Psychotropic drugs are often liable to unwanted anticholinergic effects that reduce tolerance and compliance. Especially, in certain patient groups, such as elderly patients, anticholinergic adverse effects may be hazardous. There are also occasions in therapy when antimuscarinic activity is desired, e. g. in the treatment of neuroleptic-induced extrapyramidal symptoms with biperiden and other potent anticholinergic drugs. In this review, we describe various techniques to evaluate the anticholinergic influences of psychotropic drugs in vivo and also provide examples of previous human studies where these methods have been applied. By combining subjective ratings of anticholinergic effects to in vitro measurements of antimuscarinic activity in blood, as well as the functional state of salivary glands, sweat glands, heart and eye, a researcher can obtain a detailed anticholinergic profile of the drug in question, or a clinician can estimate the anticholinergic burden of his/her psychiatric patient who often uses multiple medications.
References
-
1
Aaltonen L, Syvälahti E, Iisalo E, Peltomäki T.
Anticholinergic activity in the serum of patients receiving maintenance amitriptyline or doxepin therapy.
Acta Pharmacol Toxicol (Copenh).
1985;
56
75-80
-
2
Agelink M W, Majewski T, Wurthmann C, Lukas K, Ullrich H, Linka T, Klieser E.
Effects of newer atypical antipsychotics on autonomic neurocardiac function: a comparison between amisulpride, olanzapine, sertindole, and clozapine.
J Clin Psychopharmacol.
2001;
21
8-13
-
3
Agelink M W, Sayar K, Klieser E.
Usefulness of heart rate variability (HRV) for monitoring clozapine plasma levels.
Pharmacopsychiatry.
2003;
36
166-167
-
4
Agelink M W, Ullrich H, Baumann B, Strum S, Majewski T.
Effects of reboxetine, a selective norepinephrine reuptake inhibitor on sympathetic and parasympathetic outflow to the heart: preliminary data.
Psychopharmacology (Berl).
2002;
163
151-156
-
5
Arnold S E, Kahn R J, Faldetta L L, Laing R A, McNair D M.
Tricyclic antidepressants and peripheral anticholinergic activity.
Psychopharmacology (Berl).
1981;
74
325-358
-
6 Bazire S. Psychotropic Drug Directory 2003/04. Bath, UK; Fivepin Publishing Limited/The Bath Press 2003: 416 pages
-
7
Bolden C, Cusack B, Richelson E.
Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells.
J Pharmacol Exp Ther.
1992;
260
576-580
-
8
Brann M R, Ellis J, Jorgensen H, Hill-Eubanks D, Jones S V.
Muscarinic acetylcholine receptor subtypes: localization and structure/function.
Prog Brain Res.
1993;
98
121-127
-
9
Brodde O E, Bruck H, Leineweber K, Seyfarth T.
Presence, distribution and physiological function of adrenergic and muscarinic receptor subtypes in the human heart.
Basic Res Cardiol.
2001;
96
528-538
-
10
Bye C E, Clubley M, Henson T, Peck A W, Smith S A, Smith S E.
Changes in the human light reflex as a measure of the anticholinergic effects of drugs. A comparison with other measures.
Eur J Clin Pharmacol.
1979;
15
21-25
-
11
Bymaster F P, Felder C C, Tzavara E, Nomikos G G, Calligaro D O, Mckinzie D L.
Muscarinic mechanisms of antipsychotic atypicality.
Prog Neuropsychopharmacol Biol Psychiatry.
2003;
27
1125-1143
-
12
Carlini E L, Del-Porto J A, Zwicker A P.
Lack of agreement between the salivary flow and finger-sweat print methods for the determination of the anticholinergic effects of antidepressant drugs.
Braz J Med Biol Res.
1985;
18
163-169
-
13
Carnahan R M, Lund B C, Perry P J, Pollock B G.
A critical appraisal of the utility of the serum anticholinergic activity assay in research and clinical practice.
Psychopharmacol Bull.
2002;
36
24-39
-
14
Chengappa K N, Pollock B G, Parepally H, Levine J, Kirshner M A, Brar J S, Zoretich R A.
Anticholinergic differences among patients receiving standard clinical doses of olanzapine or clozapine.
J Clin Psychopharmacol.
