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Assessment of electroencephalographic changes during treatment with psychotropic drugs
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263
,Vrur~~~/~rrrrnu~l/li)~~, Vol. 23, No 2B. pp. 265 -267. 1984 Prrnted ,n Great Brllain. All rights reserved
0028-3908:x4 s3.00 + 0.00 Copyright (’ 1984 Pergatnon Pre\a Lrd
ASSESSMENT OF ELECTROENCEPHALOGRAPHIC CHANGES DURING TREATMENT WITH PSYCHOTROPIC DRUGS E. M. Department
Key words:
of Clinical
SEDGWICK
and J. GUY
Neurophysiology.
electroencephalogram,
psychotropic
ASSESSMENT
General
Hospital.
epileptiform activity in their EEGs and, of these, 20 (14.17;) subsequently had seizures. Such an abnormality may be due to a genetically-determined dysrhythmia or to an unrecognized neurological disease. Carrying out a pretreatment EEG may not have revealed the abnormality because of its paroxysmal nature and its appearance during a research study may not be drug-related. A dysrthymia may also be due to some other drug that the patient is taking or due to withdrawal from drugs that were discontinued when the suspect drug was introduced. A causal connection between drug and electroencephalographic change is strengthened if there is:
OF EECs
Most EEGs are assessed visually. This method does not require expensive equipment and the experienced eye can reject artefacts, detect trends (such as increasing drowsiness) and transient phenomena (for example spikes and sharp waves) and identify other relevant features (such as in increase in beta activity due to benzodiazepines). The electroencephalographer can give an informed opinion on the EEG. Against these advantages are the facts that observer bias is not uncommon and intra- and interreporter reliability not as high as we would like it to be. Although inexpensive in terms of equipment, eyeball processing of EEGs is expensive in terms of manpower, being time consuming and sometimes boring-thereby increasing the likelihood of error. INTERPRETATION
Southampton
drugs.
The EEG helps to eliminate organic disease in subjects included in research studies and is an important instrument for psychopharmacological research. It can detect early toxic effects and a lowering of convulsive threshold. The “equivalence” hypothesis suggests an association between psychotropic effects of drugs and the changes they induce in the EEG (Fink, 1975). VISUAL
EDWARDS
Wessex Neurological Centre, Southampton SO4 9XY. England
(a) a close temporal relationship between the appearance of the EEG change and administration of the drug or occurrence of toxic plasma drug levels; (b) if the EEG change disappears on discontinuing treatment; and (c) if it recurs with a rechallenge test. STRUCTURED
OF EEGs
Interpretation of the EEG is dependant on the concept of normality held by the electroencephalographer. Most neurophysiologists accept the statistical concept of normality and regard an EEG as abnormal if it differs from that of healthy drug-free individuals. Some electroencephalographers, however, stress the uniqueness of each individual’s EEG rhythms and would not diagnose abnormality after a single recording. They would require repeated EEGs before stating with confidence that any individual’s EEG is abnormal. In psychopharmacological research difficulties in interpretation arise when epileptiform activity is seen in the EEGs of subjects who have never had a fit. A study by Zivin and Marsan (1968) showed that 142 (2.2’:“) of 6497 hospitalized non-epileptic patients had
265
RATING
OF EEG
Visual rating of the EEG can be made more objective and reliable if a structured recording sheet is used. Scott and Prior (1981) have produced such a schedule for general EEG use. A description of the EEG can be transcribed from this on to a computer data base. The value of this schedule in psychopharmacological research has been recently demonstrated in a study of the effects of mianserin and maprotiline on the EEG (Sedgwick and Edwards. 1983). Ratings of specific EEG features may be a useful adjunct to the assessment of sedation. Malpas, Rowan, Joyce and Scott (1970) rated the effects of drowsiness on the EEG with the following scale: Alpha activity present > SO’!; of the time = 0 Alpha activity present < SO’;/, of the time = 1 Presence of one definite paroxysmal feature of sleep: Vertex sharp waves, sleep spindles, lambdoid waves or “K” complexes = 2 Continuous delta activity > 50”” of the time = 3 This simple scoring system has a high inter-rater reliability and has been used in this department to
266
E.
M.
