Chapter 6
Current controversies, future directions
Some people believe depression is massively over-diagnosed, some believe it to be an understandable reaction to life that should not be medicalized or treated, and some view depression as a diagnosable disorder, but disagree with the treatments that should be offered. We briefly explore these issues and then consider where the research on depression is heading in the next decade.
Is depression over-diagnosed?
Chapters 1 and 2 of this book identify remarkably consistent descriptions of depression in every type of recording that man has ever made. However, there are a few famous detractors, such as Thomas Szaz, who suggest it does not exist. At present, the major debate is not so focused on whether or not such an entity can be identified, but how depression has been classified or diagnosed, the professional and public attitudes to treatment, and the wildly varying theories about the causes. Ironically, research publications suggesting that depression is over-diagnosed and that too many prescriptions are given for antidepressants are matched closely by the number of papers highlighting that it is under-diagnosed and under-treated. Taken together these studies suggest that depression is frequently misdiagnosed and mistreated. For example, there is evidence that antidepressants are overused such as for individuals who have transient unhappiness or who have symptoms of depression that are not likely to benefit from medications. Also, at the other extreme, there is evidence that even if depression is recognized it may not be treated. For example, studies suggest that many elderly people with depression remain untreated because ‘it is common to feel depressed if you have lots of physical ailments and you are getting older’. Such a rationale is difficult to fathom; clinicians understand that diabetes is common in older people, and they understand the causes, but this knowledge does not lead to treatment being withheld. However, experts in depression are aware that even if they improve the accuracy of the diagnosis of depression, questions remain about what the most appropriate treatment is for individuals with a disorder that may differ in its causes and its level of severity or complexity.
Do antidepressants work?
Since the introduction of tricyclic antidepressants there have been arguments about whether antidepressants work or not. For every review of published studies that state that they do work, there seem to be a similar number of reviews (often examining the same scientific publications) that state that they do not work any better than placebo (such as a sugar pill). However, in 2008 a storm broke in the news as a professor of psychology at Harvard Medical School called Irvine Kirsch published a new review that suggested that antidepressants were of very little benefit for treating depression. The big difference with this review compared to previous publications was that Kirsch and his colleagues used the Freedom of Information Act to get access to all the SSRI and new antidepressant drug trials submitted to the Food and Drug Administration (the organization responsible for licensing drugs in the USA). This meant that this new review included not only the studies that showed the drugs worked but also the studies that did not show any effect for antidepressants. The latter studies often remain unpublished and so were not available to many of the previous review articles.
As usual, it is not just the data included in Kirsch’s review, but the interpretation of the findings that has contributed to the controversy. The basic scientific facts indicate that antidepressants can be beneficial to about 60–70 per cent of those who take them, but response to placebo may be around 30–50 per cent. So, in absolute terms about 20 per cent more people with depression will truly be better off because they took an antidepressant than if they did not. However, there are two important caveats about these findings. First, individuals with severe depression definitely benefit from antidepressants rather than placebo, but the benefits in mild and moderate depression are less clear. Some studies showed benefits for antidepressants in mild and moderate depression, but others showed no absolute improvement over and above that attained with placebo. Second, many of the studies were of very short duration and only examined benefits over about six weeks. Many experts suggest this undermines the validity of the review as this differs from how assessments are often made in day-to-day clinical settings, where these medications are often prescribed for longer and the response to treatment is often observed at a later time.
We would make four further observations about the prescribing and benefits of antidepressants. First, there has been significant progress in preventing drug companies from ‘burying bad news’ and in some instances data are now available online to allow independent researchers access to clinical trial information. This is an important step forward. Antidepressants are the second most commonly prescribed medications on the planet, their production is a multi-million pound industry, and the public and professionals need to be able to believe the information provided by the Pharma companies.
Second, before we write an obituary for second generation antidepressants it is worth noting than many medications prescribed for physical disorders, such as anti-inflammatory drugs, have never shown more than a 60–70 per cent response rate (versus the same 30–40 per cent placebo response rate). This means that just like antidepressants, treatments for physical disorders may only show the same 20 per cent absolute difference between the active medication and placebo treatments. However, the public have not stopped taking these medications for their physical illnesses and clinicians have not stopped prescribing them. What has happened is that prescribers have tried to target the use of medications towards those who can benefit from them.
Third, many cancer treatments are only effective for small subgroups of patients and many such improvements are short-lived (e.g. a group of patients with a certain type of tumour); it is unrealistic to expect a broad class of drugs such as antidepressants to work equally well for everyone or for every type of depression. Learning from specialities such as cancer, we need to be able to use different antidepressants or therapies more selectively and find possible predictors of which approach is best in different circumstances.
