Alternative Dosing Regimens in the Pharmacotherapy of Insomnia

Phase III Study on Alternative Dosing Regimens in the Pharmacotherapy of Mild to Moderate Insomnia

The purpose of this study is to evaluate whether drug efficiency of zolpidem and amitriptyline can be conditioned according to learning theory in patients with primary insomnia.

Previous research has shown that repeated drug treatments can be regarded as conditioning processes. Sleep disorders are especially of interest to be investigated under the perspective of conditioning with drugs, since sleep quality can be defined both in terms of subjective ratings (self-rated sleep quality parameters) and objective measures (via polysomnographic assessment PSG; e.g., total sleep time, sleep onset, sleep architecture). By using two different drugs (zolpidem, amitriptyline) that modulate sleep differentially, the investigators intend to implement a conditioning paradigm in sleep disorders dissociating conditioning effects on subjective and objective sleep parameters. Both drugs should affect objective and subjective sleep parameters positively, while only amitriptyline should modulate the objectively assessed sleep architecture by REM-suppression (latency of REM-sleep onset, percentage of REM-sleep).Patients with mild to moderate insomnia will undergo a classical conditioning paradigm with one of two study medications: amitriptyline or zolpidem. After an acquisition period and a wash-out period, conditioned sleep changes are assessed in an evocation trial. During a second treatment phase of 7 days, patients receive different doses of amitriptyline (between 0mg and 50mg per night) or zolpidem (between 0mg and 5mg per night) to evaluate alternative dosing regimens in the pharmacotherapy of mild to moderate Insomnia.

Inclusion Criteria:

1. age between 18 years to 69 years
2. fluent in German language
3. provide written informed consent
4. ability to understand the explanations and instructions given by the study physician and the investigator

Exclusion Criteria:

1. Sleep disorders caused by medical factors (e.g. sleep apnea, restless legs syndrome, narcolepsy, substance-induced insomnia)

2. Contraindications to study medication intake according to the information sheet for health professionals (Summary of medicinal Product Characteristics, SmPC; Fachinformation in Germany) assessed by physical examination (including ECG) and medical history

   • allergies to amitriptyline hydrochloride or any of its ingredients
   • allergies to zolpidem or any of its ingredients
   • acute intoxication with alcohol, analgetics, hypnotics or any other psychotropic drug
   • urinary retention
   • delirium
   • untreated closed-angle glaucoma
   • prostatic hyperplasia
   • pyloric stenosis
   • paralytic ilius
   • suicidal thoughts
   • liver/ kidney/ pulmonary insufficiency
   • myasthenia gravis
   • hypokalemia
   • bradycardia
   • coronary heart disease, cardiac arrhythmias, long QT syndrome or other clinically relevant cardiac disorders
   • increased risk of seizures/ history of seizures
   • substance dependence syndrome/ history of substance dependence syndrome

3. Allergies to ingredients of placebo or novel-tasting drink (CS)

4. currently pregnant (verified by urine pregnancy test) or lactating

5. patients scoring ≥12 on the Epworth Sleepiness Scale

6. patients scoring below 8 or above 21 on the Insomnia Severity Index

7. patients suffering from a mental disorder as verified by the SCID (major depression; psychosis; brain injury; substance abuse or dependency syndrome during the last 6 months before V1)

8. nicotine consumption > 10 cigarettes/day

9. unwillingness to refrain from alcohol consumption throughout the study

10. Concomitant medication interfering with study medication intake due to potential interactions (all psychotropic medication including analgetics and muscle relaxants, hypericum derivatives; antihypertensives; anti-arrhythmic agents; antibiotics; cisaprid; anti-malaria drugs; diuretics; imidazole antifungals; cumarin derivatives; antihistaminics; calcium channel blockers; medications that enlarge the QT interval or may lead to hypokalemia)

11. change in concomitant medication regime during the last 2 weeks prior to visit 1 or after randomization

12. intake of psychotropic medication during the last 3 months

13. participation in any other clinical trial 3 months prior to visit 1

14. women of childbearing age not using 2 highly effective contraceptive methods

15. employee of the Sponsor or the principal investigator