WO1999043307A1

WO1999043307A1 - Thyroid hormone replacement using sustained release triiodothyronine

Info

Publication number: WO1999043307A1
Application number: PCT/US1999/004311
Authority: WO
Inventors: Arthur J. Prange, Jr.; Robertas Bunevicius; Gintautas Kazanavicius; Rimas Zalinkevicius
Original assignee: Prange Arthur J Jr; Robertas Bunevicius; Gintautas Kazanavicius; Rimas Zalinkevicius
Priority date: 1998-02-26
Filing date: 1999-02-26
Publication date: 1999-09-02
Also published as: AU2794199A

Abstract

A composition and method of use in treating hyprothyroid patients with a sustained release form of triiodothyronine to treat mental depression, enhance mental performance, enhancing cognitive performance, and/or enhancing liver function. A sustained release form of triiodothyronine is administered in addition to an amount of thyroxine which is effective to render the patient euthyroid.

Description

THYROID HORMONE REPLACEMENT USING SUSTAINED RELEASE TRIIODOTHYRONINE

Background of the Invention

This invention relates to pharmaceutical compositions and methods of their use in treating patients having reduced thyroid gland function. In particular, the invention relates to a composition comprising sustained release triiodothyronine and methods of using such a composition to treat a variety of symptoms associated with decreased thyroid function.

The thyroid gland secretes two hormones: L-tetraiodothyronine (thyroxine, T₄) and L-triiodothyronine (triiodothyronine, T₃, also called liothyronine). In tissues thyroxine (T4) serves as a precursor for triiodothyronine. Most triiodothyronine in the body comes from enzymatic conversion of thyroxine by tissues rather than from secretion by the thyroid gland. Many patients suffer from reduced or impaired thyroid function which causes deficiencies in T4 and T3. Reduced thyroid function can be caused by a number of reasons, including for example thyroidectomy necessitated by thyroid cancer. In such instances, patients are normally placed on a regimen of thyroid hormone replacement therapy as treatment for hypothyroidism.

The daily production rate of thyroxine is about 100 μg, all produced by the thyroid gland. The daily production rate of triiodothyronine is about 30 μg, of which about 20 percent is produced by the thyroid gland and 80 percent by deiodination of thyroxine in extrathyroidal tissues. Thyroid hormone replacement therapy normally includes administering T4 to the patient at levels intended to approximate the T4 production levels of a normal thyroid gland. It is generally believed that since T4 is the natural precursor of triiodothyronine (T3), that adequate supplementation of T4 will result in adequate levels of T3 by way of the body's normal conversion of T4 to T3. However, all tissues that need thyroid hormone are not equally able to convert T4 to T3. While it is effective, some hypothyroid patients treated with thyroxine are not entirely rendered asymptomatic. A need therefore remains for an improved theraputic regimen which in addition to rendering hypothyroid patients euthyroid, also addresses remaining symptoms such as reduced mental performance, reduced cognitive function, and mental depression. It is therefore an object of the present invention to provide a composition and a method of use therefore in the treatment of hypothyroidism.

DETAILED DESCRIPTION OF THE INVENTION The invention will first be described in greater detail by reference to a study undertaken by the inventors in an effort to address the unmet needs of hypothyroid patients for relief from symptoms associated with reduced thyroid function.

Patients with chronic autoimmune thyroiditis or thyroid cancer treated by near- total thyroidectomy were invited to participate if they were totally, or nearly totally, dependent on exogenous thyroxine. Patients with chronic autoimmune thyroiditis were receiving replacement, therapy with thyroxme, the cancer patients suppressive therapy. Patients with other serious medical illnesses were excluded. Thirty-five patients were enrolled; 33 completed the study. There were 31

women and two men [mean age 46 ± (SD) 13 years] (Table 1). Sixteen patients had

chronic autoimmune thyroiditis; 17 had thyroid cancer. The mean dose of thyroxine at

baseline was 175 ± 53 μg per day [range 100 μg (5 patients) to 300 μg (2 patients)], and

the mean duration of treatment was 73 months ± 72. In all patients dosage had been

stable at least three months. The mean score on the Hamilton Rating Scale for

Depression (21-item "long" version) was 9.8 ± 5.4 [on a scale of 10 (no depression) to 20