Fourth, whilst some cases of mild–moderate depression can benefit from antidepressants (e.g. chronic mild depression of several years’ duration can often respond to medication), it is repeatedly shown that the only group who consistently benefit from antidepressants are those with severe depression. The problem is that in the real world, most antidepressants are actually prescribed for less severe cases, that is, the group least likely to benefit; which is part of the reason why the argument about whether antidepressants work is not going to go away any time soon.
Are all psychological therapies equally effective for depression?
There are debates within the therapy world about which approaches are most helpful for people who are depressed. For example, counselling may be useful in the short term, especially for individuals who lack social support or a confidant in the community. However, the benefits of counselling fade within 3–6 months of ending the sessions. So if the goal is longer-term gains and also prevention of future depressive episodes, therapies that explicitly aim to help people change how they act and cope may be preferred. The argument that individuals could simply repeat a course of counselling fails to take into account the fact that therapy sessions can be more costly in the short term than prescribing medication. The economic argument for therapy can only be sustained if it is shown that the long-term outcome of depression (fewer relapses and better quality of life) is improved by receiving therapy instead of medication or by receiving both therapy and medication.
Despite claims about how therapies such as CBT, behavioural activation, IPT, or family therapy may work, the reality is that many of the elements included in these therapies are the same as elements described in all the other effective therapies (sometimes referred to as empirically supported therapies). The shared elements include forming a positive working alliance with the depressed person, sharing the model and the plan for therapy with the patient from day one, and helping the patient engage in active problem-solving, etc. Given the degree of overlap, it is hard to make a real case for using one empirically supported therapy instead of another. Also, there are few predictors (besides symptom severity and personal preference) that consistently show who will respond to one of these therapies rather than to medication.
It also takes some time to establish that a therapy has short-term and long-term benefits across different patient groups (defined by age or type of mood disorder, etc.) and across countries and cultures. For example, despite the enthusiasm for mindfulness, there were fewer than twenty high-quality research trials on its use in adults with depression by the end of 2015 and most of these studies had fewer than 100 participants. So, whilst the signs are encouraging for the use of mindfulness, it is hard to argue the case to change international treatment guidelines on the basis of the examination of its use in 2,000 patients who mainly reside in Europe and the USA.
Complementary and alternative therapies
Depression is recognized as one of the most common reasons for seeking complementary or alternative therapies. Complementary medicine covers a wide range of therapies including herbal medicines and minerals as well as physical treatments such as acupuncture, reiki, and exercise, to name but a few.
Seeking alternatives may reflect dissatisfaction with conventional treatments in some individuals, whilst in others these approaches may be more in line with their health belief models or philosophy. For example, homoeopathy offers many individuals a more personalized level of input and explicitly attends to the whole person, which a person may feel is lacking in mainstream services. As noted, expectations of benefit from a treatment account for about 30 per cent of the response rate, and so the ‘placebo effect’ is relevant to any treatment whether provided by conventional or alternative services. However, in 2010 the House of Commons Science and Technology Committee in the United Kingdom concluded that there is no consistent or reliable evidence that homoeopathy is any more effective than a placebo and that the explanations of how or why homoeopathy could work are scientifically implausible. At the risk of upsetting some people we respect and admire, we concur with that report and find the so-called evidence in support of homoeopathy extremely hard to swallow.
One of the main reasons that many individuals support the use of herbal remedies is their beliefs that as these substances are naturally occurring they are by definition safe. Alas, this is not always true. One problem is that herbal remedies are not regulated or tested in the way that conventional drugs are and this can mean that two different over-the-counter preparations of the same remedy can have a twentyfold difference in their dose or potency or they may contain a range of additional substances. Secondly, many can have unwanted effects, the classic example being St John’s Wort (SJW). This is an extract of the Hypericum plant and has been described as an antidepressant throughout history. Although the findings from clinical trials suggest the effect of SJW on depression is rather weak, it can benefit some individuals with milder levels of depression. However, the down side is that it interacts with the enzyme systems responsible for the metabolism of many other drugs (altering their blood concentrations and their efficacy), for example, it can render oral contraceptives less effective. Also, it can reduce absorption of iron into the body, increasing the risk of anaemia. Thus, enthusiasm for natural remedies must still be balanced by the recognition that few substances exist that are truly free from any side effects.
