IB Docs (2) Team
GAD: Biological treatments
Biomedical approaches to treatment are based on the assumption that if the problem is based on biological malfunctioning, drugs should be used to restore the biological system. For example, since GAD is assumed to involve an imbalance in neurotransmission, then drugs that increase GABA levels in the brain may be an effective treatment. Although researchers know more than ever about how the brain regulates mood, stress, their understanding of the biology of anxiety is far from complete.
Introducing drug therapy
Watch the following short video as an introduction to the drugs discussed in this chapter.
Answer the following questions based on information in the video.
1. In addition to GABA, which other two neurotransmitters does the narrator mention in connection to medication for anxiety?
Serotonin and noradrenaline.
2. What are the advantages of drugs that affect the levels of these two neurotransmitter
They are not addictive and do not lead to substance-use disorders, effective in reducing symptoms, and suitable for long term use.
3. What are the disadvantages of benzodiazepines?
They are only suitable for short-term use as they are addictive and can lead to substance-use disorder. Should never be taken with alcohol or opioids due to the risk of fatal overdose.
Benzodiazepines
Benzodiazepines, such as valium, are part of a class of drugs called anxiolytics or anti-anxiety drugs. These drugs elicit feelings of calm and tranquility. Sometimes used before surgery to relax the patient, they are also commonly used to help people cope following stressful life events and for treating anxiety disorders.
Biological psychologists believe the symptoms of anxiety are related to the noradrenergic system and the amygdala. Noradrenaline, an excitatory neurotransmitter, activates the amygdala, leading to feelings of fear or anxiety. In response to the activation of the amygdala, GABA, an inhibitory neurotransmitter, is released. These molecules bind to GABA receptors on the postsynaptic cell, triggering a rush of negatively charged chloride ions into the neuron. This leads to hyperpolarization meaning the cell becomes less likely to fire an action potential. Thus, GABA reduces feelings of panic and anxiety, ensuring that we do not become overwhelmed in stressful situations.
When people have low levels of GABA, feelings of anxiety do not subside as readily and drugs such as benzodiazepines can lend a helping hand. These drugs are called GABA agonists and they have a high affinity with a specific type of GABA receptor called the GABAA. They enhance the effects of naturally occurring GABA by opening the chloride channels more frequently. This increases the hyperpolarization of the postsynaptic cell, decreasing the likelihood of firing.
Evaluating benzodiazepines
A benzodiazepine called clonazepam has been found to be effective in the treatment of a range of anxiety disorders including agoraphobia and panic disorder. For example, Davidson et al. (1993) found that 78% of people with social phobia were much improved or better following a ten-week course of clonazepam compared with just 20% in the placebo group, (p<0.0001). Improvements were evident after just one week.
This said, unpleasant side effects are common including drowsiness, dizziness, and decreased concentration, all of which may impair functioning at school/work. Moreover, symptoms recur in around 90% of people who cease treatment, suggesting the drugs mask the symptoms without addressing the root cause. This underlines the importance of eclectic approaches, combining drugs and therapy.
Another major drawback of benzodiazepines is potential addiction. Tolerance may develop over time meaning increasingly high doses are required to experience the same benefits. Users may also experience withdrawal syndrome when attempting to reduce or stop taking these drugs, suffering from symptoms such as irritability, tremors, insomnia, anxiety, tingling, and sometimes seizures and paranoia, (Nolen-Hoeksema 2007).
Critically, benzodiazepines must never be combined with alcohol or barbiturates. These drugs also act on GABAA receptors, increasing the duration of chloride channel opening, and leading to long-lasting inhibitory effects that can be lethal.
These risks mean benzodiazepines are a second-line treatment that should only be offered if SSRIs or SNRIS (see below) have proven to be ineffective.
SSRIs and SSNRIs
SSRIs (e.g. paroxetine) are the preferred first-line treatment for anxiety disorders as they have fewer side effects and high efficacy, while SNRIs (e.g.venlafaxine) are often prescribed for generalized anxiety disorder. These drugs inhibit the reuptake of serotonin (SSRIs) or both serotonin and noradrenaline (SSNRS) and are generally more effective than benzodiazepines (Nolen-Hoeksema 2007). They block the transporter molecules in the pre-synaptic cell membrane, inhibiting the reabsorption of these neurotransmitters back into the cell for recycling. Blocking these pumps means more of the neurotransmitter remains in the synapse, increasing availability for post-synaptic binding.