(beginning clinically significant depression)]. Four women had major depression, as defined and diagnosed by standard instruments. One patient was removed from the study because of pregnancy and another due to an event described below. Study Protocol

Patient took their usual dose of thyroxine up to and including the first day of the study. On this day each patients was assigned, according to a prearranged randomized schedule, to receive thyroxine alone first, then thyroxine plus triiodothyronine, or to receive thyroxine plus triiodothyronine first, then thyroxine alone. The thyroxine

(Berlin-Chemie, Berlin, Bermany) was given in 50 μg tablets at each patient's usual total doze, but 50 μg thyroxine of the dose was replaced by a capsule. These capsules contained 50 μg thyroxine or 12.5 triiodothyronine (Berlin-Chemie, Berlin, Bermany). They were prepared by a pharmacist and were identical in appearance. If, for example, a patient had been treated with 150 μg of thyroxine per day, she or he was instructed to take 100 μg of thyroxine in usual tablets plus one capsule each morning. If the patient had been assigned to receive thyroxine alone first, the capsule contained 50 μg thyroxine; if assigned to thyroxine plus triiodothyronine first, the capsule contained 12.5 μg triiodothyronine. Patients took medication once daily, half an hour before breakfast.

At the end of each five-week period patients were given another batch of tablets and capsules. Only the pharmacist knew which capsules had been dispensed. At the end of each treatment, each patient, when asked, asserted to have taken medication as instructed. Evaluations

The patients were systematically studied the last day of each treatment period. They reported to the clinic at about 9 A.M., having omitted breakfast but taken thyroid hormone about two hours earlier. Venous blood was taken for measurements of serum thyrotropin, thyroid hormone, cholesterol, triglycerides and sex hormone-binding globulin. Psychological tests were performed. Assessments were made of cognitive function and psychological state. Biochemical Measurements Serum samples were frozen, allowing samples from each patient to be analyzed at the same time in each assay. Serum thyrotropin was measured by immunoradiometric assay using kits obtained from Orion Diagnostica, Turko, Finland with a swnsitivity of 0.05uU/ml. Serum free and total thyroxine and triiodothyronine were measured by radioimmunoassay, using kits obtained from the same manufacturer. Serum total cholesterol and triglycerides were measured by enzymatic colorimetric methods (Sera- Pak Cholesterol Fast Color kit and Sera-Pak Triglycerides Fast Color kit, Bayer Corporation, Tarrytown, NY). Serum sex hormone-binding globulin was measured by immunoenzymometric assay, using kits obtained from Mediz Biochemica, Oy Ab, finland. The intra- assay variability of these assays ranged to 6 percent. Physiological Measurements

Cardiovascular System. Pulse rate 3 was counted after the patient was supine for five minutes. Blood pressure was measured in the sitting position. Electrocardiography was done at both sessions and was always normal.

Peripheral Nervous System. Sensory threshold (minimum intensity of vibration detected) was measured using a biothesiometer device Model PVD (Biomedical Corporation, Newbury, Ohio) applied to the fourth finger tips and toes (9). The Achilles tendon reflex time was determined by use of an electroneuromiography device (Medicor type LT1, Budapest, Hungary). Psychological Measurements

Psychological assessments were made using the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, revised (6). Symptoms were recorded using the Structured clinical Interview for assessment of non-psychotic disorders (Lithuanian edition).