Perhaps the most promising alternative approach which is increasingly being adopted by mainstream clinical services is the prescription of exercise for some individuals with clinical depression. The benefits of exercise have been widely expounded for the population at large whether they have experienced depression or not. Indeed, public health campaigns are actively promoting the need to get people ‘off the sofa’ with slogans such as ‘sitting is the new smoking’. Numerous studies demonstrate that exercise has health benefits that extend to psychological as well as physical well-being. However, this does not answer the question of whether regular exercise can reduce clinical depression. When the data from the best thirty studies are combined, the answer is a qualified ‘yes’. The evidence is that exercise improves the symptoms of depression compared to no treatment at all, but the currently available studies on this topic are less than ideal (with many problems in the design of the study or sample of participants included in the clinical trial).
Exercise as the only treatment approach is probably most beneficial for those with milder forms of depression. This is not to suggest that other depressed individuals do not benefit, but rather that some severely depressed people may find it very hard to initiate a visit to a gym, let alone execute an exercise programme. These individuals may need medication in the first instance with opportunities to participate in exercise being offered after some improvement in symptoms has occurred. Exercise is likely to be a better option for those individuals whose mood improves from participating in the experience, rather than someone who is so depressed that they feel further undermined by the process or feel guilty about ‘not trying hard enough’ when they attend the programme.
There are several plausible arguments as to why exercise interventions may be beneficial, including the idea that psychologically, exercise will actively help to distract people from their negative thinking and ruminations, and that their self-esteem may be improved as they develop their skills and master particular activities; and socially, they may re-establish or improve their networks. Physiologically, as well as changing endorphin levels there is emerging evidence that exercise may produce changes in monoamine levels, or reduce levels of the cortisol. This means exercise could help to reverse some of the biological changes that have been found in people who become depressed.
Future developments in medications
As noted, there are gaps in the theoretical models of depression and some frustrations with the currently available medications to treat it. Like the rest of medicine, psychiatry continues to explore and revise the theories of how depression develops and how to identify individuals at risk for this condition. In the latter part of the 20th century, researchers established that there were connections between the systems already implicated in the development of depression; namely, that the monoamine and stress hormone systems were interconnected and, furthermore, there were bidirectional influences on the activity of these systems and genetic and psychological vulnerabilities, and environmental factors. At the start of this century, researchers have also turned their attention to the links of the monoamine system and HPA axis to the circadian and immune systems. Whilst a detailed discussion of each topic is beyond the scope of this book, we highlight a few key elements of this new research and highlight how it may help us discover much-needed new treatments.
Mood disorders and circadian rhythms
There is evidence that many individuals are larks and get up early every day, whilst others are night owls by nature. These sleep–wake patterns can also vary somewhat with age. Many of you will have seen with your own eyes that some adolescents have an amazing ability to sleep until well after lunch-time, to complain of still feeling tired all afternoon, and then to stay up well beyond midnight into the early hours of the next morning (suggesting their entire twenty-four-hour sleep–wake activity pattern is shifted). Also, you may personally have undertaken shift work or experienced jet lag following a long-haul aeroplane flight. The sleep–wake patterns exhibited by different individuals or by the same individual in different circumstances are partly explained by the activity of the circadian system or the internal body clock.
The term circadian derives from the Latin and means about (circa) one day (diem). Many processes in the body are carefully regulated by the rhythmic release of certain chemicals and hormones. The sleep—wake cycle is the most obvious example of this but blood pressure, body temperature, and many other biological functions change in a precise and regular pattern over the course of a day. Also, like an orchestra, the activity needs to be synchronized and disruptions to the sequence of hormone secretion or pattern of circadian activity can lead to significant changes in mood, sleep, concentration, appetite, and energy, giving a picture that looks very similar to clinical depression.
Disruptions of the circadian system are also implicated in the development in some people of medical problems such as obesity, diabetes, and some cancers; suggesting it has a role in physical and mental well-being.
There are several pieces of evidence that suggest a link between circadian abnormalities and mood disorders. First, genes (such as the so-called clock genes) play a role in setting each individual’s internal biological clock and some types of clock genes are found more often than expected in families with a history of mood disorders such as depression and manic depression, and some of the clock genes that are present in individuals who develop mood disorders appear to exert weaker control over the system than in people who do not get depressed. Second, it is also known that circadian rhythms are very sensitive to environmental changes: the amount of daylight hours, social factors such as a regular lifestyle, and certain types of life events can significantly influence an individual’s rhythms.Third, there are clear connections between the areas of the brain that regulate the circadian system and those that modulate the stress hormone and monoamine systems and many SSRIs and other antidepressants increase the levels of the main hormone involved in sleep regulation (called melatonin). Taken together, these findings have led many researchers to propose that abnormalities in an individual’s biological clock may play a role in the development of mood disorders.
