Antidepressants, do they work?
CHAPTER 1
INTRODUCTION
Antidepressants are medications used to treat major depressive disorder, some anxiety disorders, some chronic pain conditions, and to help manage some addictions. Depression has become a major problem for millions of people throughout the world. The physical, emotional, and social cost of this disorder have prompted many in the health care industry to actively look for effective treatment. Extensive research has been conducted pertaining to the treatment of depression. The most popular, modern and putatively effective treatment for depression are psychotherapy and psychopharmacology. In the area of psychotherapy, cognitive behavioral therapy has emerged as the leading and generally best-accepted psychotherapeutic treatment for depression. In the area of psychopharmacology there are three major types of antidepressants, which have been prescribed to lessen symptoms of depression; tricyclics, monoamine oxidase (MOA) inhibitors, and selective serotonin reuptake inhibitors (SSRIs). Its seems that the older tablets (Tricyclics) are just as effective as the newer (SSRIs) but, on the whole, the newer seem to have fewer side-effects. A major advantage for the new generation antidepressants is that they are not dangerous if someone takes an overdose. SSRIs have become the most common form of antidepressant medication prescribed (Kroenke, West, Swindle, & Gilsenan, 2001). In fact, Prozac is now the most prescribed drug. Though the two aforementioned treatment modalities, cognitive behavior therapy and SSRIs, have gained popularity, effectiveness has been questioned by both providers and patients within the mental health community. The doubts about these treatments can be partially explained by the inconsistencies found in the experimental literature.
An extensive literature review shows that many experiments have suggested the effectiveness of psychotherapy and psychopharmacology in the treatment of depression in adults. However, other research has produced contrasting results. Further evidence has been compiled suggesting that placebos may be less, equal, or more effective than both psychotherapy and psychopharmacology.
There is an ongoing debate within psychiatry and psychology pertaining to the effectiveness of medication, psychotherapy, and placebo, in treating depression in adults. To date, one type of psychotherapy and one group of antidepressants have emerged as common treatment for depression. Cognitive behavior therapy (CBT) has emerged as a commonly used psychotherapy available for the treatment of major depressive disorder (MDD) in adults and selective serotonin reuptake inhibitors (SSRIs) appear to be the most widely used antidepressant medications available for the treatment of MDD in adults (Kroenke et al. 2001). These two current treatments enjoy the most experimental backing to date. However, studies have not produced consistent results.
There is evidence suggesting that a placebo is both superior and inferior to both CBT and SSRIs. There is also evidence suggesting that CBT both is and is not an effective treatment for depression in adults. The same holds true for SSRIs. Some research suggests SSRIs are an effective treatment for depression and some research suggests they are not. Additionally, the research is not consistent in clarifying if SSRIs combined with CBT are an effective treatment for depression in adults. These inconsistencies in the literature have influenced researchers to conduct meta-analysis in order to clarify the issue. However, these too have produced contradictory results.
Active and inactive placebo
With the growing use of placebo in order to measure the true effects of a drug or substance in clinical trial, the term active and inactive placebo has been coined by the pharmaceutical companies. They call placebo inactive or inert as, according to them, the placebo pills have no side effect. However, in reality, there is no such thing as inert or having no side effect at al (Healthier life, 2004). In fact, every pharmaceutical company has its own formula of placebo and the term ‘active placebo’ is meant to describe the pill that is designed to mimic the side effects similar to the placebo group.
Some of the existing studies have failed to control for all extraneous variables. For instance, most experiments did not use active placebo. Use of an inactive placebo may allow participants and experimenters to figure out who is receiving a drug and who is receiving placebo. Additionally, evidence has been put forth suggesting that drug companies are manipulating evidence in order to prove their drug’s effectiveness (Fava et. al, 2003).
Selective serotonin reuptake inhibitors are the most commonly prescribed class of antidepressants (Kroenke et al. 2001). Numerous studies have been published suggesting that SSRIs are an effective treatment choice for depression. Surveys, experiments, and meta-analyses have all suggested these drugs are an efficacious choice in the fight against depression.
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Concerns related to safety were raised in the early 1990s, with reports describing a possible association between SSRIs and suicidality ( Teicher MH. et. al 1990, Rothschild AJ & Locke CA. 1991, Masand P. et. al 1991). However, inferences regarding the plausibility and strength of the association between suicidality and the use of SSRIs have been divergent (Baldwin D. et. al 1991, Arif K. et. al 2003, Jick H. et. al 2004). An early meta-analysis showed that SSRIs potentially decreased suicidal ideation as measured by a single question on the Hamilton depression score (Jick H. et. al 2004). A more recent review of data from 77 trials submitted to the US Food and Drug Administration (FDA) found a non-significant increase in suicide rates between patients allocated to SSRIs and those allocated to placebo or other antidepressants (Arif K. et al. 2003). Because suicides and suicide attempts are considered rare events, the inability to document an important difference may be a function of the small number of patients in single studies and meta-analyses published to date. Nevertheless, the UK Committee on Safety of Medicines and the Food and Drug Administration (FDA) have issued public health advisories concerning the use of antidepressants and suicidality (Center for D. E. & R. US FDA. 2004, Committee on Safety of Medicine 2004)
Research questions
This research will address the following questions:
- Do old (Tricyclics) Antidepressants really demonstrate benefits on trials?
- If new drugs are better, are these agents merely better than placebo if older drugs are no better than placebo?
- What is evidence that antidepressants cause suicide? Is the evidence robust?
Aims and objectives of the Dissertation
As mentioned in the research questions, the main aim of this dissertation is to investigate the effectiveness of old (Tricyclics) antidepressants and compare their performance with the new antidepressants. A further aim of this dissertation was to review the relevance of antidepressants with suicidal behavior. For this purpose, the specific objectives of this study were:
- To examine the effectiveness of the old (Tricyclics) Antidepressants
- To investigate and compare the performance of new antidepressants with the old (Tricyclics) antidepressants
- To review the suicidal behavior associated with the antidepressants.
Research Method
This research utilized systematic review of the previous studies in order to find out the best answers of the questions set forth. For this purpose, the majority of the information was located by searching several databases including ProQuest, Medline, Psychinfo, as well as several others. These databases were searched using key words like “depression”, “cognitive behavioral therapy”, SSRIs”, “antidepressants” …. Additionally these databases were searched using specific names of SSRI antidepressants. Additional meta-analyses and experiments were located by searching the reference lists of related articles and by looking at experiments by often-mentioned authors in the field.
The experiments and meta-analyses obtained were from the years 1983 to date. All of the major sources were found in peer-reviewed journals. Included were studies that looked at the differences between Placebo and SSRIs for the treatment of depression in adults.
The criteria chosen to measure validity, reliability, and control were (a) use of control groups, (b) use of placebo, (c) use of active or inactive placebo, (d) whether the subjects were randomly assigned, (e) the number of subjects, (f) the results of the study, and (g) whether or not the subjects were representative of the general population of depressed individuals.
Coding
The researcher coded each study for systematic review in order to assess a given studies’ validity, reliability, and control. This can also be thought of as strength. Strength was defined as the percentage of possible criteria utilized in order to achieve valid and reliable results. This coded score was called a coded strength score (CSS). The CSS was quantified by assessing each study with respect to whether or not it contained the appropriate experimental controls and tools generally used in antidepressant studies. These strength criteria were chosen by reviewing the studies listed in the literature review and determining what criteria were used /reported and generally accepted as necessary and/or valuable strength measures.
Structure of the research
This research is comprised of three chapters, the first chapter includes the introduction, research questions and aims and objectives of the study. Further, this chapter describes the research method utilized for collecting primary data which is through the systematic review of the previous studies on antidepressants. The second chapter is the systematic review of the literature from the studies chosen for this dissertation. The third chapter discusses the findings of the experiments and meta-analysis and offers the conclusions of the research.
CHAPTER II
REVIEW OF THE LITERATURE
Introduction
This chapter reviews the studies conducted over the period from 1983 to date in order to assess the effectiveness of TCAs, SSRIs and other antidepressants which have been found to reduce depression among adults and compares which antidepressants are most effective.