Cognitive functioning was assessed by three standard tests: Digit Symbol Test, Digit Span Test of the Wechsler Adult Intelligence Scale, and Visual Scanning Test. In the Digit Symbol Test a key is provided. It pairs each of the numbers 1 through 9 with a nonsense symbol. Below are rows of pairs of squares, the upper of which contains a number, the lower of which is blank. With the key available the subject is allowed 90 seconds to complete each pair of squares by entering the appropriate4 symbol. The raw score is the number of correct entries completed in 90 seconds or until completion of the third row. This score measures psychomotor performance. With the key unavailable the subject is then asked to recall which symbol matches each number. Pairs correctly recalled measure incidental learning. Then the subject copies 70 symbols. The less time required for completion, the greater the subject's psychomotor speed.

The first part of the Digit Span Test requires the subject to repeat spoken digits of increasing length; it measures immediate auditory attention. The second part requires the subject to repeat the numbers in reverse order; it measures mental flexibility.

The Visual Scanning Test assesses distractibility and visual inattentiveness. The subject is shown a "target" symbol and then presented with a paper on which occurs a matrix of symbols containing 60 targets. The patient circles all the target symbols that she or he can find. Time to completion, omissions and errors are scored.

The Hamilton Rating Scale for Depression (21 -item "long" version) was used to assess severity of depressive symptoms. Clinically important depression is associated with scores of 20 or more, 69 being possible.

Three self-rating scales were used: Beck Depression Inventory, Spielberger State Anxiety Inventory, and Profile of Mood states. The Beck Depression Inventory is a self- rating scale of 21 items, in which scores of 10 or less are within normal mood variation and scores of 11 or more reflect increasing degrees of depression. The Spielberger State Anxiety Inventory is a self-rating scale consisting of 20 items. Scores less than 50 are normal. The Profile of Mood states assesses affective states. The subject chooses a number (0 through 4) for each of 65 items. When scores for combinations of items are added, values for six aspects of mood and a global score are obtained (see Table 3).

Fifteen visual Analog Scales provided more detailed self-ratings of mood and physical symptoms. Each scale consisted of a pair of phrases, —e.g. "as sad as possible, as happy as possible"— each at one end of a 100 mm line. The patient placed a mark at the point best corresponding to self-assessment at that time. Measurement in millimeters from the designated end provided a score. At completion of the study each patient was asked which treatment she or he preferred. Statistical Analysis of Data Obtained Paired t tests were used to compare paired data from the two treatment periods.

Non-paired t tests were used to compare some values from subgroups of patients, e.g. depressed versus non-depressed patients. Results pertaining to treatment preference were evaluated using McNemar's test. Probability values were based on two-sided interpretation of test results. Results

The biochemical and physiological values after each treatment period are shown in Table 2. As expected, the mean serum free and total thyroxine concentrations were lower and the mean serum triiodothyronine concentration was higher after treatment with thyroxine plus triiodothyronine than after thyroxine alone. The mean serum thyrotropin concentrations were similar. The mean serum cholesterol and triglycerides concentrations also were similar, whereas the mean serum sex hormone-binding globulin concentration was significantly higher after thyroxine plus triiodothyronine treatment, suggesting greater thyroid hormone action.

The mean pulse rate at rest was slightly higher after thyroxine plus triiodothyronine treatment, but mean blood pressure values and neurological measurements were similar after both treatments.

Scores pertaining to cognitive functioning and mood were within normal limits, except that patients were marginally deficient in pairs recalled correctly on the Digit Symbol Test after thyroxine along (Table 3). Among the 17 comparisons, six pairs showed advantage for thyroxine plus triiodothyronine treatment, none for treatment with thyroxine alone.

Among the three cognitive performance tests the patients performance after thyroxine plus triiodothyronine treatment was better on parts of two (Table 3). The higher scores for recall of pairs on the Digit Symbol Test indicated better incidental learning, and the higher backward recall scores on the Digit Span Test indicated improved mental flexibility and attention.

