Psychopathological and cognitive features in subclinical hypothyroidism

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PSYCHOPATHOLOGICAL AND COGNITIVE FEAtMIRES IN SUBCLINICAL HYPOTI3YR0IDISM I. MARINA BALDINII, ANTONIO VITA2, MASSIMO C. MAUR12, VINCENZINA AMODEIl, MASSIMJLIANO CARRIS12, SILVIA BRAVIN2 and LUIGI CANTALAMESSAl ktitute

of Internal Medicine, Infectious Diseases and Immunopathology and krstitute of Psychiatry, University of Milan, IRCCS Ospedale Maggiore di Milano, Milan, Italy

(Final form, January 1997)

Abstract Baldini I. Marina, Antonio Vita, Massimo C. Mauri, Vincenzina Amodei, Massimiliano Carrisi, Silvia Bravin and Luigi Cantalamessa: Psychopathological and cognitive features in subclinical hypothyroidism. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1997, 2L pp. 925-935. 0 1997 Else&r sciem hc. 1.

2. 3.

4. 5. 6.

To evaluate affective and cognitive dystknctions in subjects with a marginal form of thyroid hypokmction the authors studied a population of female goiter patients, divided in two groups on the basis of thyroid function: euthyroidism and subclinical hypothyroidism (SCH). The SCH patients were treated with levothyroxine (LT4) in order to obtain euthyroidism, as demonstrated by normalization of the hormonal pattern. Both groups were evaluated with a wide range of psychometric tests (Wechsler memory test, scribble test, reaction times) and psychopathological rating scales (Hamilton rating scales for depression and anxiety, brief psychiatric rating scale) at admission and after 3 months. At admission, a significant decrease in logical memory was found in SCH patients; no differences in affectivity ratings were found between the groups. Atter LT4 treatment, SCH patients showed a significant improvement in some items of memory performance. In conclusion, when interfering factors relating to the perception of disease were excluded by employing euthyroid goiter patients as a comparison group, SCH appeared associated only with memory impairment, while the impairment of affective functions described in previous studies comparing SCH patients with normal controls was not confkmed. A significant improvement of memory skills was induced by LT4 treatment in SCH patients.

Keywords: a&ctive lknctions; cognitive functions; levothyroxine treatment; dysfunctions; psychopathological dysfunctions; subclinical hypothyroidism.

neuropsychological

Abbreviations: Brief psychiatric rating scale (BPRS), euthyroid (EUT), free triiodothyronine (PT3), free thyroxine (PT4), Hamilton rating scale for anxiety (HRSA), Hamilton rating scale for depression (HRSD), immunoradiometric assay (IRMA), levothyroxine (LT4), memory quotient (MQ), radioimmunoassay @IA), standard deviation (SD), standard error (SE), subclinical hypothyroidism (SCH), thyroid-stimulating hormone (TSH), Wechsler memory scale (WMS).

925

I.M. Balclint et al.

926

Introduction Subclinical hypothyroidism (SCH) is a pathological entity characterized by elevated thyroid-stimulating hormone (TSH) concentrations

associated with normal thyroxine and triiodothyronine

serum levels

(Evered et al., 1973). The clinical relevance of this condition in terms of increased morbidity is uncertain even if some evidence indicates that SCH may have subtle longterm deleterious effects, increasing the risk of coronary (Bastenie et al., 1977; Dean and Fowler, 1985; Tunbridge et al., 1977) and peripheral arterial disease (Powell et al., 1987) More recently, on the basis of the well known neuropsychiatric consequences of my-xedema, the possibility of cognitive dysfunction even in minor degrees of thyroid failure has been pointed out by some authors, who have described an impairment of memory performance in patients with SCH (Haggerty et al., 1990; Monzani et al., 1993). In one study, such impairment was partially reversed by replacement with L-thyroxine (Nystrom et al., 1988). Other studies focused their interest on psychopathological aspects of SCH, particularly depression and anxiety, widely described in manifest hypothyroidism (Whybrow et al., 1969). The earliest observations, in psychiatric series, revealed an increased prevalence of SCH in patients in a depressed mood (Gold et al., 1981; Targum et al., 1982). Subsequently, a role of SCH as a risk factor of mood disturbances was suggested in reports evaluating patients with endocrine disorders (Haggerty et al., 1986; Haggerty et al., 1993). However, the exact correlation between SCH and neuropsychological parameters remains to be established. The aims of the present study were: 1) to evaluate affective and cognitive functions in goiter patients with SCH and in a comparison group of goiter patients with normal thyroid function; 2) to study the effects of substitutive