Overview of Antidepressants
Antidepressants were first introduced in the late 1950s and early 1960s, with the sole purpose being to treat depression. As the field has evolved, treatment with antidepressants is now used for not only depression, but anxiety, dysthymia, and chronic pain. The first antidepressants developed were monoamine oxidase inhibitors (MAOIs) and Tricyclics antidepressants (TCAs). MAOIs have been used since the late 1950s for the treatment of depressive disorders. There are two types of the enzyme monoamine oxidase (which break down neurotransmitters on the body), MAO-A and MAO-B. MAO-A is known as “good” MAO and is found in serotonin and norepinephrine nerve terminals. MAO-B is known as “bad” MAO and is found in neurons that secrete dopamine. Inhibition of MAO-A via drugs is assumed to be responsible for the antidepressant effects of the medication, while the inhibition of the MAO-B is responsible for all of the side effects (Julien, 2005).
Phenelzine, Isocarboxazid, and Tranylcypromine are all types of MAOIs. Such MAOIs have had limited use due to the serious side effects and interactions when taken with some medications and foods (cheeses, wines, liver, beers, and some beans). Blood pressure can increase and become fatal if an interaction occurs, thus a strict diet must be followed while taking MAOIs. Recently, a new formulation has been developed that is void of the drug and food interaction. Thus, the use of MAOIs has continued as they have been found as safe as TCAs, work well in the treatment of atypical depression (comorbidity with anxiety or eating disorders), and they can work in patients who respond poorly to other types of antidepressants (Julien, 2005).
TCAs are a class of drugs that consist of a three-ring molecular core. Imipramine, Desipramine, Trimipramine, Protriptyline, Nortriptyline, Amitriptyline, Doxepin, and Clomipramine are all examples of TCAs. They have been found to increase physical pursuits, improve appetite and sleep activities, elevate mood, and lessen morbid ideations (Gasto et al, 2003, as cited in Julien, 2005). Not only can TCAs relieve depressive symptoms, they also have anxiolytic and analgesic properties. There are four pharmacologic actions produced by TCAs; they block the presynaptic serotonin and norepinephrine reuptake transporters and the postsynaptic histamine and acetylcholine receptors. The block of acetylcholine receptors can result in dry mouth, memory and cognitive performance, confusion, increased heart rate, and blurred vision. Two TCAs that cause less cognitive impairment and anticholinergic effects are nortriptyline and desipramine and are therefore the preferred choice for initial treatment with TCA therapy. There are some clinical limitations with the use of TCAs. These include a slow onset of action (yet just as fast as other antidepressants), side effects on the central nervous system (not found with SSRI use), and overdose problems such as suicide attempts (Julien, 2005).
In the past, TCAs were the top choice for the treatment of depression. However, more recently, Selective Serotonin Reuptake Inhibitors (SSRIs), which will be further discussed shortly, are more often prescribed than TCAs, as they may be less toxic. TCAs are still considered the standard for comparison of other antidepressants because no other group of antidepressants has demonstrated to be more effective or have a quicker onset for treatment effect than the TCAs (Julien, 2005).
Development in antidepressants
To overcome some of the problems associated with TCAs, a second-generation of antidepressants, called atypical antidepressants, was developed in the late 1970s and early 1980s. Second-generation antidepressants include Maprotiline, Bupropion, Amoxapine, Trazodone, Venlafaxine, and Clomipramine. Maprotiline (trade name, Ludiomil) was one of the first antidepressants modified from the Tricyclics structure. Some advantages of Maprotiline are that it is as effective as Imipramine (which is thought to be the “gold standard of ( TCAs), it has minimal cognitive impairments, and it can be useful for agitation. However, there is an increased rate of seizures, it can be lethal, and it has a long half-life, which allows it to accumulate. Buproprian (Wellbutrin, Zyban) is an atypical antidepressant that is also used to treat nicotine dependence. It is unique in that it inhibits dopamine and norepinephrine reuptake. Some side effects include insomnia, restlessness, anxiety, and possible seizures. However, it is low in anticholinergic, hypotensive, and sedative effects. Amoxapine is another antidepressant which is also low in sedative and anticholinergic effects. It can relieve anxiety and agitation as well as has rapid onset. The disadvantages of amoxapine are that is can cause parkinsonian side effects such as motor tremors and tardive dyskinesia. It is a norepinephrine reuptake inhibitor and just as effective as imiprimine (Julien, 2005). Trazodone (Desyrel) is an unusual antidepressant in that it is not a potent reuptake blocker of either serotonin or norepinephrine. Yet it does block a subclass of serotonin receptors and regulates serotonin receptors. It is not lethal in overdose, and it can be useful in controlling agitation in geriatric patients as it is sedating. However, drowsiness can be a disadvantage. Thus, it is usually used as an antidepressant sleeping pill. Another disadvantage is that it also may cause ventricular arrhythmia. Venlafaxine (Effexor) is a mixed serotonin-norepinephrine reuptake inhibitor, with the serotonin blockade occurring at lower doses than the norepinephrine blockade. It is low in anticholinergic, antihistaminic, and cognitive function effects. However, it can increase blood pressure and may cause anxious symptoms such as nervousness and insomnia. Clomipramine (Anafranil) inhibits serotonin reuptake as well as norepinephrine reuptake. Thus, like venlafaxine, clomipramine is also classified as a mixed inhibitor. It has been used to treat Obsessive Compulsive Disorder (OCD) for years and has also been used for the treatment of panic and phonic disorders. It has been found to be very effective. However, several side effects limit its popularity. Toxicity, seizure risk, increased rate of psychotic episodes, activation of hypomania/mania, weight gain, and decreased libido are several of the disadvantages (Julien, 2005).
Advantages of SSRIs
Although considered the newest antidepressants, SSRIs have been used to treat depression for over 15 years. SSRIs block the presynaptic transporter for serotonin reuptake; thus allowing for more serotonin to be available in the synaptic cleft to activate postsynaptic receptors for serotonin. Not only are SSRIs used for depression, but they are also effective for the anxiety disorders, OCD, Generalized Anxiety Disorder (GAD), Post-Traumatic Stress Disorder (PTSD), panic disorder, and phobias. Currently, there are six SSRIs available; Fluoxetine, Fluvoxamine, Sertraline, Paroxetine, Escitalopram, and Citalopram.
Fluoxetine (Prozac) is a popular antidepressant which not only is efficacious as TCAs, but it is not fatal in over-dosage as it lacks the TCA-caused cardiac toxicity. As with all SSRIs, there are few anti-cholinergic or antihistaminic side effects, which suggests that there should be little sedation and impairment of learning, cognition, or memory. Also common with SSRIs is a slow onset of action (about four to six weeks). Thus, when just beginning drug therapy or attempting to switch between drugs, this period of time can be a major disadvantage. Also, some side effects specific to Fluoxetine include agitation, anxiety, and insomnia. SSRIs have also been found to spark manic or psychotic attacks in a small amount of cases. Also, sexual dysfunction is another common side effect in SSRIs.
Fluvoxamine (Luvox) is similar to imipramine in efficacy, but it has less serious side effects and better patient compliance. Like many of the SSRIs, Fluvoxamine is also used for the treatment of other disorders, specifically anxiety disorders in children and adolescents. Sertraline (Zoloft) is another popular antidepressant and was the second SSRI approved for clinical use. Like all SSRIs, it is as effective as TCAs and has been found to have fewer side effects. It is also used to treat OCD, PTSD, social phobias, and panic disorder. Devan et al, 2003 (as cited in Julien, 2005) found that elderly individuals with cognitive impairments taking sertraline showed improvement on measures of attention and executive functioning as well as relieved depression. Paroxetine (Paxil) was the third SSRI available for treatment of depression and anxiety disorders. It is also similar to the TCAs in efficacy. Not only is it effective for depression, but is highly effective in reducing anxiety; specifically GAD and PTSD. Similar to sertraline, paroxetine is more selective in the blocking of serotonin reuptake. Some disadvantages include serotonin withdrawal syndrome, paranoid ideations, temper dyscontrol, and even hallucinations and delusions.
Drugs that are specific blockers of the presynaptic transporter that capture norepinephrine in the synaptic cleft and transport the norepinephrine back to the presynaptic nerve terminal are known as selective norepinephrine reuptake inhibitors (SNRIs). There are two currently available, atomoxetine and reboxetine. Atomoxetine (Strattera) inhibits presynaptic norepinephrine reuptake. Effects include not only increase in mood and attention, but also positive effects in social functioning, motivation, energy, and self-esteem (Keller et. al, 2001 as cited in Julien, 2005). Reboxetine (Vestra, Edronax) has little effect on dopamine or serotonin neurotransmission. Thus, it is without side effects that are usually associated with those transmitters. However, it is not void of all side effects, commonly, reboxetine has been associated with increased heart rate and blood pressure, sweating, dry mouth, and urinary retention. Reboxetine is also effective for seasonal affective disorder and panic disorder.