The three mood self-rating scales pertained to depression, anxiety, or both. After thyroxine plus triiodothyronine treatment the patients tended to be less depressed (Beck Depression Inventory), and their global scores and their score on the three subscales (fatigue-inertia, depression-dejection and anger-hostility) of the Profile of Mood States were lower (better), as compared with scores after treatment with thyroxine alone (Table 3). Eight visual analog scales pertained to mood, seven to physical symptoms (Table 4). On the eight mood scales, patients felt better (for example, were less confused) after thyroxine plus triiodothyronine treatment on seven. On the seven scales pertaining to physical symptoms, patients felt better after thyroxine on seven. On the seven scales pertaining to physical symptoms, patients felt better after thyroxine plus triiodothyronine on three. Patients reported only slight physical complaints at both times, their mean visual analog scores being closer to "no symptoms" than to "severe symptoms," i.e. less than 50, the middle of each line test.

When questioned at completion of the study, 20 patients preferred thyroxine ±

triiodothyronine, 11 had no preference, and two preferred thyroxine alone (P=0.001). The order of treatment was unrelated to preference. The two patients who preferred thyroxine had noted slight "nervousness" during combined treatment. The 20 patients who preferred combined treatment noticed that they were more energetic, had better concentration and simply felt better. One woman experienced anxiety during thyroxine plus triiodothyronine treatment and was withdrawn from the study.

The order of treatments did not affect results. To determine if triiodothyronine was more beneficial in patients receiving a high ratio of triiodothyronine to thyroxine (lower doses of thyroxine at baseline), or alternatively in patients receiving a low ratio, we compared the results in the 20 patients who were taking 100 - 150 μg thyroxine at baseline with those in the 13 patients who were taking 200 to 300 μg. The results were similar. There also was no difference between the responses of the four patients with depression and those of the 29 patients without depression. Finally, the advantage of thyroxine plus triiodothyronine was not limited to only a few patients. Analysis of the six psychological variables for which combined therapy was most beneficial (see Tables 3 and 4) revealed that most patients had at least some benefit from the addition of triiodothyronine (data not shown). Discussion

Applicants have discovered by way of the foregoing study that hypothyroid patients benefited when triiodothyronine was substituted for a portion of thyroxine which is normally administered to hypothyroid patients. The patients performed better on standard neuropsychological tasks and psychological state was improved. Differences in physiological variables were slight. In any case, they are insensitive indicators of thyroid hormone actions. Serum sex hormone-binding globulin concentrations were higher after thyroxine plus triiodothyronine treatment, indicating a greater effect on the liver. Serum thyroxine concentrations were lower and triiodothyronine concentrations were higher after thyroxine plus triiodothyronine treatment but thyrotropin concentrations, a sensitive measure of thyroid hormone action, were similar after the two treatments. That brain and liver were more affected by thyroxine plus triiodothyronine than other tissues reflects differences in uptake of hormones, deiodination or thyroid hormone receptors.

The variables - all of mental function - in which the substitution of triiodothyronine result in benefit require fuller description. On cognitive performance tests and mood self-rating scales, patients scored in the normal range on 16 of 17 scores after both treatments (Table 3). On six they performed or felt significantly better after thyroxine plus triiodothyronine treatment. These results were reinforced by results of the

10 Visual Analog Scales. No test result was better after treatment with thyroxine alone. It seems clear that treatment with thyroxine plus triiodothyronine improved the quality of life of most patients. Five weeks was probably long enough to realize maximum effects of the treatments. There are at least two ways in which the exclusive use of thyroxine for replacement therapy may deprive the brain of triiodothyronine. First, delivery of triiodothyronine via the circulation, the source of about 20 percent of the brain's triiodothyronine in rats, will be deficient to the extent that thyroid glandular secretion is deficient, unless compensated for by production of peripheral tissues. Second, circulating thyroxine, and presumably thyroxine in brain, will be increased, and brain thyroxine inhibits its own conversion to triiodothyronine. However, the two hormones are differently bound to plasma proteins and may be differently delivered to brain.

Daily production of triiodothyronine by the human thyroid gland is about 6 μg; absorption of ingested triiodothyronine is almost 100 percent . Thus, the dose of triiodothyronine in one preferred embodiment of the mvention exceeds normal glandular production, and includes administration of 10 μg of triiodothyronine daily in sustained release form, along with enough thyroxine to ensure euthyroidism.

