Cognitive and Driving Performance Effects of Nefazodone and Imipramine in Healthy Volunteers

Margriet W. van Laar & Edmund R. Volkerts

University of Utrecht, Netherlands Institute for Drugs and Doping Research, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands

ABSTRACT

Nefazodone is a new serotonergic antidepressant with equivalent efficacy to the tricyclic antidepressants, yet producing clinically less side-effects, such as sedation, that might cause functional impairment. The present study compared the acute and subchronic effects of nefazodone and the tricyclic antidepressent imipramine on driving performance, cognitive functions and daytime sleepiness. Twenty-four healthy subjects (12 adults and 12 elderly from both sexes) received the treatments (nefazodone 100 mg b.i.d., nefazodone 200 mg b.i.d., imipramine 50 mg b.i.d. and placebo) for seven days with a seven days washout period. Measurements were performed on day 1 and day 7. These included a standard over-the-road driving test, a psychomotor test battery and sleep latency tests, using objective EEG recordings.

The results showed that imipramine had a detrimental effect after a single dose on driving performance, primarily in the adult group, that diminished after repeated dosing. Minor impairment of psychomotor test performance was found on both days. A single administration of both doses of nefazodone did not impair driving performance (even showed some improvement), and had also no or only minor effects on psychomotor performance. Repeated doses of nefazodone 200 mg b.i.d. (but not the 100 mg dose) produced slight driving performance impairment. Cognitive and memory functions as measured in the psychomotor tests were modestly impaired by nefazodone, most so by the higher dose. The effects were generally in the same direction in both age groups. Alerting effects of single doses of nefazodone were found in the sleep latency tests. Neither drug induced daytime sleepiness. Effects on memory were significantly related to steady state plasma concentrations of both nefazodone (200 mg b.i.d.) and imipramine.

INTRODUCTION

Antidepressants, such as the previously first-line tricyclic agents, are known to have the potential to impair psychomotor and cognitive functions. These effects may be related to several neuropharmacologic actions, such as central anticholinergic, antihistaminic and serotonergic activity, and blockade of a1-adrenoceptors. Moreover, the use of these drugs is associated with peripheral cholinergic and cardiovascular side-effects and toxicity in overdose. The search for more selective agents has resulted in a new generation of antidepressants, including the selective serotonin re-uptake inhibitors (SSRI's) and the recently marketed (USA, UK) compound nefazodone. Unlike the SSRI's, nefazodone is found to combine 5-HT re-uptake inhibiting properties with 5-HT2 receptor antagonism, while sharing the relatively reduced activity at other receptors. Its clinical efficacy has been demonstrated at doses between 200 mg and 500-600 mg/day. Kinetic studies of nefazodone in healthy volunteers showed mean peak plasma concentrations within two hours of an oral dose. Dose and time dependent kinetics are found following repeated dosing. At least three active metabolites have been isolated (OH-nefazodone, mCPP and triazole dione). The present study investigated the effects of nefazodone (in two dosages), imipramine and placebo, after single and multiple dose administration. The subjects sample included both adult and elderly volunteers because the last are generally more vulnerable with respect to side-effects of drugs. The tests were chosen to measure functions that are relevant for an outpatient's normal daily life, i.e. road tracking during highway driving, memory functions and a general state of mental alertness.

METHODS

The study was conducted according to a double-blind, placebo-controlled, four-way crossover design with respect to treatment administration (Table 1). Measurements were performed in the morning after the first AM doses on the first and seventh treatment day. Subjects were familiarized and trained with regard to all tests. They were all experienced drivers.

Table 1
Study Design

Driving Test

Subjects drove an instrumented vehicle over a 100 km circuit of a primary highway, consisting of two traffic lanes while attempting to maintain a constant speed (90 km/hr.) and a steady lateral position within the right traffic lane. The primary parameter of the test was the lateral position variability (Standard Deviation of Lateral Position in cm), i.e. the measured degree of side-to-side motions of the test vehicle within the right traffic lane. The test lasted ± 75 minutes (see Volkerts et al., 1992, van Laar et al., 1995, for a more detailed description).

Psychomotor Tests

A computerized test battery was used comprising three different choice reaction time tasks. These were, in descending order of complexity: (1) a letter matching task ('Posner'), (2) a memory scanning task ('Sternberg'), and (3) a letter/digit differentiation task ('Donders'). In all tasks, demands were placed on short-term and long-term memory. The total time-on-task was 33 minutes. Mean reaction time (RT in msec) was the primary parameter in each task.