Previous work indicates that patients suffering from depression are impaired in social, occupational, or academic functioning (Zimmerman, Sheeran, & Young, 2004). One of the deficits associated with depression is impaired cognitive processes, including diminished attention, concentration, and memory performance. Many studies have demonstrated a correlation between depression and impaired memory and impaired cognitive performance (Austin, Ross, Murray, & O’Carroll, 1992). Several studies have also demonstrated impaired cognitive performance in individuals taking anti-depressants (Sherwood & Hinmarch, 1993; Fairweather et. al,1993; and Schmitt, Kruizinga, & Riedel, 2001).
Effectiveness of Antidepressants
Studies have investigated the effects of antidepressants on cognitive, attentional, and executive performance. A small number of studies suggest that some antidepressants can negatively affect different types of cognitive functioning, such as impairment in memory or reduction in reaction time. In 2004, Jones and Ireland prepared a review paper at the request of the Aerospace Medical Association (AsMA) addressing the current status of aeromedical regulation of aviators and SSRIs. To be a safe and effective pilot requires that one be physically and mentally healthy, thus taking no medications. Due to research suggesting inattention and other cognitive impairments in individuals taking antidepressants, pilots taking antidepressant medication for depression may be unsafe to fly because he/she could be somewhat ineffective in the cockpit under certain conditions. However, the prohibition of pilots taking antidepressants can be problematic due to several reasons. There is evidence (Hudson, 2002 as cited in Jones & Ireland, 2004) of some pilots refusing to quit flying while on antidepressants, which can indicate ignorance towards seeking needed treatment for the disorder. Also, SSRIs are also prescribed for other mental disorders such as Obsessive Compulsive Disorder or Panic Disorder. Thus, the regulation not only affects individuals with depression. Also, Canadian and Australian research (Lange and O’Nell, 2000; Lange, 2002) has found that some pilots using antidepressant medication for control of depressive symptoms are able to fly safely and effectively, either with a co-pilot or as a co-pilot.
Ferguson, Wesnes, & Schwartz (2003) examined the impact of reboxetine, paroxetine, and placebo on cognitive functions. Seventy four patients with major depressive disorder were randomly assigned into one of three groups. Of the total 74 patients, 25 were given reboxetine, 23 received paroxetine, and 26 were in the placebo condition. All groups were given eight weeks of the treatment. Participants in the reboxetine group were given 4 mg/day, which increased to 8 mg/day, which then increased to 10 mg/day in some cases, depending on investigator’s discretion. In the paroxetine group, participants were administered 20 mg/day at the beginning, and were eventually administered 40 mg/day by the end of treatment.
All patients were administered a cognitive battery three times; before beginning antidepressant therapy (day 0), after 14 days of treatment, and after eight weeks (day 56) of treatment. The cognitive battery consisted of attentional tasks, working memory tasks, and the Critical Flicker Fusion tasks. First, a list of 15 words was given at the rate of one every two seconds for the participant to remember (memory was later assessed in a word recognition task). A simple reaction time test was then given; participants pressed a “yes” button as soon as possible after seeing a “yes” on a monitor. There was also a “no” button on the keyboard, however, for the reaction task, participants only used the “yes” key as needed when it matched the screen. A digit vigilance task in which a series of digits were presented in the corner of a computer screen while a participant was asked to press the “yes” button each time a target digit appeared in a time period of three minutes. Another reaction time task was the Choice Reaction Time (CRT) task asking participants to press the correct corresponding button as quickly as possible when either the word “yes” or “no” appeared on the screen. A Numeric Working Memory task required participants to hold a five digit series of numbers in memory. This was followed by a set of 30 probe digits during which participants had to determine whether or not it was from the original list. Following this, the original words from the first list of words along with 15 distracter words were presented for recognition. Finally, a Critical Flicker Fusion Threshold (CFF) required the participant to watch a light source flicker. The frequency at which the light source can no longer be observed or perceived was recorded. Pupil size was also monitored during the task.
Two scores were computed based on the battery of assessments, a “Continuity of Attention” score and a “Combined Speed” score. The Continuity of Attention factor score in the reboxetine group improved from day 0 to day 14. It increased enough by day 56 to reach significance for the reboxetine group when compared to day 0. Also, by day 56 in the reboxetine group, the Combined Speed factor increased to a statistically significant difference from placebo and day 0. In the paroxetine group, compared to day 0, there was a significant increase in the combined speed score by day 14, however, this speed decreased over time and was not significant by day 56. There were no observed differences between treatment groups for the Critical Flicker Fusion test on days 0,14, or 56. Performance of the placebo group did not vary from day 0 to day 14 to day 56, thus the results suggest that reboxetine has a more positive effect (better performance) in depressed individuals than either paroxetine or placebo.
Sherwood & Hindmarch (1993) investigated the topic of behavioral toxicity of antidepressants by comparing three studies conducted by Hindmarch and others between 1987-1988. A meta-analytical technique was used to examine placebo versus a drug. The Choice Reaction Time (CRT), Critical Flicker Fusion Threshold (CFF), and Compensatory Tracking Task (CTT) were utilized in all studies examined. The CTT is considered a lab equivalent to driving a car and is thought to provide a measure of divided attention, requiring skilled motor activity in response to visual information processing. Participants used a joystick to maintain a curser in alignment with a moving target on a screen while simultaneously pushing a button to respond to visual stimuli on the edge of the screen. In addition to these measures, participants rated their alertness/sedation levels using a subjective sedation questionnaire (SED).
The three studies compared involved the examination of effects of 50 mg amitriptyline, 50 mg dothiepin (a Tricyclics antidepressant, brand name Prothiaden and Dosulepin), and 40 mg fluoxetine on eight female participants; 50 mg amitriptyline, 20 mg mianserin, 50 mg trazadone, and 30 mg paroxetine in 10 female participants; and 50 mg amitriptyline, 100 mg nomifensine, and 70-140 mg lofepramine in 10 female participants. The meta-analysis revealed that both dothiepin and amitriptyline caused significant impairment on the CTT, CFF and CRT. However, lofepramine, fluoxetine and paroxetine caused no significant differences from the placebo on the tasks. Also, participants taking dothiepin and amitriptyline reported a higher level of drowsiness on the SED. The authors concluded that of the five medications on examination, only amitriptyline and dothiepin revealed significant impairments or drowsiness.
Hindmarch (1998) examined the effect of a placebo, amitriptyline, and , a selective noradrenaline reuptake inhibitor (SNARI), reboxetine on cognitive performance. Ten healthy male participants received either (0.5 mg, 1 mg or 4 mg) of reboxetine, 25 mg of amitriptyline, or a matched placebo. Also, each participant was either given alcohol or alcohol placebo in this double-blind “10-way” crossover study. Thus, each participant had a unique combination of drug and alcohol administration. Each participant served as his own control, meaning that a baseline measurement was taken to compare against post-medication scores. There was a seven day washout period between each treatment. One, 2.25, 3.5, 6, and 9 hours after dose, a test battery including the CFF, CRT, a tracking test, and a short-term memory test were administered.
Results indicated that reboxetine had little or no effect on the test battery when compared to the placebo. Also, alcohol did not interact with the drug. As previous research has indicated, amitriptyline did impair performance, with and without alcohol, lowering the CFF threshold compared to those in the placebo and reboxetine conditions. Even with a low dose of amitriptyline, CNS function was impaired. Also, there was a slowed CRT and more tracking errors in comparison to the other groups. Also, the drug, amitriptyline, with or without alcohol, impaired short term memory. Therefore, Hindmarch concluded that reboxetine does not impair cognitive performance measured by a short-term memory task, tracking test, CFF, and CRT and thus has an important role to play in the treatment of depression (I. Hindmarch, 1998).
Siepman, Grossmann, Muck-Weymann, & Kirch (2003) examined the impact of the antidepressant sertraline (50 mg) against a placebo on cognitive functions in 12 healthy volunteers ranging in age from 21-32. All subjects were required to abstain from caffeine and alcohol for two weeks prior through the completion of the study. Participants took the medication daily for 14 days. Psychomotor and cognitive tests were conducted on the 14th day of the continuous dosing. The battery of tests included a computerized task requiring individuals to touch fields on the screen, turn knobs, or push buttons on a bottom panel. Mood was assessed using the Profile of Mood States (POMS). Flicker fusion frequency was also used to measure ability of an individual to distinguish discrete sensory data. Reaction time was measured using the Viennese Reaction Device where subjects are presented with yellow and red lights and a beep in various combinations. Participants were asked to respond as quickly as possible anytime the yellow light was presented simultaneously with the beep.