treatment

with levothyroxine

(LT4) in patients with SCH, reexamining

psychometric and clinical variables after therapeutic normalization of circulating TSH.

Methods Patient Population 36 female patients (mean [SD] age: 52.9 [9.1] years, range: 28-68) consecutively referred to our outpatient Endocrinological

Clinic for goiter were admitted to the study after they had given their

informed consent. We selected for our study patients with goiter in diffuse or nodular form, diagnosed by clinical or ultrasonographic

evaluation. Patients with clinical or laboratory evidence of manifest

hypothyroidism or hyperthyroidism were excluded, as well as patients previously subjected to thyroid surgery and/or treated with thyroid hormones or with antithyroid drugs. All the patients were free from present or previous major psychiatric disorders; none of them was taking neither had been treated in the past with psychotropic drugs. In all patients the physical and neurological examinations findings as well as routine medical tests results were normal. On the basis of thyroid function, the patients were divided in two groups:

Subclinical hypothyroidram

927

-SCH patients: 19 goiter patients with SCH (mean [SD] age: 55.2 [8.8] years, range: 35-68) diagnosed by increased basal plasma thyroid stimulating hormone (TSH) (exceeding the upper normal limits by 20% or more in at least two consecutive occasions) associated with repeatedly normal Ike thyroxine (FT4) and free triiodothyronine (FT3) levels. The presence of significant titres of circulating thyroid antibodies without increase of basal TSH was not considered a diagnostic criterion for SCH. -Comnarison

WOUD:

17 goiter patients (mean [SD] age: 50.3 [9.2] years, range: 28-61) with FT3, FT4

and TSH within normal limits. Not relevant differences in education level were present between the two groups; all the patients admitted to the study had completed compulsory school. Drug Administration The SCH group patients were treated with levothyroxine (Eutirox, 50 ug tablets, Bracco), starting with 50 &day followed by stepwise adaptations up to the dose lowering serum TSH into normal range, and maintaining free thyroid hormones within the reference range (mean LT4 dose: 75 ug/day, range: 50-l 50 @day). In order to veri@ treatment adequacy, FT3, FT4 and TSH serum concentrations were monitored almost monthly during therapy. Studv Design In a group of female goiter patients, psychometric and psychopathologic tests evaluating cognitive and affective functions were performed to compare the results obtained in patients with SCH and in patients with normal thyroid function. To evaluate the effect of LT4 treatment, the SCH patients underwent psychometric and psychopathological tests at admission and after 3 months of replacement therapy at the optimal dose. In order to exclude the possibility that retesting could result in higher scores related to improved skills, also the euthyroid goiter patients underwent psychometric and psychopathologic evaluation at admission and after 3 months. Endocrine Assessment FT3 and FT4 were assayed with radioimrnunoassay

(RIA) methods (FT3 hit and FT4 kit

Technogenetics, Milano, Italy). Reference values range between 2.6 and 5.6 pg/ml for FT3 and between 6.3 and 15.3 pg/ml for FT4. Serum TSH was measured by highly sensitive immunoradiometric (IRMA) method (Allegro HS-TSH, Nichols Institute Diagnostics, San Juan Capistrano, CA, USA). The assay detection limit for the method is 0.04 pIU/ml; reference range is comprised between 0.5 and 4.6 yIU/ml. Antithyroglobulin

antibodies were assayed by

specific haemagglutination method (Thymune-T Kit,

Murex Diagnostica S.p.A., Pomezia, Italy); normal values for this method are lower than 1:40. Antithyroid peroxidase antibodies were detected by specific radioimmunoassay (Ab TPO kit, Sorin Biomedica, Saluggia, Italia); normal levels for this method are lower than 10 U/ml.