Evaluating SSRI and SNRIs
In a 32-week longitudinal study, Stocchi et al. (2003) examined the probability of relapse following cessation of the SSRI paroxetine in people with generalized anxiety disorder. 652 participants took this drug daily for 8 weeks. Then, in a double-blind design, anyone who made a clinically significant improvement was randomly assigned to either the paroxetine condition or the placebo condition, i.e. they did not know whether they were taking the drug anymore or not. After 24 weeks, participants were reassessed; 40% of the placebo group had relapsed compared with only 11 % of the paroxetine group. It was concluded that paroxetine was well tolerated, safe for both short and long-term use, and significantly reduced relapse with continued use.
In a meta-analysis of 57 studies (n = 16 056) comparing the efficacy of SSRIs and SNRIs, Jakubovski et al. (2018) found that those taking SSRIs showed a significant benefit in comparison with those taking placebos from four weeks while this figure was reduced to just two weeks for those taking SNRIs. A dose-response relationship was observed for SSRIs - that is, the higher the dose the greater the improvement - but this was not true of SNRIs where lower doses were associated with the greatest efficacy. Higher doses of both drugs were associated with greater side effects leading to a lack of tolerance and non-compliance, but unlike benzodiazepines, SSRIs and SNRIs are not associated with addiction.
ATL: Critically thinking about research
One of the key concerns when looking at the effectiveness of drugs is what happens to all those studies that are not published because the findings are not significant? This leads to what we call publication bias.
Sugarman et al (2014) analyzed the effectiveness of paroxetine in the treatment of GAD and panic disorder in 12 clinical trials carried out by the drug manufacturer, GlaxoSmithKline. Of the 12 trials, four of them were not published in medical journals. In order to assess the improvement that the patients made in each study, they used the Hamilton Rating Scale for Anxiety where a top score of 56 represents severe anxiety.
At the beginning of the trials, the average scores in each sample were between 19 and 26 points. The clinical trials lasted 8 - 12 weeks with an average improvement of 11.1 points for the treatment groups and 8.8 points for the placebo groups. That is a difference of only 2.3 points on a scale of 56 points! In addition, in 79% of the cases, there was no difference between the scores of those that received the treatment and those that received the placebo. The effectiveness of the drug was even lower in the unpublished trials.
Questions
1. Why do you think that these results are so different from the meta-analysis done by Jakubovski et al (2018)? What questions would you ask the researchers in order to determine why there is a difference in the results of the two studies?
2. Why do you think that publication bias exists? Is this an intentional attempt by the pharmaceutical companies to mislead us - or is there another explanation?
Teacher only box1. Why do you think that these results are so different from the meta-analysis done by Jakubovski et al (2018)? What questions would you ask the researchers in order to determine why there is a difference in the results of the two studies?
The meta-analysis by Jakubovksi et al (2018) had a much larger pool of studies. It is also possible that the studies looked at different drugs that were all SSRIs or SNRIs. The study also only included published research. The unpublished research in Sugarman's study may have had a significant influence on the findings. We would want to know if there is any indication as to why these studies were not published. We would also want to know who may have sponsored the research in both studies.
2. Why do you think that publication bias exists? Is this an intentional attempt by the pharmaceutical companies to mislead us - or is there another explanation?
It is very common for students to believe that publication bias is an intentional attempt to manipulate public opinion. But actually, it is most likely much less sinister. Of course, conflict of interest may be a reason why a study is not published; for example, the publishers support a certain type of treatment and this study did not support it. It could also be the publisher's perceived (or real) lack of interest in a study that has inconclusive or insignificant results. It could also be because of the discussion in the study in which the researcher outlines methodological limitations that may be compromise the quality of the study.
Comparing the efficacy of biological and psychological treatments
Evidence to support the use of drugs compared with psychological therapies comes from a meta-analysis by Bandelow et al. (2015). This study examined three types of antidepressants, benzodiazepines, and a wide range of psychological treatments including CBT, psychodynamic therapy, and interpersonal therapy. Findings of 234 studies including over 37 000 people were analyzed and drug therapies were found to be more effective than psychological treatments (p < 0.0001).