Visual memory scan was measured with a computer program that required participants to copy sequences of tapping on blocks that were presented on the screen. To assess psychomotor ability a two-hand coordination task was given. This task required participants to move a light dot down a path. The total time needed to complete the task as well as the ratio of error time to total time was computed. Results indicated that sertraline did not influence cognitive performance including memory, choice reaction time, vigilance, and psychomotor coordination. The authors report that this is consistent with previous research (Mattila et al. 1988; Kerr and Hindmarch, 1996, as cited in Siepman et al., 2003). Although no deficits in performance were found, nine of the 12 volunteers spontaneously reported concentration difficulties and/or sleepiness.
Kirsch and his colleagues (2008) examined a datasets from all trials of the medications (published and unpublished) submitted to the FDA as the authors though the meta-analysis of the published studies was prone to reporting bias. They identified forty-seven clinical trials obtained from the FDA. The analysis of this study suggested that the relation of baseline severity and improvement was curvilinear in drug groups and showed a strong, negative linear component in placebo groups. The authors concluded that although there was a significant improvement of initial depression, the response to the placebo was negatively associated with it. “Thus, the increased benefit for extremely depressed patients seems attributable to a decrease in responsiveness to placebo, rather than an increase in responsiveness to medication.” (Kirsch et. al 2008).
Constant, Adam, Gillain, Seron, Bruyer, & Seghers (2005) examined the impact of sertraline on attentional and executive functions in individuals with depression. The depressed individuals were recruited from an outpatient clinic. Twenty individuals (average age=47.65) diagnosed with depression, eight males and 12 females, participated in the study as well as 26 matched (for age and education level) controls. All depressed participants had a score of at least 14 on the BDI and had been recruited through an outpatient unit in Belgium. The depressed participants were administered 50 mg of sertraline daily, with the exception of two participants who were administered 75 mg of sertraline daily. Control participants were not administered any type of drug treatment.
Three cognitive tests formed the test battery. A phasic alertness task, from the Test Battery for Attentional Performance (TAP) was given to participants via a computer. The task is used to evaluate ability to increase attention level for an expected stimulus. During this task, reaction time to a target stimulus is measured. A white cross on a black background appears with a warning signal. Alertness is thus measured by how fast a person’s reaction time to the stimulus is. Also, the Classic Stroop test was given to assess executive functioning.
The Stroop test (Stroop, 1935) requires inhibition of reading a word. A participant is given a list of several words printed in different colors, usually blue, red, green, brown, and purple. The participant is asked to name the color of the word. The words, however, are all names of the colors (again, blue, red, green, brown, and purple). Thus, the individual is required to inhibit the automatic process of reading the word, and needs to instead name the color. A variation of the task presents the same words, however, all in black ink. This task shows a much faster response time for reading. Another variation is to require an individual to name the color of the letters, “XXXX”. It takes an individual much longer to name the color of a word when that word is the name of a color rather than when there is no actual word, such as “XXXX”. The computerized version of this task was given to participants after a pretest to ensure understanding of the task. The Emotional Stroop task is a variation of the Stroop test involving emotional words, usually of negative, positive, and neutral tone. Both the supraliminal and subliminal versions of the Emotional Stroop test were given to determine any attentional interference for negative words. These versions of the Stroop test are a variation of the classic test and were created for the study. Like the Classic Stroop test, reaction time was measured between the onset of a mask word and then response.
Results indicated that on the alertness tests, the individuals with depression had slower reaction times than did the control participants. On the Classic Stroop test, the Supraliminal Emotion Stroop test, and the Subliminal Emotional Stroop test the error rate was low, with no significant differences between depressed and control participants. On the Supraliminal Emotional Stroop, depressed participants had slower (indicating worse performance) reaction times for anxiety and depressive words than for neutral or congruent words, however, this was not the case for the control participants. This finding, that depressed individuals demonstrated worse performance on anxiety and depressed words than for neutral or congruent ones, was also true for the Subliminal Emotional Stroop test as well. The authors also noted that there was a psychomotor slowing correlated with attention and executive functioning in adults with major depression in their study. The authors also found a conscious attentional interference for words with negative valence (meaning that depressive and anxious words interfered with reaction time more than neutral words on the Emotional Stroop task). Also reported was that the effect of the antidepressant treatment with sertraline was associated with beneficial effects on psychomotor slowing and executive functions. Thus, in this study, the antidepressant treatment improved cognitive functioning. Not only did cognitive functioning improve, but mood improved as well. Depressed participants had an average BDI score similar with a diagnosis of major depression. Those individuals in the study that received antidepressants had significantly improved depressive symptoms are both three and seven weeks into treatment.
Two different controlled clinical trials were conducted by Ball and Kiloh (1959) and Abraham et al (1963) to compare the efficacy and safety of imipramine (Tofranil) with placebo in the treatment of depressed patients. All cases in both trials were out-patients adults diagnosed with either endogenous or reactive depression. In term of efficacy, the results of both trials indicated that imipramine is significantly more effective than placebo for treating both types of depression but with, relatively, lower effect in reactive depression. In term of safety, the number of subjects suffered from side effects (one kind or another) in imipramine group was significantly higher than those in placebo group suggesting that imipramine is not well tolerated ( Ball & Kiloh,1959, and Abraham et. al, 1963).
A recent meta- analysis by Arroll et al (2005) examined 15 out of 284 randomized, placebo-controlled trials which met the study criteria, of TCAs and SSRIs in primary care patients. Ten studies compared TCAs with placebo, three compared SSRIs with placebo, and two compared both with placebo. The authors electronically searched the Cochrane Collaboration Depression, Anxiety and Neuresis Group (CCDAN) register, MEDLINE, International Pharmaceutical abstracts, PsycINFO, and EMBASE up to February 2003 for any trial in which antidepressants were used in primary care. Pooling of the results was done using Review Manager 4.2.2. The meta-analysis revealed that “both TCAs and SSRIs are more effective than placebo”. However, bias may have occurred in some publications and many studies were small and with variable quality.
Comparison of Placebo with TCAs
On the other hand, Rogers and Clay (1975) statistically reviewed thirty controlled trials comparing imipramine with placebo in the treatment of depression in adults. They classified the trials according to type of patients (out or in-patients), type of depression (endogenous, neurotic, or mixed), and state of depression (acute or chronic). The results of the review indicated that only 10 trails (33.3%) provided the evidence that imipramine is significantly more effective than placebo, whilst the rest 20 trials (66.6%) failed to demonstrate that imipramine is significantly better than placebo in the treatment of depression in adults (Rogers & Clay, 1975).
Another study that suggests that there is no significant difference in efficacy between placebo and TCAs is that of Brimaher et. al,(1998). The objective of this randomized, placebo-controlled trial was to assess the response of adolescents with MDD to TCAs- amitryptyline. Twenty seven DSM-III-R nonpsychotic MDD adolescents, aged 12-18 years met the inclusion criteria of the trial. Subjects were admitted to a state hospital and randomized to either a maximum of 300mg/day amitriptyline ( n=13) or placebo (n=14) for 10 weeks. Symptoms were assessed using the mood disorders section of the Schedule for Affective Disorders and Schizophrenia for School Age Children-Present Code (K-SAD-P), HAM-DRS score ≥ 15, CGI, BDI, DSM-III-R, a side effect check list, and CGAS. The results of the trial revealed that both treatment groups demonstrated a similar decrease in the HAM-DRS and BDI scores from the time of baseline assessment to the time of randomization. Therefore, the researchers found that TCAs and placebo have the same efficacy in the treatment of MDD in adolescents (Brimaher et. al, 1998)
A study by Lyketos, Taragano, Treisman, & Paz (1999) demonstrates that sertraline can be effective when used both in the primary care and the psychiatric setting. This is one of the few experiments that have evaluated a psychiatric drug in these two settings. This was an open label treatment study. The subjects were diagnosed with Major Depressive Disorder. There were 469 patients in primary care and 299 psychiatric patients. The patients were treated with 50-1000 mg of sertraline a day for eight weeks. Prior to the study the groups did not differ in their severity of depression as indicated on the Hamilton Depression Rating Scale. Subjects had to score at least 10 points on this scale. The patients were made up of both male and female participants. Additionally the patients met DSM-IV (Diagnosis and Statistical Manual of Mental Disorders) criteria for Major Depressive Disorder. “After eight weeks of treatment, mean Hamilton Depression Rating Scale scores were reduced comparably in both groups, from about 25 to about 10. Adherence with treatment was high in both groups, over 95%” (Lyketsos et al. 1999, p. 70). However, the psychiatric patients required a higher dose of sertaline in order to improve. Additionally, this study discovered that the most common site of major depressive treatment is the primary care setting (Lyketsos et al. 1999).