SEDGWICK
and J. Guu
compare the hang-over effects of sedatives in young adult and elderly patients (Castleden. George and Sedgwick, 1979: Briggs. Castleden and Kraft, 1980). COMPUTER
ANALYSIS
for instance, are said to increase slow (IL8 Hz) and fast (I430 Hz) activity while decreasing the alpha rhythm (8-13 Hz). An impressive body of work in this field reached its apogee with Itil. Polvan and Hsu’s claim (1972) to have predicted the antidepressant properties of mianserin from its effect on the EEG. The hypothesis that physiological equibalency is indicative of therapeutic equivalency receives support from this and other work (Itil. Shapiro, Herrman. Schulz and Morgan, 1979). However many problems remain to be investigated before the equivalence hypothesis can be said to be proven with certainty. In most research the EEG has been recorded in normal subjects after only short periods of drug administration, drug levels in the blood arc not always known and the observed change may be due to rapidly changing drug levels rather than to steady state drug concentrations. In the study 01 electroencephalographic changes during treatment with mianserin and maprotiline (Sedgwick and Edwards, 1983). for instance. the changes seen were minimal. This may have been because any acute drug dosing effects that there were had disappeared aftcl four weeks’ treatment.
OF FM;
Computers are now more readily available but, although they have much to offer. they do not provide answers to all the problems; they should be seen as an adjunct to. rather than substitute for, existing neurophysiological investigation. The Cornputer can be programmed to give many measures of the EEG signal. Peak-to-peak amplitude, its variance, root mean square and probability density function all give a statistical description of amplitude but say nothing of frequency. Zero crossings. autocorrelation and especially power spectral density functions all give information on the frequency of the signal (Bendat and Piersol, 1971). All signal analysis techniques used for EEG analysis were developed by engineers to study physical systems in aerospace, geology, communications etc. The output of the analyses are in physical, not biological, units. Physiological and pharmacotherapeutic inferences can therefore only be drawn subsequently. An important methodological consideration is to compare like with like. The EEG changes with mental activity, apprehension, drowsiness and whether the eyes are open or closed. Its reactivity changes if the subject is fasting or has taken caffeine or alcohol. All these variables must be controlled if one wishes to identify a drug-induced change in rhythm. Sudden events. such as an epileptiform spike discharge, are not revealed in a power spectrum: pattern recognition techniques have to be used to detect such transient phenomena. These forms of analysis are extremely time consuming and, if the pattern sought is an epileptiform discharge, then the eye is a much quicker and more efficient detector. Of the many forms of analysis that can be applied it should be remembered that a computer can only do one at a time while the experienced eye can carry out several analyses simultaneously: this gives it an important advantage (see Table I). The association between EEG changes and different classes of psychotropic drugs has been studied by Fink (1975) and ltil (1975). Antidepressants, Table
processing
Relatively Identifie, Detecta Rejects Give\
Signal
processtng
Methods
A major mystery in psycopharmacology is why antidepressants have a delayed onset of action. Electroencephalography, using either visual or computer techniques, offer a means of investigating this problem. Correlations need to be made between changes in EEG parameters, plasma drug (and metabolite) levels and therapeutic response both during treatment and following drug withdrawal, with attention being paid to those aspects of methodology discussed above. Such correlations may also allow the “equivalence” hypothesis to be confirmed or finally put to rest. thank Mrs E. Rodhouse
Acknouk~d~rmc~nrWe secretarial assistance.
No
quck.
(1971) Rmdom .&r/u: Anct/~~.trs Procdur~~.~. Wiley-Interscience, New
Bendat J. S. and Piersol A. G. und
Mrrmremenr
York. Brigs R. S.. Castleden C. M. and Krali C. A. (IWO) Improved hypnotic treatment using chlormethiazolc and temazepam. Br. med. J. 1: 601-604. Castleden C. M.. George C. F. and Sedgwick E. M. (1979) of
processing
EEGs
relevant trends.
observer
More Results
phenomen;~
artefacta.
accurate
Intra-
and
Observer
lnformrd
opinion.
Inaccuracy
mtcr-reporter
Artefxts
measurements. “ruts
(V,
Hr).
Recorda mformation undetectable by eye. More reliably reproducible. Informatmn readily stored in data hank Data in form suitable for &tisCcill a”al)s~i.
Tramtents
Statuxxirq
of measurement. determines not
belectlon
recognired
not
detected.
has to he considered.