2000;
20
311-316
-
15
Christopoulos A, Parsons A M, Lew M J, El-Fakahany E E.
The assessment of antagonist potency under conditions of transient response kinetics.
Eur J Pharmacol.
1999;
382
217-227
-
16 Chung C, Remington G. Predictors and markers of clozapine response. Psychopharmacology (Berl) 2005: [E-pub ahead of print]
-
17
Cintron N M, Chen Y M.
A sensitive radioreceptor assay for determining scopolamine concentration in plasma and urine.
J Pharm Sci.
1987;
76
328-332
-
18
Clemmesen L.
Anticholinergic side-effects of antidepressants: studies of the inhibition of salivation.
Acta Psychiatr Scand Suppl.
1988;
345
90-93
-
19 Cohen D H, Sherman S M. The autonomic nervous system and its central control. In Berne RM, Levy MN, editors Physiology. St Louis, USA; The Mosby Company 1988: pp 280-296
-
20
Collaborative Working Group on Clinical Trial E valuations.
Adverse effects of the atypical antipsychotics.
J Clin Psychiatry.
1998;
59 (Suppl 12)
17-22
-
21
Davidson J, Turnbull C D.
Diagnostic significance of vegetative symptoms in depression.
Br J Psychiatry.
1986;
148
442-446
-
22
de Leon J, Odom-White A, Josiassen R C, Diaz F J, Cooper T B, Simpson G M.
Serum antimuscarinic activity during clozapine treatment.
J Clin Psychopharmacol.
2003;
23
336-341
-
23
Dose M, Tempel H D.
Abuse potential of anticholinergics.
Pharmacopsychiatry.
2000;
33 (Suppl 1)
43-46
-
24
Eschweiler G W, Bartels M, Langle G, Wild B, Gaertner I, Nickola M.
Heart-rate variability (HRV) in the ECG trace of routine EEGs: fast monitoring for the anticholinergic effects of clozapine and olanzapine?.
Pharmacopsychiatry.
2002;
35
96-100
-
25
Felder C C.
Muscarinic acetylcholine receptors: signal transduction through multiple effectors.
FASEB J.
1995;
9
619-625
-
26
Gil D W, Krauss H A, Bogardus A M, WoldeMussie E.
Muscarinic receptor subtypes in human iris-ciliary body measured by immunoprecipitation.
Invest Ophthalmol Vis Sci.
1997;
38
1434-1442
-
27
Golding J F, Stott J R.
Comparison of the effects of a selective muscarinic receptor antagonist and hyoscine (scopolamine) on motion sickness, skin conductance and heart rate.
Br J Clin Pharmacol.
1997;
43
633-637
-
28
Green M F, Nuechterlein K H, Satz P.
The relationship of symptomatology and medication to electrodermal activity in schizophrenia.
Psychophysiology.
1989;
26
148-157
-
29
Gunasekara N S, Noble S, Benfield P.
Paroxetine. An update of its pharmacology and therapeutic use in depression and a review of its use in other disorders.
Drugs.
1998;
55
85-120
-
30
Guthrie S K, Manzey L, Scott D, Giordani B, Tandon R.
Comparison of central and peripheral pharmacologic effects of biperiden and trihexyphenidyl in human volunteers.
J Clin Psychopharmacol.
2000;
20
77-83
-
31
Hayano J, Sakakibara Y, Yamada A, Yamada M, Mukai S, Fujinami T, Yokoyama K, Watanabe Y, Takata K.
Accuracy of assessment of cardiac vagal tone by heart rate variability in normal subjects.
Am J Cardiol.
1991;
67
199-204
-
32
Hedman A E, Hartikainen J E, Tahvanainen K U, Hakumäki M O.
Power spectral analysis of heart rate and blood pressure variability in anaesthetized dogs.
Acta Physiol Scand.
1992;
146
155-164
-
33
Heller P, Perry F, Jewett D, Levine J D.
Autonomic components of the pupillary light reflex.
Invest Ophthalmol Vis Sci.
1990;
31
156-162
-
34
Hooper P, Tincello D G, Richmond D H.
The use of salivary stimulant pastilles to improve compliance in women taking oxybutynin hydrochloride for detrusor instability: a pilot study.