In 2001, Keller and colleagues conducted a randomized controlled trial to compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression. 425 male and female adolescents were screened for eligibility, and 275 subjects, aged 12 through 18, met the entry criteria were randomly assigned to either 8 weeks of double blind paroxetine ( 20 to 40 mg/day), imipramine (50 to 400mg/d) or placebo. The two primary outcomes of the trial were (1) response; which was defined as a HAM-D score of ≤ 8 in the scale of 17 items or ≥ 50% reduction in baseline HAM-D at the end of the treatment, and (2) change from baseline in HAM-D total score. In this trial those adolescents administered paroxetine evidenced significant reduction in depressive symptoms compared to placebo or imipramine. The most common side effects of the paroxetine group were gastrointestinal symptoms, insomnia, somnolence, headache, dizziness, and tremor. For imipramine group, cardiovascular (eg. tachycardia, orthostatic hypotension and ECG changes), gastrointestinal symptoms, headache, dizziness and tremor were the most common side effects. As a result, the researchers indicated that paroxetine is safer and more tolerable than imipramine in the treatment of adolescent depression.. Furthermore, the response to imipramine was not found to be significantly different from placebo ( Keller et al., 2001).
Another double-blind, randomized, placebo-controlled clinical trial were conducted by Emslie and colleagues in 1997 to investigate the effectiveness of fluoxetine in children and dolescents with depression. Ninety-sex adolescent and child, aged 7 to 17 years, with MDD (DSM-IV) were randomized to fluoxetine ( 20mg/d) and placebo for 8 weeks. Primary outcome measurements of the protocol were the global improvement of the Clinical Global Impression Scale (CGIS) and Children’s Depression Rating Scale (CDRS). The results revealed that fluoxetine was significantly more effective than placebo in the treatment of MDD in child and adolescent. Differences in efficacy and safety between fluoxetine and placebo became statistically significant after the fifth week. The researchers stated that “ a 20mg/day of fuoxetine is an effective and safe therapy for treatment of major depressive disorder in child and adolescent”( Emslie et. al, 1997).
Stahl, Entsuah & Rudolph (2002) complied data from eight double-blind studies. The studies compared the efficacy of venlafaxine, SSRIs, and placebo. The studies were randomized and looked at mean changes in the Hamilton Rating Scale for Depression ( HAM-D), Montgomery-Asberg Depression Rating Scale ( MADRS), and the Clinical Global Impression Scale( CGIS). The study demonstrated that these antidepressants were effective treatments for individuals diagnosed with depression. The researchers stated “Statistically significant differences in mean HAM-D scores decrease between venlaxaxine and SSRIs and between the active treatments and placebo were observed. Venlafaxine significantly decreased the mean Montgomery-Asberg Depression Rating Scale ( MADRS ) scores more than SSRIs and both treatments were significantly better than placebo” (Stahl et al. 2002, p. 1166). Even though this study asserted that venlafaxine was superior to SSRIs for the treatment of depression, it demonstrated that SSRIs were also an effective treatment for depression.
Effectiveness of SSRIs
Another study that suggested that SSRIs are an effective treatment for depression is that of Greenberg, Bornstein, & Fisher (1992). The objective of the study was to clear up misunderstandings about experimental designs that have yielded results suggesting that antidepressant medications are no more effective than placebo but were reportedly methologically flawed. The studies reviewed showed that antidepressants are superior to placebo. It was demonstrated that the studies were not flawed and that did indeed “prove” that antidepressants are superior to placebo. The studies under question, however, did not use active placebos and therefore allowed the researchers to guess, more than by chance, who was receiving medications or placebo (Greenberg et. al, 1992).
A meta-analysis by Entsuah, Huang & Tase (2001) examining eight double-blind, randomized, active-controlled clinical trials suggested that SSRIs are effective for treating depression. The studies looked at adults ranging in age from 18 to 83. These individuals all met either the DSM-III or the DSM-IV diagnosis for Major Depression Disorder. The total number of subjects in the studies was 2045. These subjects were randomly assigned to received venlafaxine, immediate release (474 subjects), extended release (377 subjects), one of several SSRIs (748 subjects), or placebo (446 subjects). The outcome measures used was the Hamilton Rating Scale of Depression (HAM-D). Remission was defined as a Hamilton Rating Scale of Depression score ≤ 7. A response was defined as a 50% decrease in the HAM-D 21 score. Absence of depression was defined as a Hamilton score of zero. It was found that both SSRIs and Venlafaxine were significantly more effective than placebo in lessening depressive symptoms (Entsuah et al. 2001).
Studies in this area have also focused on studying elderly individuals with depression. Doraiswamy, Krishnan, Oxman, Jenkyn, Coffey, Burt, & Clary (2003) pooled data from two studies examining the effects of sertraline, fluoxetine, and nortriptyline on two cognitive measures. A total of 225 women and 185 men, age 60 and older participated in two different studies. All participants met the DSM-III-R criteria for major depressive disorder and had a Hamilton Depression Rating Scale score of 18 or higher. In one study, participants were randomly assigned to receive either 50 mg of sertraline or 20 mg of fluoxetine for 12 weeks. In the other study, participants were randomly assigned to receive either 50 mg of sertraline or 25 mg of nortriptyline for 12 weeks. In the second study, the sertraline was increase by increments of 50 mg every three weeks based on clinical response and tolerability, with a maximum dose of 150 mg. The nortriptyline was increased by 25mg weekly if needed to a maximum of 100 mg daily.
Two cognitive measures were given to participants. The first test administered was the Shopping List Task (SLT), which is also known as the Buschke-Fuld Selective Reminding Test. It has been standardized and is able to assess short-term and long-term memory as well as retrieval. Scored items are: number of items recalled, size of the learned list, and number of items retrieved from long-term storage. For the study, a 12 item list of words was red at a rate of one word every one to two seconds. Following this, each participant was asked to immediately recall the list. Any words missed were re-red to the participant, who was then asked to again recall the whole original list. Six trials were conducted. Any items recalled on two consecutive trials without any reminding were considered to be from long-term storage, while any others recalled after prompting were considered to be from short-term storage. The second test administered was the Digit Symbol Substitution Test (DSST), which is a subtest from the Wechsler Adult Intelligence Scale, which determines motor performance, coding, and visual tracking. The participant is presented with digits 0-9 arranged in rows. In a space below each digit the participant is required to write a symbol that corresponds with that number, based on a key at the top of the page.
A total of 217 patients took sertraline, 119 took fluoxetine, and 104 took nortriptyline. For the sertraline patients, the average daily dose at the end of the study was 83.8 mg, 29 mg for fluoxetine, and 70.8 mg for nortriptyline. All participants were given both pre-treatment and post-treatment tests. Results indicated that both sertraline and fluoxetine positively affected performance on the DSST and the SLT between pre and post measurements. The authors did mention that the memory and DSST scores in these patients averaged in the mild-to-moderate impairment range of scores. Cognitive impairment was positively correlated with the baseline score of depression severity and older age. Doraiswamy et al. (2003) reported that three months of treatment with antidepressants improved cognitive function in these individuals. Specifically, both of the SSRIs (sertraline and fluoxetine) had greater improvement in cognitive ability at the endpoint of treatment than nortriptyline. Also, among those who responded to treatment, the largest magnitude of improvement in functioning was in individuals with the most impairment in baseline functioning. However, even at the endpoint of treatment, these individuals (with the most improvement from baseline to post-treatment) still performed a mean score considerably worse than the mean score for the total sample. Finally, sertraline consistently demonstrated a greater degree of cognitive improvement in the patients with the worst impairment. The authors conclude that there may be noticeable differences between antidepressants in terms of DSST and SLT performance at the end of 12 weeks of medication treatment.
