6.7%) in the NP+G group (p=0.002 to N+G group and p=0.017 to N+GP group) and 8 (10.7%) in the double placebo group (p=0.013 to N+G group). There is no significant difference in retention between the N+G group and N+GP group at the end of treatment. CONCLUSION: Guanfacine had significant craving and stress reducing effect. Naltrexone was more effective than placebo for relapse prevention in opioid dependent patients. The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone alone. Guanfacine moderately reduced both stress and craving.

Beta endorphin levels during heroin, methadone, buprenorphine, and naloxone challenges: preliminary findings.

Beta endorphin (BE) is a polypeptide agonist for the brain's endogenous opioid system. Levels of BE are elevated by opioid antagonists such as naloxone and depressed by short-acting agonists such as heroin and morphine; they become normalized during steady-state methadone. Buprenorphine (BUP) is a partial opioid agonist whose effects on BE levels were examined in six former heroin addicts and 14 methadone-maintained patients before and after being switched to sublingual BUP 2 mg daily for 1 month. In six former methadone-treated subjects BE levels also were measured after stopping BUP and after naloxone challenge. Levels of BE were not significantly lower in subjects started on BUP after stopping heroin (n = 6) (8.0 versus 8.1 ng/ml) or in subjects started on BUP after stopping methadone (n = 14) (11.6 vs 15.6 ng/ml). However, BE levels were lower on BUP than after naloxone challenge (n = 6) (7.0 versus 34.9 ng/ml). Levels of BE did not significantly change between the first 2 weeks ("early") and "later," although BE levels on methadone significantly correlated with BE levels on BUP in the "early" but not the "later" phase. The BE levels on BUP also did not differ from BE levels of unmedicated normals.

Serum testosterone differences between patients with schizophrenia and those with affective disorder.

Serum testosterone levels (ng/dl) were measured at 2-week intervals during the course of hospitalization in 35 male inpatients in the following four diagnostic groups: undifferentiated schizophrenia, paranoid schizophrenia, bipolar I disorder-manic, and major depressive disorder (endogenous type). The mean (+/- SE) testosterone levels during hospitalization were significantly higher (p less than 0.001) in the schizophrenic patients (510 +/- 38) than in the affective disorder patients (347 +/- 25). This difference persisted throughout hospitalization, being present in the first sample following admission (p less than 0.03) and the final sample before discharge (p less than 0.01). The above group differences were largely due to high testosterone levels in the paranoid schizophrenic subgroup (mean +/- SE level of 559 +/- 41). A longitudinal, as well as cross-sectional, view of the hormonal and clinical data suggests that the testosterone system is linked to both state and trait psychological factors, and this issue is discussed in the light of prior basic psychoendocrine research on this system. The potential application of these findings for new approaches to the development of biological criteria for psychiatric diagnosis is discussed.

Serum thyroxine change and clinical recovery in psychiatric inpatients.

Serum free thyroxine (FT4), total thyroxine (TT4), and Brief Psychiatric Rating Scale (BPRS) measurements were obtained following hospital admission and at 2-week intervals during hospitalization in 80 male psychiatric inpatients with a variety of major psychotic and affective disorders. A strong correlation between the range values for BPRS sum and for FT4 (p less than 0.005) and TT4 (p less than 0.001) levels indicated that change in overall symptom severity was linked to change in thyroxine levels during clinical recovery. We found the relationship not to be a simple one, but to require definition of criteria for three patient subgroups for each hormone, taking into account the initial absolute thyroxine level, as well as the direction and magnitude of hormonal change during recovery. The hormonally defined "good recovery" subgroup included patients with high initial thyroxine levels that then fell substantially, patients with low initial thyroxine levels that then rose substantially, and patients with initial thyroxine levels in the middle range that subsequently changed substantially. The hormonally defined "poor recovery" subgroup included those patients not meeting these criteria. The degree of clinical improvement in the hormonally defined good recovery group was significantly greater by almost twofold than the poor recovery group both for FT4 (p less than 0.04) and TT4 (p less than 0.02). These findings suggest that a "normalizing" principle underlies the relationship between clinical recovery and thyroxine levels and that both FT4 and TT4 levels within the normal range appear to have clinical significance in either reflecting or contributing to the course of a variety of psychiatric disorders and possibly having a role in pathogenesis.