Acute Effects Of Escitalopram With Diazepam Biology Essay

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Generalised anxiety disorder (GAD) is a psychiatric illness in the general community with a lifetime prevalence of 4.1 - 6.6 %. The anxiety and worry in this condition are associated with restlessness, fatigue, poor concentration, irritability, muscle tension and sleep disturbance. Many patients with GAD also suffer from major depression, dysthymia or social phobia. The management of this condition involves both pharmacologic and psychotherapeutic interventions. However, but complete symptomatic relief is often rare.1 The pharmacologic management of this condition involves three major groups of drugs such as benzodiazepines like diazepam, lorazepam, oxazepam or tenazepam, non benzodiazepine drugs like buspirone and selective serotonin reuptake inhibitors (SSRIs) like escitalopram and paroxetine.2 The sedative effect of benzodiazepines and its ability to impair psychomotor performance is well documented and is a major limiting factor in the treatment of such patients.3,4 However, recent evidence also shows that they do not affect reaction times.5

Buspirone has been found to be free of sedative effects,6 and in addition it is proposed to have stimulant effects compared to benzodiazepines.7,8,9 Some statistically significant differences favouring escitalopram over other antidepressive agents for the acute phase treatment of major depression have been found, in terms of efficacy (citalopram and fluoxetine) and acceptability (duloxetine).10,11 However, the effects of SSRIs on cognitive impairment have not been comparatively quantified though reports of sedative effect are available.12,13 Availability of this data might be of immense help in the selection of appropriate drug with least impact on psychomotor performance for patients with generalized anxiety disorders.

In order to better evaluate the effects of centrally active drugs, computer based set of psychomotor tests have been developed. They are very flexible and easy to operate allowing the measurement of hand/eye coordination, attention and several types of reaction skills. Computerization of psychomotor testing is a recent advancement which has made the procedure easier and simpler. The software includes test procedures for assessing separately the cognitive functions, the motor functions and combined sensory motor functions. These tests are useful in cases where psychomotor functions are expected or anticipated to be compromised. It can evaluate motor system performance, sensory motor performance, attention span, concentration ability, motor coordination, reflex response, visual motor coordination, alertness, sedative effects of drugs, cognitive effects of drugs, and memory. In the present study, validated, computerized psychomotor testing equipment has been used to assess the acute effects of diazepam, escitalopram and buspirone on psychomotor and cognitive function.

Review of literature

Patients with generalized anxiety disorder experience a number of physical and psychological symptoms. The benzodiazepines are used for short-term treatment, but may need to be continued for months to years. Buspirone and antidepressants are also used for the pharmacologic management of patients with generalized anxiety disorder.1 Although, benzodiazepines are effective as short-term anxiolytics, their use is compromised by a poor adverse event profile and, like buspirone, they lack the antidepressant efficacy important for addressing the comorbid depression experienced by many patients with GAD. Antidepressants, including paroxetine and the serotonin-norepinephrine reuptake inhibitor venlafaxine, are effective anxiolytics and resolve symptoms of depression in patients with GAD.2 A study done by Manfredi et al on the sedative effects of buspirone has shown that buspirone lacks sedative effects and also suggests that the drug may have stimulant properties.7 Studies have demonstrated the sedative effect of diazepam in comparison with buspirone.6 A study done by Spadone et al has shown efficacy of escitalopram against anxiety symptoms associated with depression.11 Nausea is perhaps the only adverse effects (AE) with an incidence greater than placebo during short-term treatment with escitalopram. In general, AEs with this SSRI are mild to moderate in severity. AEs related to sexual dysfunction are similarly frequent with escitalopram and citalopram, but higher with paroxetine.12 No suicide has been reported among escitalopram-treated patients, and there have been no significant differences between escitalopram and placebo in incidence of suicidal behavior, measured by self-harm and suicidal thoughts. Reports of sedation and somnolence have been frequently reported with citalopram and it is generally agreed that escitalopram too does cause somnolence.12,13,14 Yet, there are very few studies which comment on the sedation produced by escitalopram and its effects on psychomotor and cognitive function. A comparative study of escitalopram with positive and negative controls (diazepam and placebo; respectively) can be of significance in ascertaining these effects. This study intends to do the same using a validated battery of psychomotor and cognitive function tests.