To determine improvement in depression, the Clinical Global Impressions Severity and Improvement ratings (CGI-S and CGI-I) were given. The authors reported that improvement was “most consistently related to cognitive improvement in those treated with sertraline”. The correlation was weakest for those participants who took fluoxetine and intermediate for those who took nortriptyline. Two possible mechanisms for change in cognitive functioning were discussed. One mechanism being a direct effect on neurotransmitters caused by the antidepressant’s pharmacologic actions, the other being a secondary effect caused by the improvement in depression.
Fairweather, Kerr, Harrison, Moon, & Hindmarch (1993) examined 60 elderly individuals with depression. All participants were over the age of 60 and had an average score of 16.9 on the Hamilton Depression Rating Scale. Participants were randomly assigned to one of two groups, fluoxetine or amitriptyline. The medication was administered to both groups for 42 days. Individuals in the fluoxetine group received 20 mg per day while individuals in the amitriptyline group received 75 mg per day. A battery of tests was given to all participants seven times. A baseline was conducted previous to the implementation of any medication. Following the beginning of medication, the battery of tests was given weekly for six weeks. The battery of assessments included the Montgomery-Asberg Depression Rating Scale (MADRS), the Critical Flicker Fusion Threshold (CFF), Choice Reaction Time (CRT), a Sedation rating scale, and the Leeds Sleep Evaluation Questionnaire (LSEQ). The CFF is a measure of arousal in the central nervous system, allowing for a prediction of mental alertness and cognitive potential. The CRT is a measure of sensorimotor reaction to a stimulus.
Results indicated that both medications significantly reduced depression scores across time, as indicated by the HAM-D and the MADRS. After one week on medications, shorter response times were observed in the group that received fluoxetine compared to amitriptyline. However, this difference was not significant at other measurement dates. Also, there were no significant differences in response time on components of the CRT task. There were no significant differences between groups on a tiredness scale. However, participants taking fluoxetine reported being less drowsy than the other group, significant only at weeks one and two. Onset of sleep was significantly different only in week one, those taking amitriptyline had a faster onset of sleep. The authors conclude that fluoxetine does not generate a behavioral toxicity as seen in elderly patients taking psychoactive drugs.
Schmitt, Kruizinga, & Riedel (2001) compared the effect of two SSRI’s, sertraline and paroxetine, on cognitive performance. Twenty-four healthy individuals (13 males and 11 females) were recruited through advertisements to participate in the study. All were carefully screened and only included in the study if they scored below a 50 on the Zung Depression Scale as well as met several health standards (such as good heart condition, not pregnant, no medications, etc.). Participants were randomly assigned to receive all of the following in some order: paroxetine( 20mg of for days 1-7 then 40mg for days 8-14) or sertraline( 50mg for days 1-7 then l00mg for days 8-14), and placebo. The study was a three-period cross-over design, with each treatment period lasting 14 days, and each wash-out period lasting 14 days. One week prior to beginning medication, participants were given the complete cognitive battery to minimize learning effects. Assessments were again given on day 0 (the day before medication began), day 7, and day 14.
The assessment battery consisted of three tests. First was the Visual Verbal Learning Test (VVLT) in which 15 words are presented in the same order in three trials on a computer monitor. After each trial the participant is asked to recall as many words as possible, to determine immediate recall. Thirty minutes later they were asked to again recall as much as possible to determine delayed recall. Following delayed recall, a recognition task was given, which included the original list as well as another set of 15 words for a total of 30 words. The participant was asked to quickly identify the fifteen that were in the word list. Next, a Verbal Fluency Test was given to measure semantic memory. Participants were asked to provide as many four-letter words beginning with a certain latter as possible in one minute. In a comparative study, the average number of words provided per letter was 10.1-11.0 words. Finally, a Memory Scanning Task required participants to view a set of one or three letters and asked to memorize them. They then saw a series of 75 letters, each of which was displayed on a computer screen for 1000 ms with a 2000ms break before the next letter. Half of the letters presented were part of the memory set the participant had been asked to remember. The participant was then asked to determine “yes” or “no” if the letter was part of the memory set by pressing the appropriate button.
Independent variables for the study are type of medication (sertraline, paroxetine, or placebo) and amount of time on medication (0, 7, or 14 days). Results for the VVLT indicated no difference for immediate recall between sertraline, paroxetine, or placebo at baseline or either dose level. The 30-minute delayed recall showed a main effect of treatment, but no main effect for time or treatment by time interaction. Paroxetine impaired memory in that there was a reduced number of words recalled when compared to sertraline and/or placebo. The recognition task showed no treatment, time, gender, or treatment by time effects. For the verbal fluency task, there was no main effect of treatment, time or gender. There were no significant differences between treatments on the memory scanning task.
Timoshanko, Stough, Vitetta, & Nathan (2001) examined the impact of hypericum, commonly known as St. John’s Wort, on cognitive performance. Seven males and six females ages 19-33 with no history of physical or mental disorders were recruited for the study. The 24 hours prior to testing, participants were not allowed any alcohol or caffeinated beverage. Two hours before testing participants were given a light, caffeine free, fat free breakfast. The study was double-blind and included four conditions: a placebo condition, two levels of hypericum (900 mg and 1800 mg), and one level of amitriptyline (25 mg). There was a seven-day washout period between each condition. Prior to the actual study, all participants were trained and familiarized with testing methods to prohibit any learning effects. Participants were given a battery of tests (which were counterbalanced) at one, two, and four hours after dosing. The battery included the CFF, CRT, Trail Making Test (TMT), Digit Symbol Substitution Test (DSST), Line Analogue Rating Scale for Sedation (LARS), and the Profile of Moods Scale (POMS). The TMT measures motor speed and tracking ability- both visual conceptual and visuomotor. Visual-motor coordination and speed were also assessed by the DSST. The LARS was used to determine mental sedation (ranging from drowsy to alert) and physical sedation (ranging from lethargic to energetic). Because mood can be affected by drugs, the POMS was administered to determine possible changes due to medication.
For treatment X time interactions, there were significant results on the CFF, DSST, TMT (part B), LARS (physical), and POMS. There were no significant overall effects on the TMT (part A) or the LARS (mental). When placebo and amitriptyline were compared, there was a significant impairment on the CFF, CRT, DSST, TMT (part B), POMS, LARS (physical), and LARS (mental) in participants taking amitriptyline (25 mg). In comparing 900 mg and 1800mg of hypericum to placebo, there were no significant differences on the CFF, CRT, TMT (parts A and B), POMS, or the LARS. In the 1800 mg dose of hypericum there was, however, a significant decrease in DSST.
Koetsier, Volkers, Tulen, Passchier, van den Broek, & Bruijn (2002) studied the Continuous Performance Test (CPT) performance in individuals with major depressive disorder taking either imipramine or fluvoxamine. The study, conducted in the Netherlands, included 52 depressed inpatient participants during a drug-free period and 73 healthy controls. Depressed participants, as determined by the DSM-IV criteria for major depressive disorder, had been admitted into the depression unit of a hospital in Rotterdam and were then enrolled in the study. Twenty depressed participants were male (average age 52 years) and 32 depressed participants were females (mean age 52.8 years). The control group was composed of 36 males, average age 39.8 years and 37 females, average age 39.6 years. All depressed participants (n=52) were either given imipramine or fluvoxamine, while the control participants did not receive any medications. Doses were adjusted weekly, ranging from 200-300mg for imipramine and 150-200 mg for fluvoxamine. The average dose for imipramine was 220.7 mg, and 201.0 mg for fluvoxamine. The authors reported that the CPT was conducted once during the medication free period and again after four weeks of “adequate treatment”.
The CPT was administered in the morning via a computer. The task required respondents to view the screen while random letters (A, C, E, S, and T) flashed individually in the center of the screen. Anytime the letter “S” appeared on the screen, the subject was to respond as quickly as possible by pressing a button. Letters appeared for five minutes at the rate of one per second. Reaction time, total number of omission errors (failure to respond to target letter), and commission errors (response to a non-target letter) were measured. CPT performance was measured twice, once before drug administration and then again after four weeks of treatment. Caffeine and nicotine were not allowed the evening before the measurement to eliminate stimulating effects.
Depressed, unmedicated participants had significantly higher omission errors, commission errors and reaction times than the unmedicated controls. After four weeks of treatment via drugs, CPT performance improved (from baseline performance) in both imipramine and fluvoxamine groups. There was a significant decrease in reaction time after treatment for both groups. Both groups demonstrated reduced omission errors, yet this was only significant for the fluvoxamine group. There were no significant differences between groups in the number of commission errors.