Br J Urol.
1997;
80
414-416
-
35
Hunter K D, Wilson W S.
The effects of antidepressant drugs on salivary flow and content of sodium and potassium ions in human parotid saliva.
Arch Oral Biol.
1995;
40
983-989
-
36
Johnson D E, Nedza F M, Spracklin D K, Ward K M, Schmidt A W, Iredale P A, Godek D M, Rollema H.
The role of muscarinic receptor antagonism in antipsychotic-induced hippocampal acetylcholine release.
Eur J Pharmacol.
2005;
506
209-219
-
37
Kamen P W, Krum H, Tonkin A M.
Poincare plot of heart rate variability allows quantitative display of parasympathetic nervous activity in humans.
Clin Sci Colch.
1996;
91
201-208
-
38
Knorring L, Mornstad H, Forsgren L, Holmgren S.
Acute effects of different antidepressant drugs on saliva secretion and accommodation range.
Pharmacopsychiatry.
1986;
19
106-110
-
39
Lehofer M, Moser M, Hoehn Saric R, McLeod D, Hildebrandt G, Egner S, Steinbrenner B, Liebmann P, Zapotoczky H G.
Influence of age on the parasympatholytic property of tricyclic antidepressants.
Psychiatry Res.
1999;
85
199-207
-
40
Lennard-Jones J E.
Clinical management of constipation.
Pharmacology.
1993;
47 (Suppl 1)
216-223
-
41
Levey A I.
Immunological localization of m1-m5 muscarinic acetylcholine receptors in peripheral tissues and brain.
Life Sci.
1993;
52
441-448
-
42
Lingjaerde O, Ahlfors U G, Bech P, Dencker S J, Elgen K.
The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients.
Acta Psychiatr Scand Suppl.
1987;
334
1-100; Internet: http://www.cnsforum.com/resources/ratingpsychiatry/side_effects
-
43
Low P, Opfer-Gehrking T, Kihara M.
In vivo studies on receptor pharmacology of the human eccrine sweat gland.
Clin Autonom Res.
1992;
2
29-34
-
44
Lähteenmäki M T, Salo M S, Tenovuo J O, Helminen A V, Vilja P J, Huupponen R K.
The effects of glycopyrrolate on oral mucous host defenses in healthy volunteers.
Anesth Analg.
2000;
91
467-472
-
45
Mayur P M, Gangadhar B N, Subbakrishna D K, Janakiramaiah N.
Discontinuation of antidepressant drugs during electroconvulsive therapy: a controlled study.
J Affect Disord.
2000;
58
37-41
-
46
McNair D M, Droppleman L F, Kussman M.
Finger-sweat print tape bands.
Psychophysiology.
1967;
4
75-78
-
47
Molander L, Birkhed D.
Effect of single oral doses of various neuroleptic drugs on salivary secretion rate, pH, and buffer capacity in healthy subjects.
Psychopharmacology (Berl).
1981;
75
114-118
-
48
Moritz S, Iverson G L, Woodward T S.
Reliable change indexes for memory performance in schizophrenia as a means to determine drug-induced cognitive decline.
Appl Neuropsychol.
2003;
10
115-120
-
49
Mueck-Weymann M, Acker J, Agelink M W.
Autonomic responses of blood vessels and sweat glands in patients with schizophrenia treated with olanzapine or clozapine.
Psychopharmacology (Berl).
2001;
157
368-372
-
50
Mulsant B H, Gharabawi G M, Bossie C A, Mao L, Martinez R A, Tune L E, Greenspan A J, Bastean J N, Pollock B G.
Correlates of anticholinergic activity in patients with dementia and psychosis treated with risperidone or olanzapine.
J Clin Psychiatry.
2004;
65
1708-1714
-
51
Mulsant B H, Pollock B G, Kirshner M, Shen C, Dodge H, Ganguli M.
Serum anticholinergic activity in a community-based sample of older adults: relationship with cognitive performance.
Arch Gen Psychiatry.
2003;
60
198-203
-
52
Nachum Z, Shahal B, Shupak A, Spitzer O, Gonen A, Beiran I, Lavon H, Eynan M, Dachir S, Levy A.
Scopolamine bioavailability in combined oral and transdermal delivery.