Aims and objectives

To compare the acute effects of escitalopram with diazepam and buspirone on the cognitive and psychomotor function in healthy subjects in a double-blind, crossover, and placebo-controlled study.

Materials and methods

Subjects

Subjects were 18-40 years of age and of both gender. Exclusion criteria included concomitant medication; chronic smokers and alcoholics; subjects with known sleeping disturbances and altered circadian rhythm; pregnant; and lactating women. The subjects were recruited from individuals who volunteered to be a part of the study. The study was conducted at the psychomotor testing facility, Department of Pharmacology, JIPMER; Pondicherry during the period of August through October 2009. All subjects were required to be in good health as ascertained by a medical history and general physical examination.

Study design

The study was a prospective, randomized, double-blind, active-comparator, placebo-controlled, four way crossover design.

Sample size calculation

The sample size calculations were undertaken before the study. The mean effect difference (change in choice reaction times), the standard deviation were utilized. Using the PS Power and Sample Size Calculations software (version 3.0; Vanderbilt University, Nashville, Tennessee, USA); for a power of 80% and a significance of 5%, 22 subjects were needed. With allowance for dropouts, the sample size was ascertained as 25 for each group.

Randomization

Study drugs were assigned according to a Latin-square based randomization list. The randomization list was obtained using the GraphPad Quickcals online software.

Numbered containers (A to D) were used to implement the random allocation sequence. The drugs were dispensed by a person unrelated to the trial on the day of the study.

Blinding

The study was a double blind design. The investigator and the subjects were blinded to the study. For the purpose of enhancement of blinding, the individual tablets were over encapsulated. The drugs were coded as Drug A, B, C and D. The codes were broken only after the complete analysis of data.

Groups

The study had one group of subjects who received the drugs in a crossover fashion.

Interventions

Subjects received a single dose of each of the drugs under investigation: diazepam 5 mg, escitalopram 10 mg, buspirone 15 mg and placebo. All drugs were administered as tablets, taken with 150 ml of water in an empty stomach between 3 and 5 pm on the days of study. Each treatment was separated by a washout period of 7 days or more. No medication was allowed 2 weeks prior to recruitment, nor during the study, except for the drugs under investigation.

Measurements

Computerized psychomotor testing was employed for evaluating the mental and motor functioning of subjects after treatment with the drugs under investigation. It evaluated the motor system performance, sensory motor performance, attention span, concentration ability, motor coordination, reflex response, visual motor coordination, alertness, sedative effects of drugs, cognitive effects of drugs, and memory. MindomaticsTM provided by Sristek Consulting Private Limited, Hyderabad, A.P; India; was used in this study for computerized psychomotor testing.

Before the first treatment day, subjects were trained on all psychometric measures to ensure that learning effects were minimized. The subjects arrived at the psychomotor facility between 3 and 5 pm and performed pre-treatment baseline tests for each of the psychometric measures used in the study. The baseline test battery included the finger tapping test (FTT), choice reaction test (CRT), choice discrimination test (CDT), digit picture substitution test (DPST), digit vigilance test (DVT), numeric working memory test (NWMT), immediate picture recall test (IPRT). A subjective line analog rating scale (LARS) for evaluating self-rated sedation was used.

The subjects were then administered the drug on an empty stomach. The measurements were made at 1 and 3 hours post dose. Subjects had to refrain from intense physical activity, xanthine-containing beverages, and smoking on the day of the study. They were also instructed not to drive and operate machinery on the day of the study.

Finger tapping test (FTT): This test provides information on the motor system performance. In this test, the subjects were required to tap on the "enter" button repeatedly as quickly as possible for a total duration of eight seconds. The performance was presented as an average reaction time in milliseconds, as well as total number of clicks attempted.

Choice reaction test (CRT): This test is useful to test the attention and concentration of the subject. One can assess the sensory motor performance of brain and this test is considered to measure psychomotor speed. In this test, either the picture of a boy or the picture of a girl appears in the centre of the monitor screen at irregular intervals. Every time the picture of a boy was displayed, the subjects had to press the boy symbol response button, as quickly as possible. The picture remains on the screen for 1 second and there is a time gap of 1.5 to 2.5 seconds between the appearances of pictures. The subjects were not expected to respond when the picture of a girl was displayed.