The findings described have stimulated interested in chronobiology (the study of cyclical physiological phenomena) and many studies are now being undertaken of the variation in daytime activity and night-time sleep patterns of people with mood disorders. This research is aided by the fact that it is possible for people to wear an actiwatch (a device that looks similar to an ordinary watch and can be worn on the wrist that measures motion) twenty-four hours a day, seven days a week, and carry on with their normal life. This means it is possible to record naturalistic or real world information about their patterns and routines. These so-called ecological studies demonstrate that individuals at risk of developing mood disorders (such as those with a strong family history), those with a current episode of depression, and those with a past history of depression (but who are currently well) all show differences in their sleep pattern from individuals with none of these characteristics. It has also been shown that disturbed sleep predicts worsening of mood, concentration, rumination, and lowered activity on the following day, and that improving sleep can help reverse these trends.
The research on circadian rhythms has increased interest in chronobiotics (drugs that may affect the circadian system) and chronotherapeutics (interventions such as light therapy and CBT for insomnia: CBT-I). Currently, there are major research trials of the treatment of depression examining the benefits of melatonin or synthetic compounds that mimic the effects of melatonin. Therapies used to treat insomnia, such as CBT-I, have also been adapted for use in bipolar disorders and web-based internet programmes are being used to modify the sleep-activity patterns of young people with emerging mood disorders. Studies of light therapy, using light boxes and specially designed glasses that block out blue light, are under way in individuals with depression, bipolar disorder, and in individuals who have seasonal affective disorder (mood disturbances that change according to the season). All of these approaches appear to be opening up much needed avenues for new treatments.
Depression and the immune system
Depression is not an infectious disease, but it seems that some proteins in our body, called inflammatory markers, are increased in individuals with acute episodes of depression and in children who later develop depression in adolescence. Inflammatory factors have been found to affect various activities of the brain thought to be important in depression, including altering monoamine activity, cortisol receptor responses, and the neuroplasticity of the hippocampus (neuroplasticity refers to the brain’s ability to form new neural connections). Professor Peter Jones and researchers from the University of Cambridge have suggested that early life adversity and stress can lead individuals to develop persistent increases in the levels of inflammatory markers in the body. Furthermore, individuals with persistently higher levels of inflammatory markers or those who show an excessive inflammatory response to stress are about twice as likely to get depressed as those with low levels of markers.
Even when we are healthy there will be some traces of inflammatory markers in the bloodstream (especially substances such as interleukin-6). However, when we have an infection, such as a common cold, our immune system kicks into action to fight the infection and inflammatory markers are released. These substances also act on the brain and produce ‘sickness behaviours’ (nausea, fever, loss of appetite, withdrawal from the physical and social environment), many of which overlap with the symptoms of depression. The difference between sickness-related behaviour and depression is that the former is the body’s adaptive response to the infection and the behaviour and symptoms stop once the infection is resolved. This is not always the case in depression and high levels of inflammatory markers can be more common in those who experience prolonged episodes of depression.
As with the circadian system, immune system abnormalities are linked to both mental and physical disorder. For example, we know that people with depression have a higher risk of developing heart disease and diabetes, and it has been shown that elevated levels of inflammatory markers increase the risk of these problems in the general population. A goal of future research is to establish whether immune or circadian abnormalities explain the association between mood disorders and specific physical health problems. An additional reason for interest in the immune system and circadian markers is that they can be measured objectively and so they may eventually allow researchers to develop laboratory tests similar to those used routinely in general medicine to help identify people at risk of a particular illness or to decide the best treatment options.
Future research in psychotherapy and the links to neuroscience
One of the reasons for some scepticism about the value of therapies for treating depression is that it has proved difficult to demonstrate exactly what mediates the benefits of these interventions. This has led many to claim that the improvements seen are akin to the placebo effect or are simply a consequence of having someone to confide in who provides support during a difficult time. However, it is also clear that the therapies that are most beneficial for depression help people change their thinking, emotional reactions, and behaviours, especially in response to life stress. This suggests that effective therapies include learning new skills such as changing a person’s coping strategies and revising their self-perceptions of stressors. As such, therapy researchers have started to combine psychological, social, and neuroscience approaches in their studies to explore the underlying brain activities related to depression and how these change during therapy and after recovery.
