Psychopharmacology (1989) 98 : 398-402 Psychopharmacology 9 Springer-Verlag 1989 Cholinergic dysfunction of heart, pupil, salivary glands, and urinary bladder in healthy volunteers during long-term treatment with clomipramine E. Kristensen 1, J. Jakobsen 2, U. Bartels 1, and P. Vestergaard 3 1 Psychiatric Hospital, Department C, DK-8240 Risskov, Denmark 2 Department of Neurology, Aarhus Kommunehospital, Aarhus, Denmark 3 Psychiatric Hospital, Department A, DK-8240 Risskov, Denmark Abstract. Cholinergic functions were studied in ten non- depressed healthy volunteers who were treated with 50 mg clomipramine daily for 3 weeks and subsequently with 100 mg daily for a further 3 weeks. Impairments in heart rate variation (HRV) at rest and standing, of the pupillary light response and of salivation were related to serum levels of clomipramine. Since reduction of HRV is closely related to dose (r=-0.83, P<10 -2) and is a better predictor of serum levels than the other measures examined, it is sug- gested that the easy obtainable function test of HRV at standing can be used as an estimate of over-all cholinergic dysfunction during treatment with tricyclic antidepressants. Key words: Tricyclic antidepressant Side-effects Heart rate variation - Pupillary function - Salivation mination of the vibratory perception threshold with a bioth- esiometer. A chest X-ray and the following blood tests were made: ESR, hemoglobin, fasting glucose, sodium potassi- um, prothrombin time, lactate dehydrogenase, bilirubin, al- kaline phosphatase, protein, urea and creatinine. Clomipramine tablets 50 mg daily were taken for 3 weeks and then the dose was increased to 100 mg daily for a further 3 weeks. Clomipramine in serum (measured as clomipramine+desclomipramine by reversed phase HPLC) was determined following fasting overnight after 3 and 6 weeks of treatment. The autonomic function tests were performed at the same intervals and the day before the start of medication. On the day of study all participants avoided tea, coffee and smoking for 3 h prior to examina- tion. Among the various actions of tricyclic antidepressants on the peripheral autonomic nervous system, the cholinergic blockade of the post-junctional muscarinic receptors is re- sponsible for most of the side-effects associated with the treatment. Heart rate variations (HRV) at rest are depen- dent on parasympathetic tone, decreases dose dependently during treatment with tricyclic antidepressants, is easy ob- tainable and might, therefore, be a convenient index of the anticholinergic actions (Jakobsen et al. 1984). However, it is unknown whether the impairment in HRV is paralleled by anticholinergic dysfunctions of other organs. Further- more, resting HRV depends on parasympathetic as well as sympathetic tone (Pfeifer et al. 1982), whereas standing during upright position and deep breathing exclusively are cholinergic stimuli of HRV (Ewing 1983). We therefore studied HRV at rest, at standing and during deep breathing, pupil area in darkness and during light stimulation as well as salivation and bladder functions in healthy non-de- pressed subjects after a daily dose of 50 and 100 mg clomi- pramine at steady state. Materials and methods Ten healthy volunteers (six women and four men) aged 24-48 years gave informed consent to the study. The proto- col was approved by the local committee for science ethics. All subjects had a general physical examination and a neu- rological examination for polyneuropathy, including deter- Offprint requests to: E. Kristensen Heart rate variation (HR V) HRV was studied after 15 min in a supine position, then at deep breathing and eventually at standing. HR V at rest. One hundred and fifty consecutive R-R inter- vals were registered, disregarding the influence of breathing. Heart rate variation was expressed as the mean consecutive difference of R-R intervals (MCDR_R), reflecting rapid shifts in beat-to-beat variation and as the standard devia- tion of all R-R intervals (SDg k), reflecting longer lasting shifts in heart rate. To eliminate heart rate variation due to intra- and interindividual pulse rate differences MCD was corrected as follows; MCD ..... =MCDms x 1000 (Jak- Mean R-Rm~ obsen et al. 1984). HRV at deep breathing. Heart rate variation is dependent on breathing and is maximal at a rate of five respiratory cycles per min at about half-maximal lung capacity (Ange- lone and Coulter 1964; Bennet 1983; MacKay 1983). The participants were trained to breathe for 90 s at rates of 4, 5, 6, 7,5 and 10 breaths per rain and thoracic movements were registered by a strain-gauge technique. The mean dif- ference between maximal and minimal R-R intervals was calculated and corrected for interindividual variation in resting heart rate, as described above. HRV at standing. In normal subjects heart rate increases over the first 10-20 beats after standing, and thereafter slows down over the next 10-30 beats. After standing, 60