Choice discrimination test (CDT): This test is used to test the attention, integration and co- ordination. One can assess the sensory motor performance of the brain and this test too is considered to be a measure of psychomotor speed. In this test, either the picture of a boy or the picture of a girl will appears in the centre of the monitor screen at irregular intervals. The subjects had to press the boy symbol response button with the right hand finger and the girl symbol response button with the left hand finger on seeing respective pictures, as quickly as possible. The pictures remain on the screen for 1 second and there a time gap of 1.5 to 2.5 seconds is allotted between the appearances of pictures.

Digit picture substitution test (DPST): This is one of the most widely used tests for measuring recognition of sensory information and it is a useful indicator of change in sensory processing performance. This test is used to measure the attention, response speed, central integration and visual motor coordination. In this test, a key is shown on the monitor screen, which matches a series of target picture to the digits 1-9. On click of the start button, target picture starts appearing on the centre of the monitor screen, one at a time. With appearance of a target picture, the subject had to press the corresponding digit, as quickly as possible. The total duration of test is 90 seconds. This test calculates the reaction time, total number of attempts, right attempts and wrong attempts.

Digit vigilance task (DVT): This test assesses the concentration, attention, vigilance and alertness. In this test a target digit is displayed continuously on the top right corner of the monitor screen. On click of start button, a continuous series of digits appear one at time in the centre of the screen. Every time when the digit in the centre of the monitor screen corresponded to the target digit on the right hand corner of the screen, the subject pressed the enter button as quickly as possible. This test runs for 60 seconds and total of 120 digits are displayed for 500 milliseconds. The results are displayed as reaction time, total attempts, correct attempts and wrong attempts.

Numeric working memory test (NWMT): This test detects the memory and reaction time of a subject. In this test, three target numbers appear on the centre of the monitor screen, one at a time. The subjects were made to concentrate and remember these target numbers. After few seconds, series of numbers appear on the centre of the screen, one at a time. The subjects pressed the "tick" button as quickly as possible if the number corresponded to any of the target numbers shown and press "X" button as quickly as possible, if it was some other number. Each number is displayed on the screen for 1 second. The results are displayed as reaction time, total attempts, correct attempts and wrong attempts.

Immediate picture recall test (IPRT): This test assesses memory of the subject. A total of ten pictures appear at the centre of the monitor screen one after the other. The subjects were made to carefully observe the pictures and remember them. The pictures appear one after the other on the screen. The subjects were made to press the "tick" button as quickly as possible, if the picture shown corresponded to one of the target picture. The "X" button was pressed if it was some other picture. This test runs for 60 seconds and total of 20 pictures are displayed. Each picture is displayed on the screen for 500 milliseconds. The results are displayed as reaction time, total attempts, correct attempts and wrong attempts.

Line analog rating scale (LARS) for sedation: The LARS is used as a measure of the subjective effects of psychoactive drugs. Subjects marked a series of 10 cm line analog scales, indicating their self-rated sedation. The mean scores of ratings of 'tiredness', 'drowsiness' and 'non-alertness', were taken as a measurement of perceived sedation. The higher the score, the more tired and drowsy the subject felt. This scale has been shown to correlate well with various objective measures of arousal/ sedation and has been used extensively to detect subjective sedation with many different classes of drugs.

Adverse events

All adverse events and undesirable experiences occurring during the study were reported to the investigator by the subjects. The reported adverse events were recorded in the Central Drugs Standards Control Organisation (CDSCO) provided forms for reporting ADRs. Causality assessment was done using the Naranjo's algorithm after the trial was completed.15

Statistical analysis

Data were entered in Microsoft Excel sheets. The primary endpoint was expressed as the change in the choice reaction test (CRT) time between the baseline values (predrug administration) and the one obtained at the predefined time points. A repeated measures analysis of variance (ANOVA) was used to compare treatment changes from baseline for all the time and response variables in this four-way crossover study. The factors were treatment (4 levels: diazepam 5 mg, escitalopram 10 mg, buspirone 15 mg, and placebo) and time (2 levels: 1and 3 h). Statistical tests were carried out two-tailed at the 5% level of significance using GraphPad Prism 5 for Windows (GraphPad Software, San Diego, California, USA). Bonferroni's post tests were done for pair wise comparisons between the treatment groups and placebo.