Triiodothyronine , as compared to thyroxine, is rapidly absorbed and repidly removed. By administration of triiodothyronine in sustained release form, sudden peaks in concentration, which might produce side effects, will be avoided. At the same time, benefits will be prolonged, allowing triiodothyronine to be given once per day, as is standard and rational procedure with thyroxine. This will allow administration of the two

11 hormones in one preparation, an advance in convenience, safety, and physiologic rationale.

Sustained Release Triiodothyronine Formulation

A once a day sustained release formulation preferably including 8-15 micrograms, and more preferably aboutlO micrograms of triiodothyronine is one preferred embodiment of the invention. A sustained release formula can be prepared using various available sustained release technologies. The formulation may rely on but not limited to dissolution, diffusion, or a combination of dissolution and diffusion to generate slow but continuously release of the drug to gastrointestinal tract. The sustained release triiodothyronine can be coated beads of granules, microspheres or microcapsules, plastic matrixes, osmotic pressure systems, or any other forms. The preferred dosage forms are capsules or tablets that may be derived from the mentioned sustained release particles or matrixes. It is preferable to use the water-soluble version of triiodothyronine, the sodium salt form, in these preparations. The following are examples to prepare sustained release triiodothyronine formulations.

Sustained release hydrophilic matrix tablets of triiodothyronine can be prepared according the method of Qiu et al., J. Controlled Release 45:249-256 (1997). Briefly, triiodothyronine may be mixed with a hydrophilic polymer or polymers as well as diluent such as lactose to have an optimal drug content. This finely blended mixture may pass through a mesh screen, further blended with a lubricant such as magnesium stearate, and then is directly compressed to tablets. Alternatively, the tablet may be compressed from granules through the wet granulation process. The most widely used hydrophilic polymer

12 is hydroxypropyl methylcellulose (HPMC), but other polymers such as hydroxypropyl cellulose, poly(ethylene oxide), polymethacrylates, and polyvinyl alcohol may also be used. The rate of release can be adjusted by selecting different hydrophilic polymers or varying the drug/polymer ratio of the tablet. Sustained release triiodothyronine pellets can be prepared from nonpareil seeds coated with a suitable polymer or polymers at optimal thickness. Examples of such process can be found in elsewhere (Li et al,. Pharm. Res. 12:1338-1342 (1995) and Walia et al., Pharm. Dev. Tech. 3:103-13 (1998)). Many different sizes of these nonpareil seeds are commercially available. Drug loaded pellets can be prepared by spraying triiodothyronine solution or suspension with or without other excipients onto the nonpareil seeds in a fluid bed unit. These pellets are then coated with a sustained release film. The sustained film can be made of carnauba wax, ethylcellulose, dibutyl sebacate, polyethylene glycol, providone, and other waxy or polymeric materials. The rate of drug release is determined by the coating material, the thickness of the coating, as well as the size of the pellets. Optimal drug release may also be achieved by blending together pellets with varied thickness of coating and/or sizes.

Zero-order triiodothyronine pellets containing an osmotic active ingredient can be prepared according to the method of Schultz and Kleinebudde J. Controlled Release 47:181-189 (1997). Sodium chloride or potassium chloride may be used as the osmotically active compound. A semi-permeable membrane of cellulose acetate can be used to coat the drug particles. The drug will release through the pores on the membrane induced by the osmotic pressure gradient once the particles are in contact with water.

