Know the main symptom clusters associated with affective disorders, including bipolar disorder and major depression
Be aware of the diagnostic criteria used
Know the fundamentals of the monoamine theory of depression
Understand the theoretical underpinning of current approaches to pharmacological therapy for depression, based on the monoamine theory, and appreciate the short-comings of current approaches
Understand the theoretical basis linking depression to abnormalities in stress responses in the brain and appreciate how this theoretical framework informs novel antidepressant drug development.
Overview of affective disorders
Affective disorders, or mood disorders, are a group of psychological disturbances characterised by abnormal emotional state, and generally manifest as depressive disorders. When considering depressive disorders, the two most prevalent conditions are unipolar (major) depression and bipolar disorder, characterised by alternating depression and mania, although other conditions including dysthymia, cyclothymic disorder, seasonal affective disorder and pre and post-natal depression are also important (Figure 6.4). They occur across the lifespan, although incidence in pre-adolescents is low, and their characteristics are essentially the same across all ages and across cultures.
Depression is characterised by persistent feelings of sadness, loss of interest, feelings of worthlessness and low self-esteem. Major depression and dysthymia share similar symptoms, with prolonged bouts of depressed mood: the main difference is the severity of the symptoms, with dysthymia showing less severe and less enduring symptoms. Bipolar disorder, on the other hand is characterised by similar periods of depression, but interspersed with periods of extreme euphoria, high activity and excitement and inflated self-esteem, termed mania. As with the depressive illnesses, the main difference between bipolar I, bipolar II and cyclothymia is the severity of the symptoms and the degree of interference with daily life.
Diagnosis of affective disorders uses diagnostic criteria laid down in the American Psychiatric Association International Classification of Diseases 11th Revision (DSM-5) or the World Health Organisation’s International Classification of Diseases 11th Revision (ICD-11), which focus on the key features of the condition and give guidance to clinicians for diagnosing the conditions.
Bipolar disorder
Bipolar disorder, formerly called manic depression, is characterised by cycles of extreme mood changes, from periods of a severely depressed state, resembling major depression (see below), to periods of extreme euphoria, high activity and excitement (termed mania). During a manic period people may experience inflated self-esteem and poor judgement, which may lead to them undertaking risky and often destructive behaviours; and a reduced need for sleep and a general restlessness, accompanied by physical agitation and a reduced ability to concentrate. They often deny that there is anything wrong, and become irritable, particularly when challenged about dubious decision making. It is not clear what causes mania. Genetic factors are implicated, since bipolar disorder tends to run in families, although no specific genes have yet been identified that link to it. However, genetic factors only account for around half of the vulnerability, so clearly environmental and social factors are also important.
There are three levels of severity of bipolar disorder. Bipolar I is the most severe form, and is characterised by manic episodes which last at least a week, while depressive episodes last for at least two weeks. The symptoms of both can be very severe and often require hospitalisation. Bipolar II is similar, but less severe: in particular, the manic episodes are less intense, and less disruptive (often termed hypomania) and do not last as long. People with bipolar II are normally able to manage their symptoms themselves, and rarely require hospitalisation. There is a risk of progressing to bipolar I disorder, without correct treatment, but this can be kept to around 10% with the correct management. The least severe category is cyclothymia disorder, where people experience repeated and unpredictable mood swings, but only to mild or moderate degrees.
Diagnosis
Diagnosis of bipolar disorders require presence of both depressive symptoms (as below) and three or more of the listed features of mania (extreme euphoria, high activity, inflated self-esteem, poor judgement: see ‘Diagnostic criteria for bipolar I disorder’ box below). The main difference between diagnostic criteria for bipolar I, bipolar II and cyclothymia are the degree of severity and the time course of the expression of symptoms.
For a diagnosis of bipolar I disorder, it is necessary to meet the following criteria for a manic episode. The manic episode may have been preceded by and may be followed by hypomanic or major depressive episodes.
Manic episode
A distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased goal-directed activity or energy, lasting at least 1 week and present most of the day, nearly every day.
During the period of mood disturbance and increased energy or activity, 3 (or more) of the following symptoms (4 if the mood is only irritable) are present to a significant degree and represent a noticeable change from usual behaviour:
Inflated self-esteem or grandiosity
Decreased need for sleep
More talkative than usual or pressure to keep talking
Flight of ideas or subjective experience that thoughts are racing
Distractibility
Increase in goal-directed activity or psychomotor agitation
Excessive involvement in activities that have a high potential for painful consequences
The mood disturbance is sufficiently severe to cause marked impairment in social or occupational functioning, or to necessitate hospitalisation to prevent harm to self or others, or there are psychotic features.