J Pharmacol Exp Ther.
2001;
296
121-123
-
53
Nederfors T, Dahlof C.
A modified device for collection and flow-rate measurement of submandibular-sublingual saliva.
Scand J Dent Res.
1993;
101
210-214
-
54
Pagani M, Montano N, Porta A, Malliani A, Abboud F M, Birkett C, Somers V K.
Relationship between spectral components of cardiovascular variabilities and direct measures of muscle sympathetic nerve activity in humans.
Circulation.
1997;
95
1441-1448
-
55
Parlow J, Viale J P, Annat G, Hughson R, Quintin L.
Spontaneous cardiac baroreflex in humans. Comparison with drug-induced responses.
Hypertension.
1995;
25
1058-1068
-
56
Penttilä J, Helminen A, Jartti T, Kuusela T, Huikuri H V, Tulppo M P, Coffeng R, Scheinin H.
Time domain, geometrical and frequency domain analysis of cardiac vagal outflow: effects of various respiratory patterns.
Clin Physiol.
2001;
21
365-376
-
57
Penttilä J, Helminen A, Luomala K, Scheinin H.
Pharmacokinetic-pharmacodynamic model for the anticholinergic effect of glycopyrrolate.
Eur J Clin Pharmacol.
2001;
57
153-158
-
58
Penttilä J, Syvälahti E, Hinkka S, Kuusela T, Scheinin H.
The effects of amitriptyline, citalopram and reboxetine on autonomic nervous system. A randomised placebo-controlled study on healthy volunteers.
Psychopharmacology (Berl).
2001;
154
343-349
-
59
Penttilä J, Vesalainen R, Helminen A, Kuusela T, Hinkka S, Rahi K, Kaila T, Scheinin H.
Spontaneous baroreflex sensitivity as a dynamic measure of cardiac anticholinergic drug effect.
J Auton Pharmacol.
2001;
21
71-78
-
60
Peretti S, Judge R, Hindmarch I.
Safety and tolerability considerations: tricyclic antidepressants vs. selective serotonin reuptake inhibitors.
Acta Psychiatr Scand Suppl.
2000;
403
17-25
-
61
Philipp M, Kohnen R, Benkert O.
A comparison study of moclobemide and doxepin in major depression with special reference to effects on sexual dysfunction.
Int Clin Psychopharmacol.
1993;
7
149-153
-
62
Pitschner H F, Schlepper M, Schulte B, Volz C, Palm D, Wellstein A.
Selective antagonists reveal different functions of M cholinoceptor subtypes in humans.
Trends Pharmacol Sci.
1989;
Suppl
92-96
-
63
Pomeranz B, Macaulay R J, Caudill M A, Kutz I, Adam D, Gordon D, Kilborn K M, Barger A C, Shannon D C, Cohen R J. et al .
Assessment of autonomic function in humans by heart rate spectral analysis.
Am J Physiol.
1985;
248
H151-153
-
64
Rechlin T, Claus D, Weis M.
Heart rate analysis in 24 patients treated with 150 mg amitriptyline per day.
Psychopharmacology (Berl).
1994;
116
110-114
-
65
Remick R A.
Anticholinergic side effects of tricyclic antidepressants and their management.
Prog Neuropsychopharmacol Biol Psychiatry.
1988;
12
225-231
-
66
Remick R A, Blasberg B, Patterson B D, Carmichael R P, Miles J E.
Clinical aspects of xerostomia.
J Clin Psychiat.
1983;
44
63-65
-
67
Rosenfield M, Linfield P B.
A comparison of the effects of cycloplegics on accommodation ability for distance vision and on the apparent near point.
Ophthalmic Physiol Opt.
1986;
6
317-320
-
68
Roth W T, Goodale J, Pfefferbaum A.
Auditory event-related potentials and electrodermal activity in medicated and unmedicated schizophrenics.
Biol Psychiatry.
1991;
29
585-599
-
69
Saul J P, Berger R D, Chen M H, Cohen R J.
Transfer function analysis of autonomic regulation. II. Respiratory sinus arrhythmia.
Am J Physiol.
1989;
256
H153-H161
-
70
Scheinin H, Helminen A, Huhtala S, Grönroos P, Bosch J A, Kuusela T, Kanto J, Kaila T.