Sleep Latency Test

This test is used as an objective measure of daytime sleepiness. EEG was recorded from electrodes positioned according to the international 10/20 system. Subjects lay down on bed in a sleep inducing environment and were instructed to try to fall asleep. Sleep latency was measured as the time (in minutes) the subject took to enter at least 16 seconds of stage 1 sleep within a time period of 20 minutes (Rechtschaffen & Kales, 1986).

Blood Sampling

Blood samples were taken ± 5.5 hrs. after intake of the AM dose on each testday. These were analyzed for imipramine and desipramine, and nefazodone and active metabolites, OH-nefazodone and mCPP and triazole dione.

Statistical Analysis

Data from the driving test and psychomotor test were analyzed using multivariate analyses of variance (MANOVA) for repeated measures. Factors tested for significance were 'treatments', age groups' and their interaction; in case of a significant interaction effect, treatment effects were tested within the separate age groups. Univariate drug effects were tested against placebo. Nonparametric tests were applied to data from the sleep latency test (Friedman's and Wilcoxon's) and blood analyses (Mann-Whitney test). Levels of significance were set at p<.05.

RESULTS

Side-effects in N200 (nausea, vomiting, general malaise) precluded participation in all performance tests by one elderly female subject (on both test days). Missing data were substituted by the average of the elderly female subsample. One female adult stopped the driving test on day 1 in IMI because of gastro-intestinal side-effects and drowsiness. She continued the treatment and completed all other tests.

Driving Test

Mean SDLP (+SE) is shown in Figure 1. Overall differences between age groups were not significant. However, a significant difference was found between age groups in IMI (p<.004). Unexpectedly, univariate analyses revealed that IMI produced a highly significant increase in SDLP (p<.0001) in the adult group but had no significant effects in the elderly group.

Figure 1
Mean SDLP (+SE) in N100, N200, IMI and P

In contrast to IMI, single doses of N100 and N200 had minor improving effects on driving performance (p<.04 and p<.004, respectively), showing no differences between age groups. On day 7, the impairing effect of IMI was smaller but still significant (p<.02) and comparable between age groups. N100 had no effects but N200 produced slight impairment (p<.04). There were no significant treatment differences between age groups on day 7.

An additional trend analysis on SDLP data of successive 10-km segments of the driving test (see figure 2) showed that on day 1 the linear trend in N100 and N200 differed significantly from placebo (p<.0007 and p<.03, respectively). This indicates that nefazodone decreased or slightly counteracted the performance deterioration over distance travelled that normally occurs (see placebo condition) as a consequence of a vigilance decrement.

Figure 2
Mean SDLP in Successive 10 km Segments as a Function of Distance Travelled

Psychomotor Tests

A prior analysis on data from the five training sessions confirmed that performance in both groups reached a plateau in their learning curve. In the experimental phase, mean RT in the elderly group was found to be higher than in the adult group in nearly all conditions. This is consistent with the repeatedly demonstrated decline in speed of information processing with increasing age. There were no significant interaction effects between treatments and age groups so the pooled groups data were analyzed. For purposes of graphical clarity, figure 3 shows the drug-placebo difference scores. IMI produced minor impairment after a single dose only on task 2, the memory scanning task (p<.06); the effect reached significance after repeated dosing (p<.05). N100 had no significant effects on day 1 but significantly increased RT on day 7 in task 1 and task 2 (p<.02 and p<.009). N200 had minor but significant effects on task 1 and 3 after a single dose on day 1 (p<.03 and p<.04, respectively). However, after repeated dosing of N200, consistent impairment was found in all tasks (p<.004, p<.0001 and p<.01, respectively), most clearly in the memory scanning task.

Figure 3
Mean Drug-Placebo RT Difference Scores in N100, N200 and IMI in Day 1 and Day 7

Sleep Latency

Sleep latency scores were overall shorter in the afternoon tests than in the morning tests. Overall, adult subjects showed a considerably stronger tendency to fall asleep than the elderly subjects, which was most marked on day 7 (mean of circa 9 versus 16 minutes in P). It is reported before that healthy, normal young adults, particularly college students, are sleepier than healthy, normal older subjects, although the difference was much smaller than in our sample (Levine, 1988). The analysis revealed that both N100 and N200 were found to prolong sleep latency scores in test 1 (p<.03 and p<.05, respectively) and in test 2 (p<.005 and p<.001, respectively) after a single dose. Drug effects were in the same direction in both age groups but effects in the elderly group reached significance only in test 2 in N200. Sleep latency was not affected by IMI. No significant drug effects were found on day 7.