No ovcr\1ew. No
varublht!
lxaa.
Programmtng
bia\
m physical
requxed
Boredom.
features. transient
Disadvantages Experience
lnexpensivc
for her
REFERENCES
Advantages
Method Eyeball
I.
EDWARDS
interpretation
of data
267
Psychotropic drugs and EEG Chlormethiazole: No hangover effect but not ideal hypnotic for the young. Postgrad. med. J. 55: 159-160. Fink M. (1975) Cerebral electrometry-quantitative EEG applied to human psy~hopha~acology. In: C&&V: Computerized EEG Analysis (Dolce G. and Kunkel H., Eds), pp. 271-288. Gustav Fischer Verlag, Stuttgart. Itil T. M. (1975) Digital computer period analysed EEG in psychiatry and psychopharmacology. In: CEAN: Computerized EEG Analysis (Dolce G. and Kunkle H., Eds), pp. 289-308. Gustav Fischer Verlag, Stuttgart. Itil T. M., Polvan N. and Hsu W. (1972) Clinical and EEG effects of GB-94, a tetracyclic antidepressant. (EEG model in discovery of a new psychotropic drug). Curr. Ther. Res. 14: 395413. ftil T. M., Shapiro D. M.. Hernnann W. H., Schulz W. and Morgan V. (1979) HZ1 systems for EEG parametrization
and
classification
of
psychotropic
drugs,
Pharma-
kopsychiatry 12: 4-l 9.
Malpas A., Rowan A. J., Joyce C. R. B. and Scott D. F. (1970) Persistent behavioural and electroencephalographic changes after single doses of nitrazepam and amylobarbitone sodium. Br. med. J. 1: 762-764. Scott D. F. and Prior T. F. (1981) An EEG Dala Storage and Retrieval System; Notes on the Use of The London Hospital Computer File. EEG Department, The London
Hospital, London. Sedgwick E. M. and Edwards J. G. (1983) Mianserin, mapropiline and the el~tr~n~phalogram. Br. J. c&r. Pharmac. 15: 255S-259s.
Zivin’L. and Marsan C. A. (1968) Incidence and prognostic significance of “epileptiform” activity in the EEG of non-epileptic subjects. Brain 91: 757-775.
263
,Vrur~~~/~rrrrnu~l/li)~~, Vol. 23, No 2B. pp. 265 -267. 1984 Prrnted ,n Great Brllain. All rights reserved
0028-3908:x4 s3.00 + 0.00 Copyright (’ 1984 Pergatnon Pre\a Lrd
ASSESSMENT OF ELECTROENCEPHALOGRAPHIC CHANGES DURING TREATMENT WITH PSYCHOTROPIC DRUGS E. M. Department
Key words:
of Clinical
SEDGWICK
and J. GUY
Neurophysiology.
electroencephalogram,
psychotropic
ASSESSMENT
General
Hospital.
epileptiform activity in their EEGs and, of these, 20 (14.17;) subsequently had seizures. Such an abnormality may be due to a genetically-determined dysrhythmia or to an unrecognized neurological disease. Carrying out a pretreatment EEG may not have revealed the abnormality because of its paroxysmal nature and its appearance during a research study may not be drug-related. A dysrthymia may also be due to some other drug that the patient is taking or due to withdrawal from drugs that were discontinued when the suspect drug was introduced. A causal connection between drug and electroencephalographic change is strengthened if there is:
OF EECs
Most EEGs are assessed visually. This method does not require expensive equipment and the experienced eye can reject artefacts, detect trends (such as increasing drowsiness) and transient phenomena (for example spikes and sharp waves) and identify other relevant features (such as in increase in beta activity due to benzodiazepines). The electroencephalographer can give an informed opinion on the EEG. Against these advantages are the facts that observer bias is not uncommon and intra- and interreporter reliability not as high as we would like it to be. Although inexpensive in terms of equipment, eyeball processing of EEGs is expensive in terms of manpower, being time consuming and sometimes boring-thereby increasing the likelihood of error. INTERPRETATION
Southampton
drugs.