Institute Ethics Committee approval

The study protocol was approved by the Institute Research Committee of JIPMER. The study protocol, subject information document and the informed consent forms were approved by the JIPMER Institute (Human) Ethics Committee. The informed consent documents were provided to the subjects in English as well as Tamil (the predominant vernacular language). All subjects accorded written informed consent. The subjects were encouraged to clarify their queries before signing the consent forms. No compensation was paid to any of the subjects. The guidelines laid down in the Declaration of Helsinki (amended October 2008) were adhered to at all stages of the trial.

Figure 1. Flowchart of the study procedure.

Observation and results

Subjects

Thirty subjects were screened, 25 were included out of which all completed the study. Of the Thus, 25 subjects received escitalopram, 25 received diazepam, 25 received buspirone and 25 received placebo treatment. The demographic characteristics of the subjects are presented in Table 1.

Table 1. Baseline characteristics of the subjects (n=25)

Characteristics

Value

Age (years)*

20 ± 1.2

Males

17

Females

8

Handedness

Right

25

Left

0

Body mass index (BMI)*

22.2 ± 4.5

*Values expressed as Mean ± SD

Assessments for percentage change from baseline in response time

Analysis of results was done for the percentage change from baseline of the response time in different groups at different post dose time points.

Choice Reaction Test (CRT): The analysis of results revealed that the effect of treatment was significant (F = 3.63 [3, 96], p = 0.025), as was the treatment by time interaction (F = 2.47 [6, 192], p = 0.016). As the treatment by time interaction was significant, post-tests for separate post dose time points were carried out. At 1 hour post dose, diazepam 5 mg significantly increased the CRT time over baseline (difference = 9.4, 95% confidence interval [CI] = 2.1 to 17, p < 0.01) compared with placebo but not at 3 hours post dose. Diazepam 5 mg was also significantly different from escitalopram 10 mg (difference = 9.44, 95% CI = 1.6 to 17.4) and buspirone 15 mg (difference = 10.53, 95% CI = 18.33 to 2.73) at 1 hour post dose. At 3 hours post dose the differences were not significant. None of the other treatments could be differentiated from placebo (Figure 4).

In the immediate picture recall test (IPRT), the effect of treatment was significant (F = 6.47, [3, 96], p = 0.0005) as was the interaction between time and treatment (F = 4.21, [6, 192], p = 0.0005). On post tests it was revealed that diazepam 5 mg significantly increased the response time as compared to placebo (difference = 14, 95% CI = 6.4 to 21, p < 0.05) at one hour post dose and at three hours (difference = 6.5, 95% CI = 0.62 to 14, p < 0.05) (Figure 5).

Figure 2. Flowchart showing the allocation and follow up of study participants.

Similarly, repeated measures ANOVA was used to analyse the results from other tests of psychomotor and cognitive function (the choice discrimination test [CDT], the digit picture substitution test [DPST], the digit vigilance test [DVT], the numeric working memory test [NWMT]) and no significant change was observed for any factor with any of the treatments. The treatment differences in response time between escitalopram 10 mg (or diazepam 5 mg and buspirone 15 mg) compared with placebo are summarized in Table 2.

Assessments for percentage change from baseline in number of valid responses

The analysis of the results using repeated measures ANOVA revealed that there were no significant differences in the percentage change from baseline in the number of valid responses in any of the test of psychomotor function. The differences in the number of valid responses between escitalopram (or diazepam and buspirone) compared with placebo for all the computerized psychomotor function tests have been summarized in Table 3.

Adverse events

Somnolence was the most commonly reported adverse event. It was reported with all the treatments including placebo. There were no serious adverse events. There were no withdrawals due to adverse events in the study. The incidence of sedation was greater in the diazepam and buspirone groups as reported spontaneously by the subjects. Buspirone was associated with the most number of adverse events (10), followed by escitalopram (4). The adverse events as reported by the subjects have are shown in Figure 3.