I.M. Baldini et al.

928

Psvchometric and Psvchooathological Evaluation Memory functions were assessed with the Wechsler Memory Scale (WMS), consisting of seven items (logic memory, numeric span, visual memory, associative memory, information, space/time perception, mental control) and providing a total “memory quotient” @IQ) that accounts for age and education levelrelated mnemonic variability (Wechsler, 1987). Visuo-spatial perception analysis was studied with the Scribble Test (Spinnler and Tognoli, 1987); the patients received 32 couples of paintings and were asked to indicate, within ten seconds, if the two paintings of each pair differed significantly. The reaction times were evaluated using an apparatus yielding combined visual and auditory stimuli (Monti et al., 1964). After three test stimuli, a further ten were administered in close succession, and the patients were asked to press a button at stimulus. Both mean reaction time (quickness) and mean value of deviations from the mean response (regularity) were calculated. This battery of neuropsychological tests can be globally considered a sensitive measure of attention and information processing speed. Psychopathology was evaluated using: a) the 21 items Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960); b) the Hamilton Rating Scale for Anxiety (HRSA) (Hamilton, 1959), consisting of 14 items; c) the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962) including 18 items, which provides a comprehensive psychopathological evaluation. These scales were chosen in order to detect the presence of clinically significant psychopathological alterations, especially in the areas of anxiety and depression, and for their large and established use in psychiatric literature.

The researchers who rated

psychopathological symptoms were blind regarding the medical diagnosis. Data Analvsis Statistical analyses included both parametric and non parametric statistics, as appropriate. SCH goiter patients and euthyroid goiter subjects were compared with the Mann Whitney U test. To compare basal and second examina tions in both groups, Wilcoxon test and Student t test for matched pairs were utilized. All p values were two-tailed.

Results Hormonal Data In all the patients with SCI-I, TSH exceeded the upper normal value, ranging between 5.6 and 28.6 uIU/ml. In plasma samples obtained during treatment with LT4 at the optimal dose, TSH concentrations fell within normal limits (ranging between 0.7 and 4. I uIU/ml) and were similar to the values found in the euthyroid goiter group ( mean [SE]: 2.2 [ 1S] @/ml

vs 1.2 [ 1.2] pIIJ/ml; p>O.Ol). Plasma FT3 and FT4

were within normal limits in all the SCH patients as well as in controls. However, in the SCH patients the mean FT4 concentration, at admission, was significantly lower (pCO.001) than in the comparison group as

subclinical hypothyroidism

929

well as in the same patients after therapy (Table 1). Elevated titres of antithyroglobulin and antiperoxidase antibodies were present in 16 out of the 19 SCH patients and in 6 out of the 17 euthyroid goiter patients. The endocrine parameters of the different groups are reported in Table 1.

Table 1 Mean + SD (range) of Endocrine Parameters Found in Goiter Patients with Subclinical Hypothyroidism (SCH) Before and After LT4 Treatment and in Euthyroid (EUT) Goiter Patients, at Admission (Tl) and after 3 Months (T2)

SCH GOITER preLT4

TSH (0.5-4.6 nIU/ml) FT3 (2.6-5.6 pg/ml) FT4 (6.3-15.3 pg/ml)

12.0 f 7.2 a (5.6-28.6) 3.6 + 0.9 (2.6-4.8) 6.8 * 0.7 a (6.3-9.0)

PATIENTS

EUT GOITER

PATIENTS

post-LT4

Tl

T2

2.2 f 1.5 b (0.7-4.1) 3.3 * 0.7 (2.7-4.9) 8.8 + 1.7 b (6.4-l 1.7)