The episode is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or to another medical condition.
Source: The Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5; American Psychiatric Association, 2013)
Incidence of bipolar disorder
Bipolar disorder is present in around 2% of the population, with bipolar I more common than bipolar II: lifetime prevalence is 1% and 0.4% respectively. Unlike major depression (see below) bipolar disorders are equally prevalent in males and females. Bipolar disorder can occur at any stage in the lifespan, although it is rare in pre-adolescents. Peak age of onset is between 15 and 25 years, although diagnosis may be considerably later, with the average age of onset of bipolar I disorder (18 years) a little earlier than for bipolar II disorder (22 years). It is a major cause of cognitive and functional impairment and suicide in young people.
Pathology of bipolar disorder
A number of brain abnormalities have been described in bipolar disorder, some of which overlap with those seen in unipolar depression (see below), but others appear to be specific to bipolar, and may represent changes responsible for the episodes of mania. Although the underlying neuronal abnormality causing mania is not well understood, changes in a number of chemical markers related to the regulation of pathways modulating neurotransmitter function and neurotrophic pathways have been described in cortex, amygdala, hippocampus and basal ganglia, suggesting compromised intracellular chemical signalling. Notably, there is evidence for dysregulation of intracellular signalling pathways which regulate the function of a number of neurotransmitters, most notable of which are dopamine, serotonin, glutamate and GABA. This in turn may lead to the dysregulation of these transmitters which has been reported in mania. The decreased brain tissue volume reported in bipolar disorder, reflecting reduced number, density and size of neurones, may link to the compromised neurotrophic pathways leading to mild neuro-inflammatory responses and neurodegeneration reported in localised brain regions in mania. Therefore, although the pathology of mania seen in bipolar disorder is not well understood, it appears most likely that it derives from abnormalities in intracellular signalling cascades, perhaps related to localised neurodegeneration through decreased neurotrophic factors.
Treatment
First line treatment for bipolar disorder is antipsychotic medication: haloperidol, olanzapine, quetiapine or risperidone. These drugs target dopamine and serotonin signalling in the brain, and are likely to be downstream of the primary abnormalities associated with mania. If antipsychotic treatment is ineffective, then the mood stabilisers, including lithium, valproate or lamotrigine may be prescribed, either alone or in combination with antipsychotic drugs. Lithium has been widely used in the treatment of mania since its introduction in 1949, but the mechanisms through which is has its mood-stabilising effects are still poorly understood. However, recent evidence has linked it to modulation of intracellular signalling pathways, particularly involving adenyl cyclase, inositol phosphate and protein kinase C: by competing with other metal ions which normally regulate these reactions (e.g, sodium, calcium, magnesium), but which may have become dysregulated, it is able to reverse instabilities in these reactions. Interestingly, other drugs, which also have mood-stabilising effects, including valproate and lamotrigine, also modulate these same intracellular signalling cascades. Therefore, the actions of lithium and other mood-stabilising drugs on these pathways provide supporting evidence for abnormalities in these intracellular signalling mechanisms in mania, perhaps opening novel routes for pharmacological therapy, but also provide plausible mechanism through which the drugs exerts their therapeutic action.
In addition to pharmacological treatment, psychotherapy has an important role to play in treatments of bipolar disorder. This may include cognitive behaviour therapy, which helps the individual to manage stress, and replace unhealthy negative beliefs with healthy positive beliefs; and well-being therapy which aims to help the individual manage stress, replace negative beliefs with positive beliefs and improve quality of life generally, rather than focusing on the symptoms. Psychotherapy is particularly important in managing cyclothymia, to minimise the risk that it will develop into bipolar I or II disorder.
Major depression
Major depression is characterised by persistent feelings of sadness, which manifests as enduring and pervasive, ‘blocking out’ all other emotions. Associated with this is a loss of interest in aspects of life (termed anhedonia) which may start as general lethargy, but in its extreme it is a complete loss of interest in all aspects of daily life, including health and well-being. In addition to these emotional symptoms there is also a spectrum of physiological and behavioural symptoms, including sleep disturbances, psychomotor retardation or agitation, catatonia, fatigue or loss of energy. There are also cognitive symptoms including poor concentration and attention, indecisiveness, worthlessness, guilt, poor self-esteem, hopelessness, suicidal thoughts and delusions with depressing themes. Dysthymia, also termed persistent depressive disorder (DSM-5) essentially relates to similar symptoms, but less severe and with a more chronic time course. An individual can suffer from both major depression and dysthymia, which is termed double depression.