Spectral analysis of heart rate variability as a quantitative measure of parasympatholytic effect-integrated pharmacokinetics and pharmacodynamics of three anticholinergic drugs.
Ther Drug Monit.
1999;
21
141-151
-
71
Schneider B, Weigmann H, Hiemke C, Weber B, Fritze J.
Reduction of clozapine-induced hypersalivation by pirenzepine is safe.
Pharmacopsychiatry.
2004;
37
43-45
-
72
Siepmann M, Muck-Weymann M, Joraschky P, Kirch W.
The effects of reboxetine on autonomic and cognitive functions in healthy volunteers.
Psychopharmacology (Berl).
2001;
157
202-207
-
73
Silver H, Geraisy N, Schwartz M.
No difference in the effect of biperiden and amantadine on parkinsonian- and tardive dyskinesia-type involuntary movements: a double-blind crossover, placebo-controlled study in medicated chronic schizophrenic patients.
J Clin Psychiatry.
1995;
56
167-170
-
74
Stanton T, Bolden Watson C, Cusack B, Richelson E.
Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics.
Biochem Pharmacol.
1993;
45
2352-2354
-
75
Syvälahti E K, Lauren L, Markkanen J, Kunelius R.
Interaction of psychotropic drugs with brain muscarinic cholinoceptors: similarities of biperiden with pirenzepine in receptor binding properties.
Pharmacol Toxicol.
1987;
60
66-69
-
76
Szabadi E, Bradshaw C M, Boston P F, Langley R W.
The human pharmacology of reboxetine.
Hum Psychopharmacol Clin Exp.
1998;
13
S3-S12
-
77
Szabadi E, Gasner P, Bradshaw C M.
The peripheral anticholinergic activity of tricyclic antidepressants: comparison of amitriptyline and desipramine in human volunteers.
Br J Psychiatry.
1980;
137
433-439
-
78
Task Force of the European Society of Cardiology and the North American Society of Pacing and E lectrophysiology.
Heart rate variability: standards of measurement, physiological interpretation and clinical use.
Circulation.
1996;
93
1043-1065
-
79
Theofilopoulos N, McDade G, Szabadi E, Bradshaw C M.
Effects of reboxetine and desipramine on the kinetics of the pupillary light reflex.
Br J Clin Pharmacol.
1995;
39
251-255
-
80
Toichi M, Kubota Y, Murai T, Kamio Y, Sakihama M, Toriuchi T, Inakuma T, Sengoku A, Miyoshi K.
The influence of psychotic states on the autonomic nervous system in schizophrenia.
Int J Psychophysiol.
1999;
31
147-154
-
81
Tracy J I, Monaco C A, Abraham G, Josiassen R C, Pollock B G.
Relation of serum anticholinergicity to cognitive status in schizophrenia patients taking clozapine or risperidone.
J Clin Psychiatry.
1998;
59
184-188
-
82
Tulen J H, Bruijn J A, de Man K J, Pepplinkhuizen L, van den Meiracker A H, Man in 't Veld A J.
Cardiovascular variability in major depressive disorder and effects of imipramine or mirtazapine (Org 3770).
J Clin Psychopharmacol.
1996;
16
135-145
-
83
Tune L, Coyle J T.
Serum levels of anticholinergic drugs in treatment of acute extrapyramidal side effects.
Arch Gen Psychiatry.
1980;
37
293-297
-
84
Turner P.
Some methods to assess the autonomic effects of psychotropic drugs in man.
Rev Pure Appl Pharmacol Sci.
1980;
1
343-356
-
85
Whooley M A, Simon G E.
Managing depression in medical outpatients.
N Engl J Med.
2000;
343
1942-1950
-
86
Zorn S H, Jones S B, Ward K M, Liston D R.
Clozapine is a potent and selective muscarinic M4 receptor agonist.
Eur J Pharmacol.
1994;
269
R1-2
Jani Penttilä M.D.
Department of Adolescent Psychiatry
Hospital for Children and Adolescents
Helsinki University Central Hospital
P.O.B. 590
00029 Hus
Finland
Fax: +358 9 471 63025
eMail: jani.penttila@utu.fi