1.2 + 1.2 (0.7-3.9 ) 4.5 fl.1 (3.3-5.5) 10.2 f 1.3 (8.6-l 1.4)

1.5 f 1.0 (0.6-3.5) 4.2 f 0.8 (285.3) 11.3 f 1.2 (7.0-11.3)

SCH patients versus EUT goiter patients: ap < 0.01, SCH patients pre- versus post-treatment: bP< 0.001

Psvchometric and Psvchonatholoaical Results Psychopathological features, evaluated by means of one scale for depression (HRSD) and one for anxiety (HRSA), and a comprehensive psychiatric rating scale (BPRS), showed nonsignificant differences between the goiter patients with normal thyroid timction and those with SCH. LT4 therapy did not induce statistically significant modifications of these parameters, In both groups the analysis of visuospatial perception and of the reaction times for visual and auditory stimuli were in the normal range at admission, without appreciable differences between euthyroid goiter patients and SCH group. In SCH patients, no differences were found before and after LT4 therapy. On the other hand, memory tknction resulted impaired in SCH patients. In particular, a sign&ant decrease of logical memory was detected (mean [SE] scores: 4.1 [0.8] vs 6.7 [0.8]; U = 1.94, p
Comparing the WMS

performance of the SCH patients at admission and after LT4 therapy with a statistical analysis for matched pairs, the authors found a significant improvement of logical memory (mean [SE] scores: 4.1 [0.8] vs 5.2 [0.7]; Z = 1.94, pcO.05) numeric span (9.7 [0.5] vs 10.8 [0.5]; Z = 2.06, pcO.03) visual memory (6.5 [0.8] vs 7.6 [0.8]; Z = 2.06, ~~0.03) and total memory quotient (92 [3.6] vs 99.2 [4.0]; Z = 2.91, p
I.M. Baldini et al,

930

function scores of the SCH patients became similar to the euthyroid patient ones. No differences in the neuropsychological scores were found in the comparison group reexamined after 3 months. The results of psychometric tests in the control group could be considered in the range of existing normative data. The results of psychometric and psychopathological evaluation are shown in Table 2. Plasma TSH and FT4 levels were correlated with the single ratings obtained in the psychometric and psychopathological tests, without displaying significant correlations between the examined parameters both in basal conditions and after treatment.

Table 2 Psychometric and Psychopathological Scores (mean f SE) in Goiter Patients with Subclinical Hypothyroidism (SCH) and in a Comparison Group of Euthyroid (EDT) Goiter Patients. Values Observed at Admission (Tl) and at Reexamination (T2), after LT4 Treatment in SCH Patients.

SCH GOITER PATIENTS (pr::T4)

HRSD HRSA

EUT GOITER PATIENTS Tl T2

(posET4)

9.2 f 1.1

8.5 rt 1.2

9.2 f 1.4

7.1 f 1.4

13.0 * 1.3

11.8 k 1.5

13.8 rt 1.6

8.6 f 1.9 24.3 k 1.4

BPRS

26.6 k

25.8 + 1.2

28.5 + 1.7

Scribble test

29.2 k 0.8

30.9 * 0.4

29.6 AZ0.9

26.6 + 1.0

30.7 f3.1

26.2 k 1.6 3.7 * 0.7

Visual reaction time quickness regularity Auditory reaction time quickness regularity Wechsler Memory Scale -logical memory -numeric span -visual memory -associative memory -information -space/time perception -mental control Total memory quotient