The study of antidepressants and cognitive performance has also included the examination of memory specifically. Thompson (1991) conducted a literature review of the research on several antidepressants. Thompson listed 15 studies that examined the effect of amitriptyline on memory tasks. One study reported improvement on a set of tasks (Sternberg and Jarvik, 1976 as cited in Thompson, 1991). However, seven of the remaining 15 studies indicated impairment on various memory tasks. Specifically, McNair et al. (as cited in Thompson, 1991) reported that amitriptyline at an average daily does of 116 mg for three weeks was correlated with impairments on learning and memory. In Thompson’s review of studies involving imipramine, only one of 12 studies reported impairment of memory. Whereas eight reported no effect and the remaining three studies actually reported improvement in memory performance. Thompson reviewed six studies on doxepin and cognitive and psychomotor performance. Four of these studies did not examine memory specifically, and of the four, three studies reported impairments following the drug.
Thompson (1991) also included information on 5-HT reuptake inhibitors Zimeldine, Trazodone, Fluvoxamine, and Fluoxetine. Two studies investigated Zimeldine, which is no longer available due to toxic side-effects, however when investigated no effects on cognitive learning tasks were found. One of two studies on Trazodone found impairments on memory tests such as free recall, digit span, semantic recall, and news recall. There were no effects on memory for participants taking fluvoxamine in three studies, a fourth reported improvements. And finally, a study by Moskowitz and Burns (1988, as cited by Thompson, 1991) found no significant impairments on memory for words and numbers in participants taking fluoxetine.
The effects of medications on cognitive performance have not only been examined in depressed patients, but in anxious patients too. Jensen, Hasle, & Birket-Smith (1997) studied 30 patients with diagnoses of panic disorder without agoraphobia (PD, n=8), agoraphobia with panic attacks (AGOR, n=12), generalized anxiety disorder (GAD, n=7), and anxiety disorder not otherwise specified (ADNOS, n=3). The average age of participants was 43.2, with an average length of illness of 8.3 years. The total group of participants was divided into medicated and un-medicated patients at the time of testing. Nine of the participants took benzodiazepines. Of those nine, four people took them in combination with antidepressants, two in combination with neuroleptics, one in combination with both antidepressants and neuroleptics, and two without any other drugs. Three participants took solely antidepressants and three took solely neuroleptics. Thus, a total of half (n= 15) of the participants were medicated. A control group, six men and six women, had an average age of 42.8.
Cognitive performance was measured using a word pairs test, visual gestalts test, and a word fluency test. The word pairs test was comprised of ten pairs of words. Participants were asked to recall one word after being given its pair immediately after the initial presentation of the pair, one hour later, and one week later. The visual gestalts test included four complex figures that were each presented for ten seconds. The participant was then given a shape to prompt a gestalt to draw. For the gestalt task, the immediate and delayed categories were the same as for the word pairs test. For the word fluency test, the participant was asked to produce as many words as possible in 45 seconds for each of three different categories; animals, “m” words, and words used to describe emotional states.
Results indicated that on the word pairs test, the effect of group was only marginal for the immediate recall. After the one week delay, there was a significant difference between groups, with the rate of forgetting being greater in the anxious participants than the control group. For the visual gestalts test, the medicated participants had lower performance score when compared to the un-medicated and the control groups. In the delayed (one hour and one week) sessions, both anxious groups had poorer memory when compared to the control group. On the word fluency test there were no significant differences between any of the groups for any conditions.
Recently the effect of antidepressants on driving ability has also been studied. Wingen, Ramaekers, & Schmitt (2006) recruited 24 depressed patients who were taking an SSRI or venlafaxine (an SNRI) ranging from 6-52 weeks. They compared these individuals to 24 healthy control participants who matched the depressed/medicated group on lifestyle, demographics, and health history. Participants in the control condition were not on any medications other than oral contraceptives. Of the medicated participants, four were taking citalopram, four were taking sertraline, eight were taking paroxetine, and eight were taking venlafaxine. No other psychoactive medications were allowed. Two of the participants were concurrently taking an antihypertensive medication as well.
A training day was given to participants to practice the driving and cognitive tests as well as procedures and test instructions. The complete testing day with breaks required about four hours to complete. A road tracking test required participants to operated a vehicle on a highway while maintaining a speed of about 58 mph as well as a steady lateral control (keeping the car within the lane boundaries). A measure of lateral position was taken to determine the SDLP (Standard Deviation of Lateral Position), essentially the amount of weaving, overcorrection and swerving. Participants were also measured on their ability to drive 15-30 meters behind another car, which was controlled by the researchers. Time to speed adaptation (TSA) was measured in milliseconds as well as reaction time to brake lights (the participant was asked to remove his/her foot from the gas pedal as fast as possible in reaction to the forward car’s break lights). Cognition was measured using a short- and long- term memory function, a visual scene analysis for memory (a series of 100 photographs from various traffic situations to which participants reported changes in traffic scenes), a stroop task, CPT, and critical flicker fusion threshold.
An ANOVA revealed that SDLP was significantly higher for medicated participants than controls. The TSA was also significantly impaired in medicated participants as compared to healthy controls. However, the brake reaction time, speed and headway did not differ significantly between groups. The average score for the critical flicker fusion threshold was significantly lower in medicated participants versus controls. The accompanying driving instructor rated all drivers; the perceived level of alertness and driving quality was not significantly different between groups. However, the self-ratings of driving ability were significantly lower in the medicated group than control group. The variables SDLP, TSA, average critical flicker fusion threshold frequency were not significantly different when the two types (SSRI versus SNRI) of antidepressants were compared.
Another study investigating the effect of medications on driving performance was conducted by van Laar, van Willigenburg, & Volkerts (2005). The researchers included 24 healthy volunteers to participate. Half of the participants were considered adults and ranged in the ages of 24-38 years old. The other half of the participants were considered elderly with an age range from 60-72 years old. Each group had six males and six females. Participants were given an oral dose of either Imipramine, Nefazodone, or placebo two times per day, 12 hours apart. Participants were dosed for seven consecutive days with testing being given on days one and seven. Before beginning the study, all participants were given a practice run through with the driving test and then five training sessions to attain a baseline as well as reduce practice effects.
The dependent variables for their study included a road driving test, self-ratings of driving, and a psychomotor test battery. The “Over-the-Road” driving test required participants to maneuver a vehicle over a 100 kilometer circuit of a two-lane highway while attempting to maintain a constant speed of 90 kilometers per hour as well as a steady position within the right lane. This lasted about 75 minutes. Next, participants then rated themselves on their perceived driving quality, level of effort, and level of mental activation. Finally, a 33 minute psychomotor test battery was given to each participant. The first part of the psychomotor testing was a letter matching task requiring subjects to determine if two simultaneously-presented letters matched (vowels versus consonants). A memory scanning task was then given, which was a string of digits presented at one per second. A probe digit was then presented one second after the string of letters. Participants were asked to decide if the probe digit was given in the memorized list. The third psychomotor task was a letter/digit differentiation task. Participants needed to determine if the item presented was a letter or digit.
Analysis of the data from Day One revealed that the effect of Imipramine was significantly different between the age groups in that the Imipramine caused a significant increase in SDLP (Standard Deviation of Lateral Position) in the adult group. In contrast to this, the single doses (l00mg and 200mg) of Nefazodone showed minor improvement in driving performance which were not significantly different between age groups. By day seven the Imipramine impairment had diminished but was still significant compared to the placebo. Also by day seven, the l00mg dose of Nefazodone was no longer significantly different than placebo; however, the 200 mg dose did produce a slight impairment in driving ability. On Day One there were significant differences between those taking Imipramine in self-rating of driving, the adults rated themselves as driving worse than normal whereas the elderly participants were not significantly different from the placebo. The average reaction time was higher in the elderly group than the adult group in nearly all of the conditions, which was expected as there is a decline in processing speed with an increase in age.