Effect sizes were calculated as 2.25 for SNRIs, 2.15 for benzodiazepines, 2.09 for SSRIs, and 1.83 for tricyclic antidepressants, compared with an effect size of 1.29 for placebo pills. Medications were significantly more effective than placebos. Effects sizes for the psychological therapies were considerably lower, ranging from 1.56 for mindfulness and 1.03 for interpersonal therapy, and 0.83 for placebo psychological therapy. Psychological therapies were, therefore, more effective than placebos, but not as beneficial as medication. It was concluded, however, that given the many drawbacks of drug treatments, individuals must make their own decisions regarding whether to pursue pharmacological or psychological treatment.
Effect size
Many meta-analyses quote effect sizes as a way of comparing the efficacy of various treatments.
Effect size describes the size of the difference between the average score in one condition compared with the average score in the other condition. They are calculated by subtracting the mean score for the control group away from the mean score for the experimental group and dividing by the standard deviation of all the scores combined. This means that an effect size of 0.8 would mean that the average person in the experimental group scores 0.8 of a standard deviation higher than the average person in the control group, or more than 79% of the sample, (Coe et al. 2002).
ATL: Thinking about research
Stocchi et al. (2003) and Davidson et al. (1993) both used the Clinical Global Impressions-Severity of Illness (CGI-S) scores as a dependent variable in their studies. The CGI-S requires the clinician to answer the following question: “Considering your total clinical experience with this particular population, how ill is the patient at this time?”. Answers are given as ratings on a 7 point scale at the time of assessment where 1 is ‘not ill at all’ and 7 is ‘among the most extremely ill patients’.
What are the strengths and weaknesses of using a scale like the CGI-S to measure severity of symptoms?The CGI-S collects quantitative data meaning statistical tests can be employed to assess the significance of any changes in scores. Furthermore, scores are assigned by a clinician thus avoiding problems with self-reported data, which can be hampered by the degree to which the participant has insight into the severity of their condition. This said, the clinician’s judgment is subjective and validity hinges entirely on the diversity of their past experience and the extent to which they have conducted detailed clinical interviews and observations in order to assess the individual. Also, the ratings refer only to the time at which the assessment is conducted whereby a person’s current suffering may depend upon the nature of their relationship with their assessor. Scores could also be affected by researcher bias if the clinician is aware of the individual’s treatment status. Furthermore, scores could be affected by factors such as the age, gender, or ethnicity of the individual.
The studies were randomized control trials or RCTs. What does this term mean and why is this an important design strength?
Participants are randomly assigned to two or more groups to test a specific drug, treatment, or other intervention. This is a strength as it decreases participant variables, which could otherwise limit internal validity.
The control groups in these studies took placebo pills and the designs are described as double-blind. What is meant by these terms and why are these design features a strength of studies such as this one?
A placebo drug looks, tastes, and smells exactly like the real drug, but does not contain the same active ingredient(s). The people taking the placebo will not know this and therefore should have the same level of expectancy, in terms of a reduction in symptoms. At the end of the trial, the symptoms experienced by both groups can be compared. If the experimental group improves more than the control group then this can be said to be due to the drug itself, as opposed to the expectation of improvement.
In a double-blind study, the participants do not know whether they have taken a placebo or the real drug and the researchers tasked with assessing their symptoms before and after the trial also do not know whether the person was in the experimental or control (placebo) group. This means the results cannot be affected by researcher-bias or expectancy effects.
The key strength of drug therapy is that for many people who suffer from anxiety disorders, it alleviates the symptoms that make day-to-day living difficult.
In spite of the strengths of drug treatments, there are also some rather serious limitations. One limitation is the problem of side-effects – the negative effect of using the drug itself. For example, SSRIs are known to have the following side effects in some patients: nausea, increased weight gain, loss of sexual desire, insomnia, blurred vision, constipation, dizziness, and anxiety.
Relying too heavily on drug treatments may lead to the neglect of important psychological or social factors that may play a significant role in the disorder. It can be argued that simply using a drug to treat GAD is a reductionist approach.
The use of drug therapies has increased the amount of out-patient care and decreased institutionalization.