1.1

31 f0.6 22.7 f1.3 2.5 k 0.7

3.0 f 0.4

5.4 k 2.4

19.5 f 1.0

20.0 * 1.4

2.2 f 0.4

2.9 f 1.0

4.1 rt 0.8 a 9.1 Ik0.5

5.2 f 0.7 b

6.7 f 0.8

6.9 f

10.8 f 0.5 C

10.9 Ic 0.4

10.5 f 0.7

17.5 * 1.4 2.1 Ii 0.3

17.1 k 0.8 2.1 f0.3

1.1

6.5 f 0.8 11.4 f 1.0

7.6 f 0.8 C

8.2 rt 1.0

5.3 * 1.3

10.1 f 0.8

10.1 f 1.1

11.4f

4.9 * 0.2

5.1 kO.2

4.9 k 0.3

4.6 f 0.4

4.9 zko.1 5.9 * 0.4

4.9 kO.1

4.9-f:O.l

4.9 * 0.1

6.5 k 0.3

6.1 + 0.4

4.8 rt 0.4

92.0 ?I:3.6

99.2 k 4.0 d

96.0 k 3.9

92.5 zk5.2

SCH versus EDT goiter patients: a p < 0.05; SCH patients pre- versus post-treatment: b p< 0.05; c p < 0.03; d p< 0.003

1.0

Subclinical

hypothyroidtsm

931

Discussion The present

study was designed to evaluate the effect of borderline

hypothyroidism

on

psychopathological and cognitive functions, comparing a group of goiter patients suffering from subclinical hypothyroidism with a matched group of goiter patients with normal thyroid function. A significant impairment of logical memory performance emerged in SCH patients, while no significant differences in psychopathological parameters evaluating depressive and anxious symptomatology were found.

AlTective and Cognitive Functions in Subclinical Hvoothvroidism

Previous clinical studies on SCH demonstrated various degrees of impairment of affective and cognitive functions (Krahn, 1987; Haggerty et al., 1986; Haggerty et al., 1990; Haggerty and Prange, 1995; Nystrom et al., 1988; Szabadi, 1991). The differences could be partially due to different study designs, and in particular to the characteristics of patients and controls selected. In fact, several studies evaluated the prevalence of borderline hypothyroidism in psychiatric patients (Custro et al, 1994; Gold et al., 1981; Joffe and Levitt, 1992; Maes et al., 1993; Prange et al, 1990) while others were performed to evaluate the neuropsychological abnormalities present in patients with SCH (Haggerty et al., 1990; Haggerty et al., 1993; Monzani et al., 1993; Nystrom et al., 1988). Moreover, in the latter studies, SCH patients were compared with control groups composed of healthy subjects, So, the increased anxiety and depression ascribed to subclinical hypothyroidism could be nonspecifically related to patients’ perception of their own disease rather than to thyroid hypoiimction. In order to eliminate this bias, and to identity the depressive and anxious symptomatology and cognitive changes strictly related to SCH, in the present study a homogeneous group of female patients with goiter was evaluated, comparing psychometric and behavioural features in goiter patients with SCH and in goiter patients with normal thyroid function. With this study design, the depressive and anxious disturbances previously described (Monzani et al. 1993; Szabadi, 1991; Whybrow et al., 1969) were not confirmed. In fact, none of the items evaluating depressive or anxious symptomatology was significantly decreased in SCH patients. HRSD and HRSA scores were both rather low in patients and in controls. Although in non-clinical range, some affective symptoms were present, but no specific symptomatologic pattern could be detected for both SCH patients and comparison group. The low score might be justified in the SCH patients by mild/moderate signs of anxiety, and in the controls by somatic symptoms. Conversely, a decrease of memory performance, with a statistically significant decrease for the item evaluating logic memory, was confirmed in the present series of SCH patients.

I.M. Eiakhi

932

et al.

Brain and Thvroid Hormones

Old and recent evidences (Hemressey and Jackson, 1996; Jackson and Whybrow, demonstrate

the critical role of thyroid

hormones

in development

influence of thyroid hormones on brain function is demonstrated throughout

the brain. Moreover,

to thyroid hormones,

iodocompound

and function

of CNS

1977)

The direct

by the wide distribution of T3 receptors

there is much evidence that brain cognitive functions are very sensitive

as known by the tight control of T4 and T3 concentrations

1983; Bauer and Whybrow,

1995; Sokoloff

1990). Such a local regulation

in SNC (Dratman et al.,

suggests that relatively small variations

in

economy can produce significant behavioural effects, and that even minor changes in T4

circulating levels may have neuropsychiatric

consequences.