Table 2
Summary of the Effects of N100, N200 and IMI

^, ^^, ^^^ = improvement (or stimulation) on p<.05, p<.01 and p<.0001, respectively.

*, **, *** = impairment (or de-activation) on p<.05, p<.01 and p<.001, respectively.

(*) means that the effect is approaches significance (p<.06).

(A) means that a significant drug effect occurred only in the ADULT group.

Blood Analyses and Correlations

Analyses of the blood samples confirmed the compliance of subjects with respect to drug intake. Disproportionate increases in concentration by dose and treatment duration were found, for nefazodone and OH-nefazodone. In line with previous studies, these results suggested nonlinear kinetics. Blood concentrations of drugs and metabolites were not significantly different between adults and elderly. However, concentrations of imipramine were significantly higher in females than in males, both on day 1 (p<.03) and on day 7 (p<.04). No significant gender differences were found for any of the other drugs or metabolites. Correlational analyses revealed significant relationships between steady state plasma concentrations of nefazodone (N200) and reaction time changes (r=.48; p<.03), and between imipramine plasma concentrations and reaction time changes (r=.45; p<.03), both measured in the memory scanning task (task 2).

Test-Retest Reliability

Correlational analyses were performed to determine the fundamental reliability of the primary test parameters by means of the test-retest method. For this purpose data obtained in the placebo conditions on day 1 and day 7 correlated by means of calculations of Pearson's product moment coefficients of correlation (see Table 3).

Table 3
Correlations between Day 1 and Day 7 Scores

*** p<.0001; SDLP = standard deviation of lateral position;

RT = reaction time; SL = sleep latency

The results imply that SDLP, RT and SL are stable indicators of an individual's normal driving performance, memory functioning and daytime sleepiness, respectively.

CONCLUSIONS

1. Nefazodone in doses of 100 mg and 200 mg b.i.d. is relatively safe with respect to car control during prolonged highway driving. The impairing subchronic effect of the higher dose is small when compared to the (acute) effects of imipramine, and also when compared to the effects of other sedative drugs, including alcohol (O'Hanlon et al., 1986).
2. Nefazodone has the potential to impair cognitive and memory functions, especially with increased dosages and prolonged treatment.

   Both conclusions may hold as far as results can be generalized to a depressed patient's population. In this respect it should be noted that depression itself is associated with psychomotor and cognitive deficits and antidepressants may potentiate these effects or improve them, secondary to the clinical effects. Moreover, effects on the long run, that are more clinically relevant, remain to be determined.

3. Neither drug induced daytime sleepiness. On the contrary, nefazodone prolonged sleep latency after a single dose, but not after repeated dosing. Although the most logical conclusion based upon our results is that nefazodone has some acute alerting effects, the influence of secondary side-effects can not be excluded. A relatively high frequency of acute side-effects (see van Laar, 1995), such as headache and nausea, might have prevented subjects to fall asleep easily.
4. Elderly do not show an increased sensitivity to the effects of nefazodone when compared to adults. However, some caution is warranted with respect to cognitive and memory functions because of the higher absolute level of impairment in elderly, that may result from both an age-related decline in mental processing capabilities and drug-related impairment.
5. In addition, some of the expected differences in response on the reference drug, imipramine, between adults and elderly did not appear. It is hypothesized that characteristics and test attitude (relatively 'young', fit & healthy, strong motivation to perform well, reluctant to 'complain') of our elderly sample might reduce or compensate somehow for possible age-related increased drug sensitivity. The generalizability to the total, higher aged, elderly population can be questioned.

REFERENCES

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O'Hanlon JF, Brookhuis KA, Louwerens JW, Volkerts ER. Performance testing as part of drug registration. In JF O;Hanlon and JJ de Gier (Eds.). Drugs and Driving; 311-330, London, Taylor and Francis, 1986.

Rechtschaffen A, Kales A (Eds.). A manual of standardized terminology, techniques and scoring systems for sleep stages of human subjects. Bethesda: National Institute of Health, 1986.

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