Figure 3. Adverse events (as reported by the subjects during the study period)

Table 2. Mean treatment differences (percent change from baseline) in response time between escitalopram (or diazepam and buspirone) and placebo with 95% CI at 1 and 3 hours time point for the computerized psychomotor function tests.

Test

Time (h)

Escitalopram 10 mg

Diazepam 5 mg

Buspirone 15 mg

CDT

1

-34 (-89 to 22)

-26 (-81 to 30)

-30 (-85 to 25)

3

-33 (-88 to 23)

-32 (-88 to 23)

-34 (-89 to 22)

CRT

1

-0.081 (-7.3 to 7.1)

9.4 (2.1 to 17)**

-1.2 (-8.4 to 6.1)

3

3.2 (-4.0 to 10)

4.1 (-3.1 to 11)

-0.7 (-7.9 to 6.5)

DPST

1

-1.7 (-8.8 to 5.5)

4.3 (-2.8 to 11)

5.1 (-2.1 to 12)

3

-0.56 (-7.7 to 6.6)

4.2 (-2.9 to 11)

2.1 (-5.0 to 9.3)

DVT

1

1.4 (-2.3 to 5.1)

0.19 (-3.5 to 3.9)

-1.9 (-5.6 to 1.8)

3

-1.6 (-5.3 to 2.1)

0.7 (-3.0 to 4.4)

-2.1 (-5.8 to 1.7)

NWMT

1

-5.9 (-26 to 14)

-12 (-32 to 7.9)

2.9 (-17 to 23)

3

-4.7 (-25 to 15)

-14 (-34 to 5.9)

-1.9 (-22 to 18)

IPRT

1

-0.48 (-7.6 to 6.6)

14 (6.4 to 21)**

2.8 (-4.3 to 9.9)

3

0.6 (-6.5 to 7.7)

6.5 (-0.62 to 14)*

1.6 (-5.6 to 8.7)

CRT, Choice reaction test; CDT, Choice discrimination test; DPST, Digit picture substitution test; DVT, Digit vigilance test; NWMT, Numeric working memory test; and IPRT, Immediate picture recall test. * p < 0.05; ** p < 0.01.

Table 3. Mean treatment differences (percent change from baseline) in valid responses between escitalopram (or diazepam and buspirone) and placebo with 95% CI at 1 and 3 hours time point for the computerized psychomotor function tests.

Test

Time (h)

Escitalopram 10 mg

Diazepam 5 mg

Buspirone 15 mg

FTT

1

-2.7 (-11 t0 5.2)

-4.5 (-12 to 3.4)

-0.75 (-8.7 to 7.2)

3

-3.1 (-11 to 4.8)

-1.5 (-9.4 to 6.4)

1.8 (-6.2 to 9.7)

CDT

1

-4.5 (-14 to 4.9)

-4.9 (-14 to 4.5)

-2.8 (-12 to 6.6)

3

0.79 (-8.6 to 10)

3.5 (-5.9 to 13)

1.3 (-8.1 to 11)

CRT

1

0.011 (-2.2 to 2.2)

-0.021 (-2.2 to 2.2)

-1.2 (-3.4 to 1.0)

3

-0.99 (-3.2 to 1.2)

-0.39 (-2.6 to 1.8)

-1.4 (-3.6 to 0.82)

DPST

1

1.6 (-5.4 to 8.5)

-2.8 (-9.7 to 4.2)

-4.8 (-12 to 2.2)

3

1.5 (-5.5 to 8.4)

-3.0 (-10 to 4.0)

-2.3 (-9.3 to 4.7)

DVT

1

1.4 (-4.2 to 6.9)

2.5 (-3.0 to 8.1)

-0.98 (-6.5 to 4.6)

3

0.0092 (-5.6 to 5.6)

-1.2 (-6.8 to 4.4)

-0.63 (-6.2 to 4.9)

NMWT

1

7.5 (-4.7 to 20)

5.3 (-6.8 to 17)

0.79 (-11 to 13)

3

6.3 (-5.8 to 18)

3.2 (-8.9 to 15)

2.2 (-9.9 to 14)

IPRT

1

-1.4 (-5.9 to 3.1)

-3.5 (-7.9 to 1.0)

-0.16 (-4.6 to 4.3))

3

-0.34 (-4.8 to 4.1)

-1.0 (-5.5 to 3.5)

1.3 (-3.2 to 5.8)

FTT, Finger tapping test; CRT, Choice reaction test; CDT, Choice discrimination test; DPST, Digit picture substitution test; DVT, Digit vigilance test; NWMT, Numeric working memory test; and IPRT, Immediate picture recall test.