13 This, triiodothyronine, sodium chloride, and other fillers such as microcrystalline cellulose are mixed and extόruded to produce the drug pellets. These pellets may be rounded and dried using proper equipment. A cellulose acetate membrane may then be coated on the pellets as described by Schultz and Kleinebudde. In other preferred embodiments of the invention, sustained release triiodothyronine (T4) is administered in amounts of between about 5 to 15 micrograms, although the invention is not intended to be limited thereto. The amount of T4 administered can be in combination with T3, for example an effective amount of T3 to ensure euthhyroidism in the patient. Embodiments include a unit dosage form which includes 5-10 micrograms of T4 in combination with 50 - 100 micrograms of T3. In other preferred embodiments of the invention, sustained release triiodothyronine (T3) is administered in amounts of between about 5 to 15 micrograms, although the invention is not intended to be limited thereto. The amount of sustained release T3 administered can be in combination with thyroxine (T4), as usually prepared, enough to ensure euthyroidism in the patient. Embodiments include a unit dosage form which includes 5-10 micrograms of T3 in combination with 50-100 micrograms of T4.

Having described the preferred embodiments of the invention, it will be recognized by those skilled in the art that insubstantial differences in dosage amounts and order of administration are possible without departing from the scope of the following claims.

14 Table 1 Initial Characteristics of Patients (means ± S.D.)

T₄ first (AB) T₄+T₃ first (BA) All patients

Women 15 16 31

Men 2 0 2

Age (years) 45 ±10 48 ±15 46 ±13

Autoimmune Thyroiditis 4 12 16

Thyroid Cancer 13 4 17

T₄ pre-study dose (ug/day) 181 ±56 169 ±51 175 ±53

T₄ pre-study duration (months) 54 ±41 92 ±96 73 ±72

Serum TSH (μU/dL) 0.3 ± 0.8 1.3 ±1.9 0.8 ±1.5

Serum Free T (ng/dL) 2.0 ±0.7 1.9 ±0.5 2.0 ±0.6

Ha D* 10.0 ±5.5 9.5 ±5.3 9.8 ±5.4

Current depression** 2 2 4

*Hamilton Rating Scale for Depression, 21 item version (11). ** Determined by use of Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 3^rd edition, revised (8). Converstion factors: TSH: not applicable Free T₄: 1 ng/dL = 12.9 pmol/L

15 Table 2

Pre-study and Study Doses of Thyroid Hormones

Number Pre-study B

Of dose of T Study dose of T₄ Study dose of T₄ and T₃ Patients (μg/day) (μg/day) (μg/day)

T₄ in tabs. T₄ in caps. T in tabs. T₃ in caps.

5 100 50 50 50 12.5

13 150 100 50 100 12.5

2 175 125 50 125 12.5

7 200 150 50 150 12.5

1 225 175 50 175 12.5

3 250 200 50 200 12.5

2 300 250 50 250 12.5

16 Table 3

Biochemical Values at End of Experimental Treatments (means ± S.D.)

After T₄ After T₄ + T₃ P values* Normal Range

TSH (μU/dL) 0.75 ±1.50 0.52 ±1.10 0.55 0.3-5.0

Free T(ng/dL) 2.3 ± 0.7 1.8 ±0.6 O.001 0.7-2.1

Total T₄ (μg/dL) 15.2 ±3.8 11.3 ±3.3 O.001 4-11

Total T₃ (ng/dL) 87 ±38 117±42 <0.001 75-175

Triglycerides (mg/dL) 129 ±54 132 ±55 0.76 47-228

Cholesterol

(mg/dL) 219 ±46 217 ±43 0.66 152-268

* paired t tests Conversion factors:

TSH: not applicable Free T₄: 1 ng/dL = 12.9 pmolL Total T₄: 1 ng/dL - 12.9 pmol/L Total T₃: 1 ng/dL = 0.015 nmol/L Triglycerides: 1 ng/dL = 0.011 molL Cholesterol: 1 ng/dL = 0.026 molL

17 Table 4

Physiological Variables at End of Experimental Treatments (means ± S.D.)