One of the best-known advocates of this research strategy is Eric Kandel, who won a Nobel Prize for his laboratory research on the physiological basis of learning and memory in 2000. What makes his contribution so fascinating is that although he is well known as a basic scientist, he originally trained as a psychoanalyst. Kandel has continued to emphasize the importance of understanding that what we call the mind can be understood as the activity of the brain and that all mental processes, even the most complex, derive from operations of the brain. Kandel is not the only academic to discuss these issues, but he has clearly articulated how neuroscience, and especially the use of brain imaging techniques, could allow researchers to develop new ways for exploring mental processes, of identifying the brain changes that may occur in depression and also examining how these may be modified by antidepressants or psychological treatments. This type of approach is critical to attempts to uncover the connections between specific mental functions and specific brain mechanisms, but also the links to genetics, biology, and psychosocial models.
In 2008, Kandel published a paper on a new intellectual framework for psychiatry. He argued that research repeatedly demonstrates that genetic influences are not fixed (i.e. the old notion that you inherit a behaviour pattern that cannot be changed is wrong), and that we know that internal stimuli (events within the body) and external events are involved in the development of the brain, such as stress, learning, and social interactions. Importantly, all these events can alter ‘gene expression’ (which is termed epigenetic regulation). When learning and experience produce these alterations in gene expression this in turn affects the patterns of neuronal connections and leads to anatomical changes in the brain; a process that can continue throughout life.
A simple example of this brain plasticity comes from the frequently quoted study of London taxi drivers. During their probation period, would-be taxi drivers have to learn a detailed roadmap of London (known as The Knowledge), which may take four to five years to achieve. Researchers used brain scans to demonstrate that these navigational demands stimulated brain development and it was found that the individuals learning The Knowledge showed an increase in the size of the hippocampus in the brain. Further, the scans showed that their intensive training was responsible for the growth in their memory centre (i.e. it was not that individuals who already had a large hippocampus were more likely to decide to become taxi drivers). In clinical studies, it has been shown that normal development of the cortex (the large lobes of the brain) may be retarded by exposure to neglect or deprivation in early life and that the effects of this include reduced modulation of other brain areas involved in emotional reactivity, fear, and responses to danger (areas called the limbic, midbrain, and brain stem regions).
These studies are important to depression and to psychotherapy research in a number of ways. First, in depression it is likely that certain life experiences lead to the growth (or retraction) of neural networks in the brain that are then reactivated under stress. As the researcher Carla Schatz stated, this can be described as ‘cells that fire together wire together’. This model provides a potential neural basis to cognitive structures such as our underlying beliefs and our ability to regulate emotions. Also, it offers insights into neuroplasticity and the investigation of the substances in the brain, such as the protein called brain-derived neurotrophic factor (BDNF), that stimulate the growth of new nerve cells and improve their healthy functioning and survival time. Interestingly, research reports increased BDNF levels can be associated with repeated exercise, therapy, or taking medication.
Kandel argues that psychological interventions can produce long-term changes in behaviour through learning, which in turn produces changes in gene expression, and therefore alters the strength of connections between nerve synapses and brings about structural changes in the brain. The race is now on to try to use new technology to determine if he is right and to examine whether therapy works in this way and, if so, where the therapy-induced changes occur (see Figure 10). Researchers are also trying to examine whether the structural reorganization produced by therapy occurs in the same parts of the brain that are altered by the depression itself, or in different brain regions (which would suggest that therapy produced compensatory changes). Lastly, researchers are comparing the brain scans of individuals receiving therapy or medications to determine whether the effects on the brain are similar or different.
10. Understanding the mind and brain. This brain scan (using positron emission tomography or PET) provides a window to view the activity of the brain of a person with depression before and after receiving sixteen sessions of therapy. The image on the left shows the brain of the person when they were depressed and the scan on the right shows the brain of that person after successful treatment.
The research so far has produced interesting but inconsistent results. For example, a Finnish study demonstrated that depression was associated with reduced serotonin uptake in some frontal areas of the brain and that this abnormality was corrected in patients who received a course of therapy, but did not change in patients who did not receive treatment. North American research has indicated that the changes in brain activity following a course of CBT and IPT were similar to each other (suggesting they may have comparable effects on similar brain areas), but differed from the effects of antidepressants. In some CBT studies, changes have been found in blood flow in parts of the frontal lobes associated with the appraisal of emotions and ideas, which have been interpreted as a possible indication that the person is ruminating less as they recover from their depression. This research is in its infancy and it will take some time to be confident about the interpretation of the findings. However, this scientific approach holds out the prospects of being able to identify which individuals will respond to which type of treatment for depression and also to show how the use of antidepressants or therapy can produce changes in the brain that lead to recovery from depression. Not surprisingly, this has caught the attention of many parts of the scientific community working in psychiatry, psychology, general medicine, and neuroscience.