* + #

Figure 4. Choice reaction time (ms). Mean change in reaction time from baseline (%) following the administration of diazepam 5 mg, escitalopram 10 mg, buspirone 15 mg and placebo. Data are expressed as mean ± SEM. (*p < 0.05 when compared with placebo. +p < 0.05 when compared with escitalopram. # p < 0.05 when compared to buspirone).

* + #

*

Figure 5. Immediate picture recall test. Mean change in reaction time from baseline (%) following the administration of diazepam 5 mg, escitalopram 10 mg, buspirone 15 mg and placebo. Data are expressed as mean ± SEM. (*p < 0.05 when compared with placebo. +p < 0.05 when compared with escitalopram. # p < 0.05 when compared to buspirone).

Discussion

The purpose of this study was to investigate the acute effects of antianxiety medications namely, diazepam 5 mg, escitalopram 10 mg, and buspirone 15 mg on the aspects of psychomotor and cognitive function in healthy Indian subjects using a battery of tests developed to serve as markers for CNS impairment. The results are in congruence with findings of previous studies which have demonstrated that escitalopram and buspirone when administered at therapeutic doses have no significant detrimental effect on CNS arousal, reaction time, attention, vigilance, or subjective feelings of sedation.6,12,14

The use of a well recognized positive control is important for validating the methodology of the trial. Diazepam 5 mg, used in this study as a positive control showed impairment of some of the aspects of psychomotor and cognitive performance. This effect was expected as diazepam has profound sedative effects. The most pronounced impairment of psychomotor function with diazepam 5 mg was seen at 1 hour postdose at which it happens to be at its peak blood level.16

Escitalopram and buspirone were not shown to be different from placebo with regard to any of the objective and subjective measures used in this study. Citalopram has often been rated as sedating subjectively and evidence from clinical trials for this adverse effect also confirm the fact.13 In accordance to this "subjective sedation", trials with citalopram have shown pronounced antianxiety activity with some evidence of cognitive or psychomotor impairment at therapeutic doses. The serotonin/norepinephrine reuptake inhibitors and selective serotonin-reuptake inhibitors, with the possible exception of escitalopram, derange sleep architecture and decrease restorative sleep.12 In this crossover trial too, escitalopram did not differ in objective as well as subjective assessments compared with placebo. Buspirone is an important drug for the treatment of anxiety disorders, devoid of disruptive influence on motor and cognitive processes.6,8 This has been validated by earlier studies and in the present trial; it appears to be free from any impairment of the psychomotor and cognitive functions.

Crossover designs are most appropriate in studies where the effect of the treatment(s) is short-lived and reversible and using this method the between and within group comparisons were made.17

Choice reaction time (CRT) is used as an indicator of sensorimotor response, assessing the efficiency of the attention and response mechanisms in the information processing chain without the need for extended cognitive processing. Measurements of CRT provide information on the constant, very rapid adjustments individuals must make to their environment, which require them to attend to several potential stimuli at once. The primary endpoint in this study was an increase in CRT which would be indicative of psychomotor impairment. Using computerized psychomotor function testing equipment, it was observed that diazepam 5 mg produced significant increases in CRT compared with placebo, whereas no significant changes were seen with escitalopram and buspirone. There were no significant changes in valid responses in this test though. This test has been used in many trials as an objective marker for assessing subjective function and the findings of this study are similar to those reported earlier.18

Significant changes with diazepam 5 mg were also prominent in the immediate picture recall test (IPRT) which intends to assess the concentration, memory and alertness of subjects.

Subjective reports of sedation in this study were also in agreement with the objective findings. Subjects reported significantly higher scores for drowsiness and non alertness with diazepam 5 mg compared with the other treatments. Somnolence was the most common adverse event reported and mainly with diazepam 5 mg, as expected.