The EEG helps to eliminate organic disease in subjects included in research studies and is an important instrument for psychopharmacological research. It can detect early toxic effects and a lowering of convulsive threshold. The “equivalence” hypothesis suggests an association between psychotropic effects of drugs and the changes they induce in the EEG (Fink, 1975). VISUAL
EDWARDS
Wessex Neurological Centre, Southampton SO4 9XY. England
(a) a close temporal relationship between the appearance of the EEG change and administration of the drug or occurrence of toxic plasma drug levels; (b) if the EEG change disappears on discontinuing treatment; and (c) if it recurs with a rechallenge test. STRUCTURED
OF EEGs
Interpretation of the EEG is dependant on the concept of normality held by the electroencephalographer. Most neurophysiologists accept the statistical concept of normality and regard an EEG as abnormal if it differs from that of healthy drug-free individuals. Some electroencephalographers, however, stress the uniqueness of each individual’s EEG rhythms and would not diagnose abnormality after a single recording. They would require repeated EEGs before stating with confidence that any individual’s EEG is abnormal. In psychopharmacological research difficulties in interpretation arise when epileptiform activity is seen in the EEGs of subjects who have never had a fit. A study by Zivin and Marsan (1968) showed that 142 (2.2’:“) of 6497 hospitalized non-epileptic patients had
265
RATING
OF EEG
Visual rating of the EEG can be made more objective and reliable if a structured recording sheet is used. Scott and Prior (1981) have produced such a schedule for general EEG use. A description of the EEG can be transcribed from this on to a computer data base. The value of this schedule in psychopharmacological research has been recently demonstrated in a study of the effects of mianserin and maprotiline on the EEG (Sedgwick and Edwards. 1983). Ratings of specific EEG features may be a useful adjunct to the assessment of sedation. Malpas, Rowan, Joyce and Scott (1970) rated the effects of drowsiness on the EEG with the following scale: Alpha activity present > SO’!; of the time = 0 Alpha activity present < SO’;/, of the time = 1 Presence of one definite paroxysmal feature of sleep: Vertex sharp waves, sleep spindles, lambdoid waves or “K” complexes = 2 Continuous delta activity > 50”” of the time = 3 This simple scoring system has a high inter-rater reliability and has been used in this department to
266
E.
M.
SEDGWICK
and J. Guu
compare the hang-over effects of sedatives in young adult and elderly patients (Castleden. George and Sedgwick, 1979: Briggs. Castleden and Kraft, 1980). COMPUTER
ANALYSIS
for instance, are said to increase slow (IL8 Hz) and fast (I430 Hz) activity while decreasing the alpha rhythm (8-13 Hz). An impressive body of work in this field reached its apogee with Itil. Polvan and Hsu’s claim (1972) to have predicted the antidepressant properties of mianserin from its effect on the EEG. The hypothesis that physiological equibalency is indicative of therapeutic equivalency receives support from this and other work (Itil. Shapiro, Herrman. Schulz and Morgan, 1979). However many problems remain to be investigated before the equivalence hypothesis can be said to be proven with certainty. In most research the EEG has been recorded in normal subjects after only short periods of drug administration, drug levels in the blood arc not always known and the observed change may be due to rapidly changing drug levels rather than to steady state drug concentrations. In the study 01 electroencephalographic changes during treatment with mianserin and maprotiline (Sedgwick and Edwards, 1983). for instance. the changes seen were minimal. This may have been because any acute drug dosing effects that there were had disappeared aftcl four weeks’ treatment.