Interestingly,

in our SCH patients, in spite of

normal FT3-FT4 circulating levels in individual subjects, the mean circulating FT4 was significantly lower than in euthyroid patients and a relative deficiency of the thyroid hormones in brain cannot be excluded. Several hypotheses fimctions.

Most

neurotransmitters. hormones

have been formulated

studies have focused

on the relationships

Though the exact mechanisms

affect neuropsychic

receptors

at different

Whybrow

and Prange,

sites (Engstrom

thyroid

are still under discussion,

thyroid state and CNS hormones

it seems likely that thyroid

effect on catecholamine

et al., 1974; Gross et al., 1980; Howland,

system was given by quantitative

affects receptor uptake of norepinephrine

and central

actions; several

increase the number and/or the activity of beta catecholamine

1981). A direct demonstration

regions of rat brain (Tejani-Butt

between

between

functions through a potentiating

findings indicate that thyroid hormones

catecholaminergic

to explain the correlation

of an interaction

autoradiography,

between

1993; Sulser, 1987; thyroid t?mction and

showing that altered thyroid status

in the CNS, by altering synaptic levels of epinephrine in various

and Yang, 1994).

Effect of LT4 Treatment The improvement (Nystrom

of memory skills observed after LT4 treatment

et al., 1988; Monzani et al., 1993). In particular, comparing the present results with those of

the recent study of Monzani et al. (1993) visual

is in agreement with previous reports

memory.

improvement

In SCH

patients

the authors found a significant improvement

reexamined

after

correction

of

hypothyroidism,

numeric

span and visual memory.

The improvement

after LT4 treatment

memory items that did not appear reduced in basal conditions cannot easily be explained.

is well

activity induced by LT4 administration

known

prerequisites

a significant

was found not only in the logical memory score but also in the total memory quotient and in

items evaluating

catecholamine

in logical and

that

catecholamines

for memory performance.

stimulate

The increased

could represent a reasonable explanation.

subjects’

An improvement

attention

and

of performance

alertness,

which

due to increased

second test can be excluded, because a similar trend was not observed in the reexamination

of some

In fact, it constitute skill in the

of comparison

SuhcIinical

hypothyroidism

group. A possible bias could be due to the d&rent

933

methods of analysis used to compare SCH and

euthyroid groups and SCH patients before and after LT4 therapy, because the latter comparison was performed with the more sensitive analysis for paired data. Finally, considering that an improvement of neuropsychic symptoms was described after LT4 administration regardless of previous thyroid status (Bauer and Whybrow, 1990) an aspecific effect of LT4 on memory function cannot be excluded.

The study on SCH indicates that, when interfering factors related to disease perception and to individual vulnerability to depression (as indicated by personal history) were excluded, a direct correlation beween SCH and mood or anxiety pictures seems not to emerge. Conversely, memory impairment is confirmed even comparing SCH patients with euthyroid goiter patients rather than with healthy subjects. Correction of SCH with LT4 treatment appears to significantly improve memory functions. The opportunity of substitutive therapy in SCH is still a matter of debate (Cushing, 1993; Oppenheimer et al., 1995). The present observations indicate that LT4 administration improves memory skills and validates the opinion that LT4 may represent a valuable therapeutic tool in SCH.