Drug therapy shows results more quickly than psychological therapies. Often drug therapy is necessary so that the patient is able to engage in psychological therapy. Studies have often found that eclectic approaches to treatment that combine both drug and psychological therapy, may be the most effective treatment method.
This approach may neglect important social and cognitive factors that contribute to the disorder. Relapse rates tend to be high when patients discontinue the use of the drug. This may be the result of a failure to develop coping or social skills that are necessary for preserving mental health.
Drug therapy often has side effects. Sometimes these side effects can be misinterpreted as a symptom of the disorder - what is known as an iatrogenic effect.
Drug therapies may lead to addiction and to withdrawal symptoms when the use of the drug is discontinued. In addition, drug therapy may result in negative effects when used in combinations with other drugs or certain foods.
Checking for understanding
Which of the following neurotransmitters alleviates feelings of anxiety?
Answer: GABA is an inhibitory neurotransmitter that makes neighboring neurons less likely to fire and reduces the impact of excitatory neurotransmitters such as noradrenaline, which lead to feelings of panic and unrest.
Which of the following is not true regarding SSRIs as a treatment for anxiety disorders?
Answer: SNRIs are prescribed for generalized anxiety disorder whereas SSRIs are suitable for a wider range of anxiety disorders. They are not addictive like benzodiazepines and are a first-line treatment because the risks are reduced, e.g. fewer and less serious side effects and they do increase serotonin in the synapse as they block reuptake back into the pre-synaptic cell.
Which of the following is not true regarding benzodiazepines?
Answer: Alcohol and barbiturates bring about similar feelings to benzodiazepines by increasing the duration of calcium channel opening on the GABAA receptors. Benzodiazepines also bind to GABAA receptors but increase the frequency of calcium channel opening thus enhancing the natural effects of GABA. They are addictive and this is why they are a second-line treatment.
Which of the following drugs is not used to treat anxiety?
Answer: In addition to benzodiazepines, beta-blockers are sometimes used as an anti-anxiety medication as they reduce the impact of the excitatory neurotransmitter noradrenaline while antihistamines are sometimes prescribed due to their sedative effect. Amphetamines are not an anxiolytic. This is a stimulant drug, sometimes called an ‘upper’ - it is a dopamine agonist that increases feelings of alertness and increases energy levels.
Hyperpolarization means…
Answer: Hyperpolarization occurs when negatively charged chloride ions flood into the postsynaptic cell making it less likely to fire, as is the case when an inhibitory neurotransmitter such as GABA binds to its receptors. Depolarization occurs when positively charged sodium ions flood into the postsynaptic cell as is the case when an excitatory neurotransmitter such as noradrenaline binds to its receptors.
Which of the following is the correct description of benzodiazepines?
Answer: Benzodiazepines bind to GABA receptors, increasing the frequency of the opening of the chloride channels thus enhancing the inhibitory effects of GABA and making hyperpolarization more likely.
What percentage of the placebo group relapsed in the study of paroxetine by Stocci et al. (2013)?
Answer: Past research has indicated that 90% of people relapse once they stop taking benzodiazepines, yet only 11% relapsed in Stocchi et al. (2013) after paroxetine treatment (an SSRI) where as 40% relapsed following cessation of the placebo treatment. This shows that the research on the effectiveness of paroxetine may lack reliability.
Which of the following is not true regarding the Jakubovski et al. (2018) meta-analysis of SSRIs and SNRIs?
Answer: People taking SNRIs took just two weeks to show a significant improvement in comparison with the placebo group - that is, half the time taken for the SSRI group to show the same degree of improvement.
Bandelow et al. (2015) found that…
Answer: In Bandelow et al SNRIs, in fact, had the highest effect size of 2.25 compared to just 1.29 for the placebo pills group. Mindfulness had an effect size of just 1.56 whereas benzodiazepines had an effect size of 2.15. Overall drug therapies were more effective than psychological therapies.
The CGI-S used in Stocci’s study is…
Answer: The CGI-S is a 7 point scale completed by clinicians as a way of answering the following question “Considering your total clinical experience with this particular population, how ill is the patient at this time?” where 1 is “Normal, not at all ill” and 7 is “Among the most extremely ill patients”. The mean score in the treatment group minus the mean score in the placebo group divided by the standard deviation of all scores is the formula for calculating effect size.
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