OF FM;
Computers are now more readily available but, although they have much to offer. they do not provide answers to all the problems; they should be seen as an adjunct to. rather than substitute for, existing neurophysiological investigation. The Cornputer can be programmed to give many measures of the EEG signal. Peak-to-peak amplitude, its variance, root mean square and probability density function all give a statistical description of amplitude but say nothing of frequency. Zero crossings. autocorrelation and especially power spectral density functions all give information on the frequency of the signal (Bendat and Piersol, 1971). All signal analysis techniques used for EEG analysis were developed by engineers to study physical systems in aerospace, geology, communications etc. The output of the analyses are in physical, not biological, units. Physiological and pharmacotherapeutic inferences can therefore only be drawn subsequently. An important methodological consideration is to compare like with like. The EEG changes with mental activity, apprehension, drowsiness and whether the eyes are open or closed. Its reactivity changes if the subject is fasting or has taken caffeine or alcohol. All these variables must be controlled if one wishes to identify a drug-induced change in rhythm. Sudden events. such as an epileptiform spike discharge, are not revealed in a power spectrum: pattern recognition techniques have to be used to detect such transient phenomena. These forms of analysis are extremely time consuming and, if the pattern sought is an epileptiform discharge, then the eye is a much quicker and more efficient detector. Of the many forms of analysis that can be applied it should be remembered that a computer can only do one at a time while the experienced eye can carry out several analyses simultaneously: this gives it an important advantage (see Table I). The association between EEG changes and different classes of psychotropic drugs has been studied by Fink (1975) and ltil (1975). Antidepressants, Table
processing
Relatively Identifie, Detecta Rejects Give\
Signal
processtng
Methods
A major mystery in psycopharmacology is why antidepressants have a delayed onset of action. Electroencephalography, using either visual or computer techniques, offer a means of investigating this problem. Correlations need to be made between changes in EEG parameters, plasma drug (and metabolite) levels and therapeutic response both during treatment and following drug withdrawal, with attention being paid to those aspects of methodology discussed above. Such correlations may also allow the “equivalence” hypothesis to be confirmed or finally put to rest. thank Mrs E. Rodhouse
Acknouk~d~rmc~nrWe secretarial assistance.
No
quck.
(1971) Rmdom .&r/u: Anct/~~.trs Procdur~~.~. Wiley-Interscience, New
Bendat J. S. and Piersol A. G. und
Mrrmremenr
York. Brigs R. S.. Castleden C. M. and Krali C. A. (IWO) Improved hypnotic treatment using chlormethiazolc and temazepam. Br. med. J. 1: 601-604. Castleden C. M.. George C. F. and Sedgwick E. M. (1979) of
processing
EEGs
relevant trends.
observer
More Results
phenomen;~
artefacta.
accurate
Intra-
and
Observer
lnformrd
opinion.
Inaccuracy
mtcr-reporter
Artefxts
measurements. “ruts
(V,
Hr).
Recorda mformation undetectable by eye. More reliably reproducible. Informatmn readily stored in data hank Data in form suitable for &tisCcill a”al)s~i.
Tramtents
Statuxxirq
of measurement. determines not
belectlon
recognired
not
detected.
has to he considered.
No ovcr\1ew. No
varublht!
lxaa.
Programmtng
bia\
m physical
requxed
Boredom.
features. transient
Disadvantages Experience
lnexpensivc
for her
REFERENCES
Advantages
Method Eyeball
I.
EDWARDS
interpretation
of data
267
Psychotropic drugs and EEG Chlormethiazole: No hangover effect but not ideal hypnotic for the young. Postgrad. med. J. 55: 159-160. Fink M. (1975) Cerebral electrometry-quantitative EEG applied to human psy~hopha~acology. In: C&&V: Computerized EEG Analysis (Dolce G. and Kunkel H., Eds), pp. 271-288. Gustav Fischer Verlag, Stuttgart. Itil T. M. (1975) Digital computer period analysed EEG in psychiatry and psychopharmacology. In: CEAN: Computerized EEG Analysis (Dolce G. and Kunkle H., Eds), pp. 289-308. Gustav Fischer Verlag, Stuttgart. Itil T. M., Polvan N. and Hsu W. (1972) Clinical and EEG effects of GB-94, a tetracyclic antidepressant. (EEG model in discovery of a new psychotropic drug). Curr. Ther. Res. 14: 395413. ftil T. M., Shapiro D. M.. Hernnann W. H., Schulz W. and Morgan V. (1979) HZ1 systems for EEG parametrization
and
classification
of
psychotropic
drugs,
Pharma-
kopsychiatry 12: 4-l 9.
Malpas A., Rowan A. J., Joyce C. R. B. and Scott D. F. (1970) Persistent behavioural and electroencephalographic changes after single doses of nitrazepam and amylobarbitone sodium. Br. med. J. 1: 762-764. Scott D. F. and Prior T. F. (1981) An EEG Dala Storage and Retrieval System; Notes on the Use of The London Hospital Computer File. EEG Department, The London
Hospital, London. Sedgwick E. M. and Edwards J. G. (1983) Mianserin, mapropiline and the el~tr~n~phalogram. Br. J. c&r. Pharmac. 15: 255S-259s.
Zivin’L. and Marsan C. A. (1968) Incidence and prognostic significance of “epileptiform” activity in the EEG of non-epileptic subjects. Brain 91: 757-775.