Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism.

OBJECTIVES: There is evidence from recent controlled clinical studies that replacement therapy of hypothyroidism with T4 in combination with a small amount of T3 may improve the well-being of the patients. As the issue is still the subject of controversial discussion, our study was assigned to confirm the superiority of a physiological combination of thyroid hormones (absorbed molar ratio 14 : 1) over T4 alone with regard to mood states and cognitive functioning. DESIGN AND PATIENTS: After a run-in period with the T4 study medication for 4 weeks, a controlled, randomized, double-blind, two-period (each 12 weeks), cross-over study without washout between the treatment periods was performed in 23 hypothyroid patients (three males, 20 females, age 23-69 years, 21 subjects after surgery/radioiodine, two with autoimmune thyroiditis) to compare the effects of the previous individual T4 dose (100-175 micro g) with a treatment in which 5% of the respective T4 dose was substituted by T3. MEASUREMENTS: Standard hormonal characteristics and standardized psychological tests to quantify mood and cognitive performance were measured after the run-in period and at the end of each treatment period. In 12 subjects, the concentration-time profiles of fT3 and fT4 were compared after the last administration of the respective study medication. TSH, fT3 and fT4 were measured with immunological assays. CLINICAL RESULTS: Replacement therapy with T4 and T4/T3 was not different in all steady-state hormonal, metabolic and cardiovascular characteristics except for TSH, which was more suppressed after T4/T3. The efficacy of replacement therapy with the T4/T3 combination was not different from the T4 monotherapy with regard to all psychological test scores describing mood and cognitive functioning of the patients. Mood was even significantly impaired by the T4/T3 combination in eight subjects, with TSH < 0.02 mU/l, compared to patients with normal TSH (Beck Depression Inventory: 8.25 +/- 5.01 vs. 4.07 +/- 5.60, P = 0.026). PHARMACOKINETIC RESULTS: The area under the concentration-time curve (AUC(0-8h)) of fT3 was significantly higher after T4/T3 compared to the T4 monotherapy (42.8 +/- 9.03 pmol x h/l vs. 36.3 +/- 8.50 pmol x h/l, P < 0.05) and was significantly correlated to serum TSH (r(s) = -0.609, P < 0.05). After T4/T3, patients with a history of Graves' disease or autoimmune thyroiditis had significantly higher serum trough levels of fT3 whereas the fT4 concentrations were significantly lower in patients with a nonautoimmune background. CONCLUSION: Replacement therapy of hypothyroidism with T4 plus T3 does not improve mood and cognitive performance compared to the standard T4 monotherapy. There is even a higher risk of signs of subclinical hyperthyroidism associated with impaired well-being of the patients, which is clearly caused by significant fluctuations in the steady-state fT3 serum concentrations.

Sensorimotor gating and attitudes related to schizotypal proneness.

The magnitude of the startle eyeblink response is diminished when the startle eliciting probe is shortly preceded by another stimulus. This so called prepulse inhibition is interpreted as an automatic sensorimotor gating mechanism. There is substantial support for prepulse inhibition deficits in subjects suffering from schizophrenia spectrum disorders and in psychosis-prone normals as well. Thus, prepulse inhibition deficits may reflect vulnerability on the hypothesized psychopathological continuum from "normal" to "schizophrenia." The present experiment investigated the amount of prepulse inhibition in a sample selected for "belief in extraordinary phenomena," an attitude related to measures of psychosis-proneness. Believers and skeptics were tested in an acoustic prepulse-inhibition paradigm. As expected presentation of prepulses clearly diminished magnitude of startle response, with greatest inhibition effects gained by lead intervals of 60 and 120 msec. Patterns of response were identical for believers and skeptics, i.e., attitude towards extraordinary phenomena did not seem to be related to functional information-processing deficits as has been observed in psychosis-prone normals.

The effect of neuroleptic medication on prepulse inhibition in schizophrenia patients: current status and future issues.

RATIONALE: Prepulse inhibition (PPI) of the startle reflex is a powerful tool for investigating sensorimotor gating in both animals and humans. Evidence of impaired PPI in patients with schizophrenia suggests that PPI performance might serve as a promising model to investigate the neurobiological mechanisms of this disorder. Animal data show that experimentally induced PPI deficits can be removed by the administration of antipsychotic agents. Recent clinical studies suggest that neuroleptic medication is capable of improving deficient PPI performance in schizophrenia patients as well. OBJECTIVES: The present paper reviews the published data on PPI performance in schizophrenia patients, focussing on medication effects. Using a modified meta-analytic approach, the consistency of PPI deficits in schizophrenia patients across studies is explored. In particular, methodological issues of defining PPI deficits and assessing PPI improvements are considered. METHOD: Literature search produced 12 original studies that investigated PPI performance in schizophrenia patients using comparable experimental conditions. Percentage change scores were calculated to compare the actual amount of PPI observed in schizophrenia patients and healthy controls across studies. RESULTS: Results revealed that the amount of PPI in medicated schizophrenia patients was fairly consistent across all studies. For medicated schizophrenia patients, the amount of PPI varied between 30% and 65% for the critical lead intervals. Moreover, medicated patients showed around 20% less PPI than healthy controls. Whether these group differences were statistically significant depended on the composition of the control group that showed large variability across studies. CONCLUSIONS: To delineate the effects of neuroleptic medication on PPI performance more precisely, future research should not further rely on between-group comparisons. Rather, future clinical research should take advantage of longitudinal designs to disentangle state-dependent medication effects from more stable, trait-linked factors that contribute to PPI deficits in schizophrenia.

Effective neuroleptic medication removes prepulse inhibition deficits in schizophrenia patients.

BACKGROUND: The magnitude of the startle eyeblink response is reduced if the startle eliciting stimulus is shortly preceded by another stimulus. There is evidence that schizophrenia patients exhibit impairments in this so-called prepulse inhibition. Our study investigated whether prepulse inhibition is affected by neuroleptic drug treatment as is suggested by animal research. METHODS: Prepulse inhibition was tested in five unmedicated and 20 medicated inpatients with schizophrenia, and 12 normal controls. RESULTS: The unmedicated schizophrenia patients showed a strong impairment of sensorimotor gating as indexed by the absence of prepulse inhibition. By contrast, the medicated patients showed a pronounced prepulse inhibition that did not differ from that of the normal controls. There was a substantial covariation between the rated severity of the positive syndrome and the amount of prepulse inhibition--i.e., the patients whose positive symptoms were rated as more severe showed less prepulse inhibition. CONCLUSIONS: These data suggest that the impaired sensorimotor gating of schizophrenia patients is not a stable vulnerability indicator, but may rather be related to the positive syndrome and may be improved by treatments with neuroleptic medication.