After T After T₄ + T Normal Range

Peripheral nervous system

Sensory threshold, 7.5 ± 2.6 7.4 ± 2.4 6 to 10

4 .t^ιhⁿ finger (volts)

Sensory threshold,

4 -ith toe (volts) 9.4 ± 3.0 9.3 ± 2.9 8 to 12

Achilles reflex, relaxation half time (msec.) 282 ± 22 286 ± 28 240-320

Cardiovascular system

Pulse rate at rest (beats/min) 69 ± 11 * 72 ± 12

Blood pressure, sitting position (mmHg) 130/79 124/77

P=0.04, paired t test

18 Table 5 Various Psychometric Variables at End of Experimental Treatments (means ± S.D.)

After T₄ After T₄ +T₃ P values* Normal Range

Cognitive performance tests

Digit Symbol Test Pairs correctly recalled 5.5 ±2.3 6.3 ±2.1 0.04 >6 Time, copy condition (sec.) 58 ±15 56 ±16 0.07 — Raw score 48 ±12 47 ±12 0.76 >43

Digit Span Test Digit span, backward recall 5.5± 1.6 6.0 ±1.33 0.05 >5 Digit span, forward recall 6.9 ±1.9 6.9 ±1.8 0.99 >5

Visual scanning test Time (sec.) 75 ±23 71 ±25 0.15 <120 Total correct 58 ±2 59 ±2 0.53 >56 Errors of commission

1J±1.8 1.5 ±2.1 0.58 <3

Mood self-rating scale

Beck Depression Inventory 9.8 ±7.7 7.9 ±5.3 0.10 <11 Spielberger State Anxiety Inventory 44 ±11 45 ±8 0.38 <50

Profile of Mood States

Global score 33 ±28 24 ±24 0.01

Fatigue-inertia 9.3 ±4.3 7.2 ±3.9 0.001 <18

Depression-dej ection 13.4 ±9.5 10.5 ±8.9 0.01 <26

Anger-hostility 9.1 ±7.3 7.3 ± 5.2 0.04 <17

Confusion-bewilderment 5.3 ±4.5 4.3 ±3.5 0.13 <17

Tension-anxiety 8.5 ±5.3 7.7 ±5.4 0.23 <21 Vigor-activity

12.4 ±4.6 13.0 ±3.7 0.39 >9

''paired t tests

19 Table 6 Visual Analog Results Before and After Experimental Treatments (means ± S.D.)

Pre-study After T₄ After T₄+T₃ P values* 1 2 3 1 vs2 lvs3 2vs3

Mood Scales

Sad 32 ±27 40 ±24 26 ±19 0.14 0.20 <0.001

Confused 34 ±23 34 ±24' 23 ±20 0.96 0.03 <0.001

Fearful 24 ±24 30 ±29 20 ±22 0.14 0.33 0.001

Irritable 35 ±33 39 ±28 27 ±22 0.44 0.15 0.002

Tense 44 ±29 42 ±29 28 ±23 0J4 0.008 0.007

Angry 32±31 32 ±28 25 ±20 0.92 0.12 0.02

Tired 43 ±26 49 ±26 39 ±28 0.20 0.44 0.04

Agitated 44 ±28 39 ±30 34 ±26 0.30 0.01 0.18

Physical Scales

Feel cold 41 ± 31 37 ±27 23 ±24 0.45 0.003 0.004

Blurred vision 23 ±30 30 ±29 22 ±27 0.16 0J1 0.01

Nauseated 19 ±29 22 ±23 13 ±17 0.57 0.14 0.02

Sleepy 26 ±26 39 ±29 29 ±27 0.03 0.68 0.09

Light-headed 30 ±29 35 ±26 31 ±28 0.18 0.80 0.22

Drowsy 30 ±26 36 ±27 31 ±25 0.32 0.97 0.29

Feel hot 24 ±28 24 ±21 25 ±27 0.96 0.84 0.80

* paired t tests

Note: On every scale higher scores represent less favorable states.

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Claims

We claim:

1. An antidepressant composition for use with hypothyroid persons which comprises an effective amount of triiodothyronine in sustained release form.

2. An antidepressant composition according which further comprises thyroxine and wherein the ratio of triiodothyronine to thyroxine is between 1:3 and 1 :13.