Suicidal behavior and antidepressants
Severe headache and psychiatric illness are statistically associated with suicidal thoughts or behavior (Guillem, Pelissolo andLepine, 1999). Some authors have suggested that psychiatric illness is a necessary precursor for suicidality, which suggests that the apparent association between severe headache and suicidality may be due to confounding by psychiatiric illness. However, results of a previous study suggested that psychiatric illness does not entirely explain the risk of suicidality associated with severe headache (Breslau, Davis, and Andreski, 1991). Depression is the psychiatric illness most often cited in the development of suicidality (Mann, Waternaux, and Malone, 1999). One previous cross-sectional study examined the association between migraine headhache and suicidal indeation or attempts while controlling for co-morbid depression and other psychiatric illness (Breslau, Davis, and Andreski, 1991). In that study, in the absence of major depressive disorder (MDD), respondents who had migraine were more likely than those who did not have migraine to want to die, think about committing suicide, and attempt suicide. The investigation controlled for mania, dysthymia, anxiety disorders and substance abuse or dependence. No study has restated this association although many past studies have shown that physical pain of any type is associated with increased suicidality (Fishbain, Goldberg and Rosomoff, 1991).
Recent studies have also investigated whether there is any association between the use of antidepressants and suicidal thoughts or behavior. One such study conducted by Milane and his colleagues (2006) investigated this association with two hypotheses: (a) antidepressants stimulate suicidal thoughts and (b) antidepressants help in reducing suicidal behavior. However, the researchers found that antidepressants positively reduced the suicidal thoughts significantly (Milane et al., 2006). Similarly, another study by Arif Khan and his colleagues (2003) analysed the relationship between antidepressants and suicidal behavior through clinical trial data for nine antidepressants (fluoxetine, sertraline, paroxetine, venlafaxine, nefazodone, mirtazapine, sustained-release bupropion, extended-release venlafaxine, and citalopram) pertaining to the period from 1985 and January 2000. This research also failed to find the correlation of antidepressants and the suicidal behavior or thoughts. Thus, it can be concluded that instead of stimulating patients with severe depression for suicide, the use of antidepressants reduce the risk of suicide in them.
Baune (2006) conducted a research in order to seek relationship between antidepressants and suicidal behavior. The study has two underlying hypothesis: (1) (1) antidepressants can trigger suicide and subsequently increase suicide rates, and (2) through the treatment of depression with antidepressants, suicide rates decline over time. For this purpose, the data was collected from the National Vital Statistics System from 1960 to 2002. The findings suggested there was an inverse correlation between suicide rates and the prescription of fluoxetine. Thus, the hypothesis that antidepressants can trigger suicide and subsequently increase suicide rates was not supported.
Another study by Carlos et al., (2005) utilized the nested case study in primary care setting in the UK in which there were 146 participants. The purpose of this study was to compare the risk of suicide taking SSRIs and the tricyclic antidepressants. The main findings of this study were:
- In adults, there was no difference between SSRIs and tricyclic administration and relationship with suicidal behavior.
- In children, the likelihood of suicide was significant with SSRIs as compared with tricylic antidepressants.
- The most significant finding of this study was that “no children taking antidepressants in this study committed suicide” (Carlos et al., 2005).
The systematic overview of these studies suggests there is no correlation between administration of antidepressants and suicidal behavior.
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CHAPTER III
DISCUSSION AND CONCLUSION
Introduction
In the previous chapter a detailed review of the studies has been presented. These studies were chosen on the bases of their relevance to the topic, fulfilling the criteria of reliability and validity and their experiment nature. This chapter discusses the findings of these studies and offers conclusions.
Discussion
The results of the current research have several significant findings. It seems as though individuals taking an antidepressant are just as able to complete the tracking task with divided attention as those not taking any medications. The results of the meta-analysis reveal that that individuals taking an antidepressant perform significantly different than those taking no medications on a driving task but not on a tracking task. Recently, Lau, Christensen, Hawley, Gemar, & Segal (2007) found depressed individuals scored worse on an inhibition task than a control group. Koetsier et al. (2002) also found that unmedicated, depressed individuals had more commission errors (inability to inhibit a response) on the CPT. These findings suggest that the inhibition difficulties are due to depression, not medication. Yet Koetsier et al. (2002) found that performance on the CPT (a sustained attention task) improved in depressed individuals taking imipramine and fluvoxamine. The authors also found that depressed, unmedicated participants did have higher commission errors, omission errors, and reaction times, supporting the notion that depression, not medication, reduces ability in these cognitive tasks. Brunnauer et al. (2006) found that depressive patients treated with TCAs displayed more impairment than depressed patients treated with mirtazapine or SSRIs supporting the idea that certain antidepressants (TCAs) do impair reaction time and visual perception.
Ball and Killoh (1959) and Abraham et. al (1963) found that imipramine is significantly more effective than placebo in treating depression. Moreover, a meta-analysis by Arroll et. al (2005) revealed that TCAs, as well as SSRIs, are significantly better than placebo in the treatment of depression in primary care. On the othe hand, imipramine failed to prove superiority to placebo for treating depression in 20 clinical trials according to a statistical review by Rogers and Clay’s (1975) and a clinical trial by Keller et.al (2001). Moreover, a study by Brimaher et. al (1998) suggested that there were no difference in efficacy between TCAs and placebo in treating adolescents with MDD.
Numerous studies have reported that SSRIs are significantly more effective than placebo in treatment of major depression in adults ( Arroll et.al, 2005; Entsauh et. al, 2001; Greenberg et. al, 1992; and Stahl et. al, 2002) and adolescents ( Emslie et. al, 1997 and Keller et. al, 2001).
Ferguson, Wesnes, and Schwartz (2003) found inhanced performance in depressed individuals taking reboxitine for both speed and attention measures. Hindmarch (1998) found that reboxitine did not affect (improve nor hinder) performance. His study found no differences on a tracking task, reaction time, or the CFF (Critical Flicker Fusion threshold). However, Sherwood & Hindmarch (1993) found that the antidepressants dothiepin and amitriptyline caused impairments on a tracking task, a reaction time task, and the CFF whereas lofepramine, fluoxetine and paroxetine did not cause impairments. Dothiepin, amitriptyline, and lofepramine are TCAs, while fluoxetine and paroxetine are SSRIs. Constant et al. (2005) found no differences between depressed individuals taking sertraline and healthy controls on the Stroop task. However, they did find that the depressed (also medicated) group did have slower reaction times than the control group (not depressed, not medicated) on an alertness task. The research has found that while taking some medications, individuals perform better on cognitive tasks, and while taking other medications, individuals may actually perform worse on some cognitive tasks.
Some individuals not only take just one antidepressant but several other kinds of psychotropic medications such as trazedone, rozerem, neurontin, tramadol, flexeril, chonazepam, cyclobenzaprine. Thus, differences between groups can possibly be due to other types of medications that participants taking as all of the medications listed can cause drowsiness. Thus, a future study might seek to compare individuals taking different types of depressants who are not currently on any other type of medication.
Limitations of the Study
A significant limitation to the study is that differences between groups taking one kind of antidepressant and the ones taking multiple type of medication have not been studied. Thus, it is hard to predict the results of a particular medication. As a result, the significant differences between groups could possibly be due to the differences in their moods. Depressed individuals may have concentration and decision making difficulties; therefore it is very possible that mood may be correlated with the performance differences, not medication use. A future study might recruit individuals taking antidepressants, individuals not taking any medications but do qualify for depression, and individuals who are on no medications and do not qualify for depression. If possible it would be beneficial to include individuals on antidepressants who do not qualify for a diagnosis of depression. This research supports previous findings that depression and/or antidepressants are correlated with diminished cognitive performance. Further research should seek to differentiate the effects of mood and medication on several types of cognitive performance. Implications of such research could benefit several individuals in various occupations as well as increase safety not only for depressed and/or medicated individuals but for those affected by their actions (driving, flying, etc).
Conclusion
From the studies reviewed, it can be concluded that both SSRIs and CBT work better than placebo in treating major depression in adults and adolescents. It appears that SSRIs are as effective as TCAs, but the superiority of TCAs to placebo remains unsurpassed. As far as safety is concerned, SSRIs are considered better and more tolerable than TCAs due to safer side effects and lower risk of cardiotoxicity, and lack of lethality in the event of overdose, which makes SSRIs the drugs of choice in the treatment of depressive disorders in clinical practice.
A further significant finding of this research is the inverse association of suicidal though or behavior with the antidepressants as the use of antidepressants can help reduce the risk of suicide among the depressed adults.
The assertion that CBT is effective is supported by Ellis, Hickie, & Smith (2003). They conducted a study that highlighted some treatment guidelines from the National Health and Medical Research Council (NHMRC).
Finally, the researchers support the use of both cognitive-behavioral therapy and interpersonal psychotherapy to decrease depressive symptomology. It can be asserted, “The most important factor in the management of depression is to maintain compliance with an effective treatment” (Ellis, Hickie, & Smith, 2003, p. 37).