One of the limitations associated with performance based tests is that the subjects can try and nullify the effects of the treatment by altering their performance and motivation levels.18 Given the intermittent nature of these tests, it is possible that the subjects may have a better attention span while performing the tests which are usually of a few minutes duration only. Besides, they are aware of the protocol and get forewarned before each session of performance. This may not reflect the actual levels of alertness throughout the day. An interview with the subjects after analysis of all the results revealed that a majority of them did not feel sedated while performing the computerized psychomotor function tests. A suggested way to overcome this is the use of wrist actigraphy which provides for continuous measurement of the motor component of behaviour. It has been demonstrated to detect impairments in performance throughout the day produced by psychoactive drugs. 19

Subjective assessments and self reports are much more likely to be influenced by transient fluctuations and factors such as environmental stimuli than objective measures of psychomotor performance. A major reason for this can be attributed to the fact that sleepiness, somnolence and sedation themselves can impair self assessment and hence lead to erroneous results.18

In this study, there were no dropouts, and hence the power of the study was not affected. A major limitation in this study was the inability to assess subjects beyond the 3 hours post dose interval. In part a major factor for this was the "unwillingness" of the subjects to stay at the testing facility due to "excessive sedation" produced by the treatments.

The strength of this study is its double blind, verum and placebo controlled design. The trial was conducted in a crossover fashion which minimises confounding factors and interindividual variability.

This study has demonstrated that escitalopram and buspirone do not impair psychomotor and cognitive functions compared with placebo when administered at therapeutic doses in Indian subjects. The sedation often reported with these agents is probably subjective and does not impair an individual in performing daily activities.

Conclusions

The aim of this study was to assess impairment induced by antianxiety medications, namely, escitalopram and buspirone on psychomotor and cognitive function in comparison to diazepam and placebo in healthy human subjects. The general conclusion that can be drawn from this study is that there were no subjective or objective effects on psychomotor and cognitive function following the administration of single doses of escitalopram 10 mg and buspirone 15 mg. These drug at doses studied are free from sedation and detrimental effects on the central nervous system.

Summary

Generalised anxiety disorder (GAD) is a psychiatric illness in the general community with a lifetime prevalence of 4.1 - 6.6 %. The management of this condition involves both pharmacologic and psychotherapeutic interventions. However, complete symptomatic relief is often rare. The sedative effect of benzodiazepines and its ability to impair psychomotor performance is well documented and is a major limiting factor in the treatment of such patients. Buspirone and escitalopram are recent additions to the pharmacotherapy of GAD. Though they are said to be devoid of sedation, there have been reports of this particular concern with their use too. This was a randomized, double-blind, placebo-controlled, four way cross over clinical trial conducted to assess the impairment caused by escitalopram on psychomotor function and cognition in comparison to diazepam 5mg (positive control) and placebo (negative control).

Healthy subjects of both genders between 18 to 40 years of age were recruited. They were administered diazepam 5mg, escitalopram 10 mg, buspirone 15mg and placebo in a crossover fashion based on a four by four Latin square method. Psychomotor function and cognition were tested using the computerised psychomotor function testing apparatus. Initial baseline measurements were taken followed by measurements taken at 1 and 3 hours after drug administration. Subjects reported their subjective sleepiness using Linear Analogue Rating Scale for sedation. The adverse events reported by the subjects were noted by the investigator. Statistical tests were carried out two-tailed at 5% level of significance using (GraphPad Software, San Diego, California, USA). The primary outcome was an increase in choice reaction time which serves as a marker for impairment of psychomotor function.

Out of the 30 subjects screened 25 were recruited and all completed the study. Analysis was performed as per the protocol. It was found that diazepam 5 mg significantly increased the choice reaction time from baseline at 1 hour compared with placebo. Significant changes were also prominent with diazepam 5 mg at in immediate picture recall test at 1 hour and 3 hours postdose when compared with placebo. Escitalopram and buspirone did not show any significant change in any of the psychomotor function tests when compared with placebo. Maximum numbers of adverse events were reported with buspirone. The general conclusion that can be drawn from this study is that there were no subjective or objective effects on psychomotor and cognitive function following administration of single dose of escitalopram 10 mg and buspirone 15 mg.

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Exams can be one of the most stressful experiences you’ll ever have! Revision is key, and we’re here to help. With custom created revision notes and exam answers, you’ll never feel underprepared again.