Diagnosis
The diagnostic criteria for major depression according to DSM-5 require the occurrence of feelings of sadness or low mood and loss of interest in the individual’s usual activities, occurring most of the day for at least two weeks (Table 2). Importantly, the symptoms must cause the individual clinically significant distress or impairment in social, occupational, or other important areas of functioning, and must not be a result of substance abuse or another medical condition. Diagnosis of dysthymic disorder is similar to that for major depression, but less severe: symptoms in all domains are at the mild to moderate level.
Five (or more) of the following have been present during the same two-week period and represent a change from previous functioning; at least one of the symptoms is either (a) depressed mood or (b) loss of interest or pleasure:
Depressed most of the day, nearly every day
Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day
Significant weight loss when not dieting or weight gain or decrease or increase in appetite nearly every day
Insomnia or hypersomnia nearly every day
Psychomotor agitation or retardation nearly every day
Fatigue or loss of energy nearly every day
Feelings of worthlessness or excessive or inappropriate guilt nearly every day
Diminished ability to think or concentrate, or indecisiveness, nearly every day
Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
The episode is not attributable to the physiological effects of a substance nor to another medical condition
The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders
There has never been a manic episode or a hypomanic episode.
Source: The Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5; American Psychiatric Association, 2013)
Incidence
The overall prevalence of depression worldwide is estimated at around 5% of the population. Although there are some regional variations, prevalence rates world-wide are fairly similar with women around twice as likely (5 to 6%) as men (2 to 4%). As with bipolar disorder, incidence in pre-adolescents is very low, but the condition begins to emerge in adolescence, peaks in late middle age and then declines in old age. World-wide, depression is the leading cause loss of functionality at the population level, including absence from work and treatment costs, and major depression is the most prevalent mental disorder associated with the risk of suicide.
Causes of depression
Like many mental illnesses, the underlying cause is not yet known. It is likely that genetic, environmental and social factors contribute, and the exact origin may be different in different people. The main risk factors for an individual developing depression are a family history of depression, particularly if they experience severe or recurrent episodes, a history of childhood trauma, and major stressful life changes. In addition, some physical illnesses and medications can bring on a depressive episode.
Evidence suggests that offspring of people who suffer major depression are 2 to 3 times more likely to suffer from major depression themselves compared to the rate in the populations as a whole. This figure rises to 4 or 5 times greater risk if we consider only offspring of parents with recurrent depression or depression which developed early in life. Studies on identical twins suggest that major depression is around 50% hereditable, although this may be higher in the case of severe depression. Although there is clearly a genetic link, there is no one gene which is responsible for this vulnerability. Rather a vulnerability for depression is promoted by combinations of genetic changes. In adoption studies, a higher risk of an adopted child developing depression has been found if an adoptive (unrelated) parent has depression than if they are unaffected. This gives a clear indication that, as well as genetic influences, parents also clearly have a social influence.
Stress seems to be the most important environmental factor involved in the incidence of depression. The stress-diathesis model puts forward the notion that it is the interaction between stress and the individual’s genetic background which determine the expression of depression. Studies on childhood trauma show that children who have experienced emotional abuse, neglect and sexual abuse have an increased likelihood of developing depression in the future of around three-fold, and around 80% of depressive episodes in adults are preceded by major stressful life events. Therefore it is likely that stressful life events, be they in the distant past or more recent, are both a vulnerability factor and a precipitatory factor in the origin of depression.
Beck’s cognitive triad provides a mechanism through which stressful life events may impact on altered cognition leading to a tendency to interpret every-day events negatively leading to the development of depression. Essentially he proposed that the combination of early life experiences and acute stress led to negative views of oneself, the world and the future (the cognitive triad), which in turn created negative schema with a cognitive bias towards negative aspects of a situation, an overemphasis on negative inferences and an overgeneralisation of negative connotations to all aspects of a situation. While these factors may in themselves be sufficient to invoke a depressive episode, it becomes more likely in those with a genetic predisposition (Figure 6.5).