3. An antidepressant composition according to claim 2 which comprises about 50 to 100 ug of thyroxine and about 5 - 10 ug of triiodothyronine.

4. An antidepressant composition according to claim 2 wherein the ratio of triiodothyronine to thyroxine is about 1:10.

5. An antidepressant composition according to claim 1 wherein the amount of triiodothyronine is greater than the amount of triiodothyronine which would be secreted by the thyroid gland.

6. A composition for improving subjective mental state and cognitive function of a hypothyroid person which comprises an effective amount of triiodothyronine in combination with thyroxine wherein the ratio of triiodothyronine to thyroxine is between 1:3 and 1:13.

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7. A composition according to claim 5 wherein the ratio of triiodothyronine to thyroxine is about 1:10.

8. A composition according to claim 6 which comprises about 50 - lOOug of thyroxine and about 5-15 ug of triiodothyronine .

9. A composition according to claim 6 wherein the triiodothyronine comprises a sustained release triiodothyronine.

10. A composition according to claim 6 wherein the amount of triiodothyronine is greater than the amount of triiodothyronine which would be secreted by the thyroid gland.

11. A composition for improving the subjective mental state and mental performance of hypothyroid persons which comprises an effective amount of triiodothyronine in combination with thyroxine wherein the ratio of triiodothyronine to thyroxine is between 1:3 and 1:13.

12. A composition according to claim 11 wherein the ratio of triiodothyronine to thyroxine is about 1:10.

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13. A composition according to claim 11 which comprises about 50 - 100 ug. of thyroxine and about 5 -15 ug of triiodothyronine.

14. A composition according to claim 11 wherein the triiodothyronine comprises a sustained release triiodothyronine.

15. A composition according to claim 11 wherein the amount of triiodothyronine is greater than the amount of triiodothyronine which would be secreted by the thyroid gland.

16. As an article of manufacture, a sustained release formulation comprising an effective amount of triiodothyronine in combination with thyroxine wherein the ratio of triiodothyronine to thyroxine is between 1:3 and 1:13.

17. An article of manufacture according to claim 16 wherein the ratio of triiodothyronine to thyroxine is about 1:10.

18. An article of manufacture according to claim 16 which comprises about 50 - 100 ug of thyroxine and about 5-15 ug of triiodothyronine .

19. An article of manufacture according to claim 16 wherein the triiodothyronine comprises a sustained release of triiodothyronine .

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20. An article of manufacture according to claim 16 wherein the amount of triiodothyronine is greater than the amount of triiodothyronine which would be secreted by the thyroid gland.

21. A method of reducing depression in a hypothyroid patient which comprises administering to the patient a composition comprising between about 5-15 ug of triiodothyronine in sustained release form.

22. A method of enhancing cognitive function in a hypothyroid patient which comprises administering to the patient a composition comprising between about 5-15 ug of triiodothyronine in sustained release form.

23. A method of enhancing mental performance in a hypothyroid patient which comprises administering to the patient a composition comprising between about 5-15 ug of triiodothyronine in sustained release form.

24. A method for achieving an effect in a hypothyroid patient comprising administering an effective amount of triiodothyronine in sustained release form.to the patient, wherein the effect is reducing mental depression, enhancing cognitive function, enhancing mental performance, enhancing psychomotor performance, enhancing incidental learning, enhancing psychomotor speed, improving immediate auditory

24 attention, improving digital span, reducing distractibility, improving visual attentiveness, or enhancing liver function.

25. A method for achieving an effect in a hypothyroid patient to whom is administered an effective amount of thyroxine to render the patient euthyroid which comprises administering to the euthyroid patient an effective amount of triiodothyronine in sustained release form, wherein the effect of the triiodothyronine is reducing mental depression, enhancing cognitive function, enhancing mental performance, enhancing psychomotor performance, enhancing incidental learning, enhancing psychomotor speed, improving immediate auditory attention, improving digital span, reducing distractibility, improving visual attentiveness, or enhancing liver function.

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