BASTENJE, P. A., VANHAELST, L., GOLDSTEIN, J. and SMETS, P. (1977) Asymptomatic autoimmune thyroiditis and coronary heart-disease. Lancet a: 155-158. BAUER, M. S. and WHYBROW, P. C. (1990) Rapid cyclic bipolar affective disorder. Treatment of refractory rapid cycling with high-dose levothyroxine: A preliminary study. Arch. Gentile Psychiat. 47: 35-440. CUSHJNG, G. W. (1993) Subclinical hypothyroidism. Understanding is the key to decision making. Postgraduate Medicine B(l): 95-107. CUSTRO, N., SCAFIDI, V., LO BAIDO, R., NASTRI, L., ABBATE, G., CUFFARO, M. P., GALLO, S., VIENNA, G. and NOTABARTOLO, A. (1994) Subclinical hypothyroidism resulting from autoimmune thyroiditis in female patients with endogenous depression. J. Endocrinol. Invest. 12: 641646. DEAN, J. W. and FOWLER, P. B. S. (1985) Exaggerated responsiveness to thyrotrophin releasing hormone: a risk factor in women with coronary artery disease. Brit. Med. J. 290: 1555-1557. DRATMAN, M. B., CRUTCHFIELD, F. L., GORDON, J. T. and JEN-NB’JGS, A. S. (1983) Iodothyronine homeostasis in rat brain during hypo- and hyperthyroidism. Am. J. Physiol 245: E185E183. ENGSTROM, G., SVENSSON, T. H. and WALDECR, B. (1974) Thyroxine and brain catecholamines: Increased transmitter synthesis and increased receptor sensitivity. Brain Research n: 471-483. EVERED, D. C., ORMSTON, B. J., SMITH, P. A., HALL, R. and BIRD, T. (1973) Grades of hypothyroidism. Brit. Med. J. 1: 657662.

934

I.M. Baldlni et al.

GOLD, M., POTTASH, A. L. C. and EXTEIN, I. (1981) Hypothyroidism and depression. Evidence for complete thyroid function evaluation. JAMA 245: 19 19- 1922. GROSS, G., BRODDE, 0. E. and SCHMANN, H. J. (1980) Decreased number of P-adrenoreceptors in cerebral cortex of hypothyroid rats. Eur. J. Pharmacol. 61: 191-194. HAGGERTY, J. J. Jr, EVANS, D. L. and PRANGE, A. J. (1986) Organic brain syndrome associated with marginal hypothyroidism. Am. J. Psychiatry M(6): 785.786. HAGGERTY, J. J. Jr, GARBUT’T, J. C., EVANS, D. L., GOLDEN, R. N., PEDERSEN, C., SIMON, J. S. and NEMEROFF, C. B. (1990) Subclinical hypothyroidism: A review of neuropsychiatric aspects. Int. J. Psychiatry in Medicine z(2): 193-208. HAGGERTY, J. J. Jr, STERN, R. A., MASON, G.A., BECKWITH, J., MOREY, C. E. and PRANGE, A. J. (1993) Subclinical hypothyroidism: A modifiable risk factor for depression? Am. J. Psychiatry 150: 508-S 10. HAGGERTY, J. J. Jr and PRANGE, A. J. Jr (1995) Borderline hypothyroidism and depression. Annu. Rev. Med. 46: 37-46. HAMILTON, M. (1959) The assesssment of anxiety states by rating. Brit. J. Med. Psychol. 22: 50-54 HAMILTON, M. (1960) A rating scale for depression. J. Neurol. Neurosurg. Psychiatry

2: 56-62.

HENNESSEY, J. V. and JACKSON, I. M. D. (1996) The interface between thyroid hormones and psychiatry. The Endocrinologist 4: 2 14-223. HOWLAND, R. H. (1993) Thyroid dys&nction in refractory pathophysiology and treatment. J. Clin. Psych. B(2): 47-54.

depression:

implications

for

JACKSON, I. M. D. and WHYBROW, P. C. (1995) The relationship between psychiatric disorders and thyroid dystinction. Thyroid update 9: l-7. JOFFE, R. T. and LEVITT, A. J. (1992) Major depression and subclinical hypothyroidism. Psychoneuroendocrinology l7(2/3): 215-221. KRAHN, D. D. (1987) Affective disorder associated with subclinical hypothyroidism. Psychosomatics B(8): 440-44 1. MAES, M., MELTZER, H. Y., COSYNS, P., SUY, E. and SCHOTTE, C. (1993) An evaluation of basal hypothalamic-pituitary-thyroid axis hnction in depression: Results of a large-scaled and controlled study. Psychoneuroendocrinology l8(8): 607-620. MONTI, M., BELLINI, A. and TOSI, E. (1964) Un apparato elettronico per la determinazione collettiva dei tempi di reazione. Ing. Ferroviaria 6: l-12. MONZANI, F., DEL GUERRA, P., CARACCIO, N., PRUNETI, C. A., PUCCI, E., LUISI, M. and BASCHIERI, L. (1993) Subclinical hypothyroidism: neurobehavioral features and beneficial effect of L-thyroxine treatment. Clin. Investig. 71: 367-371. NYSTROM, E., CAIDAHL, K., FAGER, G., WIKKELSO, C., LUNDBERG, P. A. and LINDSTEDT, G. (1988) A double-blind cross-over 1Zmonth study of L-thyroxine treatment of women with subclinical hypothyroidism. Clinical Endocrinology 29: 63-76. OPPENHEIMER, J. H., BRAVERMAN, L. E., TOFT, A., JACKSON, I. M. and LADENSON, P. W. (1995) A therapeutic controversy. Thyroid hormone treatment: when and what? J.Clin. Endocrinol. Metab. 80( 10): 2873-288 1. OVERALL, J. E. and GORDON, D. R. (1962) The brief psychiatric rating scale. Psychol. Rep. .@: 799812. POWELL, J., ALAGHBAND ZADEH, J., CARTER, G., GREENHALGH, R. M. and FOWLER, P. B. S. (1987) Raised serum thyrotrophin in women with peripheral arterial disease. Br. J. Surg. zfl: 11391141.

Subclinical hypothyroidism

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PRANGE, A. J., HAGGERTY, J. J. Jr, BROWEN, J. L. and RICE, J. D. (1990) Marginal hypothyroidism in mental illness: preliminary assessment of prevalence and significance. In: Neuropsychopharmacology, W. E. Bunney Jr, H. Hippius, G. Laakmamr and M. Schmauss (Eds.), pp 353-36 1, Springer-Verlag Berlin, Heidelberg. SOKOLOFF, L. (1977) Biochemical mechanism of the action of thyroid hormones: relationship to their role in brain. In: Thyroid hormones and brain development, G. D. Grave (Ed.), pp 73-91, Raven Press, New York. SPINNLER, H. and TOGNONI, G. (I 987) Taratura e standardizzazione italiana di test neuropsicologici. Ital. J. ScienceG(8): 21-120. SULSER F. (1987) Serotonin-noreprinephrine receptor interactions in the brain: implications for the pharmacology and pathophysiology of affective disorders. J. Clin. Psychatry a(3): 12- 18 SZABADI, E. (1991) Thyroid dysfunction and affective illness. Check the hypothalamic-pituitary-thyroid axis in patients resistant to treatment. Brit. Med. J. 301: 923-924. TARGUM, S. D. , SULLIVAN, A. C. and BYRNES, S M. (1982) Compensatory pituitary-thyroid mechanism in major depressive disorder. Psichiatr. Res. 6: 85-96. TEJANI-BUTT, S. M. and YANG, J. (1994) A time course of altered thyroid states on the noradrenergic system in rat brain by quantitative autoradiography. Neuroendocrinol. 3: 235-244. TUNBRIDGE, W. M. G., EVERED, D. C., HALL, R., APPLETON, D., BREWIS, M., CLARK, F., GRIMLEY EVANS, J., YOUNG, E., BIRD, T. and SMITH, P. A. (1977) The spectrum of thyroid disease in a community: the Whickham survey. Clinical Endocrinology S: 48 I-493. WECHSLER, D. (1987) Wechsler memory scale-revised. Psychological Corporation, New York. WHYRROW, P. C., PRANGE, A. J., TREADWAY, C. R. and CHAPEL, H. (1969) Mental changes accompanying thyroid gIand dysmnction. Arch. Gen. Psychiat. 20: 48-63. WHYBROW, P. C. and PRANGE, A. J. (1981) A hypothesis of thyroid-catecholamine-receptor interaction. Arch. Gent. Psychiat. j&3:106-l 13.

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