Depression is feelings of sadness, low mood, hopelessness, and a loss of interest in life, combined with a sense of reduced emotional well-being. Most people experience these feelings occasionally, usually as a normal response to an upsetting event; for example, it is natural to feel depressed when a close relative dies. When a person's behaviour and physical state are also affected, however, this is an indication that the symptom is part of a depressive illness. Depression that occurs without any apparent cause, deepens, and persists may occur as part of a variety of psychiatric illnesses. Some people who suffer from depression are eventually diagnosed as having manic depressive illness (also known as bipolar affective disorder) a condition characterized by episodes of depression alternating with mania (periods of overly excitable mood and uncontrolled behaviour).
Symptoms vary with the severity of the condition. In a person suffering from mild depression, the main symptoms are anxiety and a variable mood; the person may also have fits of crying that occur for no apparent reason. More severe depression may cause loss of appetite, difficulty in sleeping, tiredness, loss of interest in social activities, and impaired concentration. Movement and thinking become slower; alternatively, the opposite occurs, and the person may become extremely anxious. Severely depressed people may have thoughts of committing suicide and feelings of worthlessness. Hallucinations or delusions may occur in extreme cases.
Often, there is no single obvious cause, and a combination of factors may be involved. Depression may be triggered by physical illnesses (such as a viral infection), by hormonal disorders (such hypothyroidism), or by the hormonal changes that occur following childbirth (see postnatal depression). Certain drugs, such as oral contraceptives, may contribute to the condition. Inheritance may play a part in manic depressive illness. Some people become depressed in the winter (a condition known as seasonal affective disorder (SAD) syndrome), probably in response to the long hours of darkness. Aside from these causes, there are social and psychological factors that may play a role. Depression may also be related to the number of disturbing changes or events in a person's life.
Depression is the most common serious psychiatric illness. The World Health Organization ranks it fourth in the ten leading causes of disease worldwide. One person in six is estimated to suffer some degree of depression in their life-time, and one person in 20 develops clinical depressive illness. Depression is particularly common in people over 50, and appears to be more common in women; twice as many women as men seek help for the condition. This difference may result from the fact that women are more prepared to seek help for their symptoms, while men may be more likely to express their discontent in the form of problems such as alcohol abuse and violence.
There are three main forms of treatment for depression, depending on the type and severity of the illness. Treatment usually includes a form of psychotherapy, given either individually or in a group. This form of treatment is most useful for people whose personality and life experiences are the main causes of their illness. Types of therapy range from counselling to help deal with practical problems to more structured approaches such as cognitive behavioural therapy or psychoanalysis. Antidepressant drugs may be very effective, with up to seven in ten affected people responding well to the first drug that is offered. Antidepressants are not addictive. Many drugs, however, do not start to take effect until about two weeks into treatment, and all types need to be continued after the symptoms of depression have cleared. ECT (electroconvulsive therapy) is infrequently used in the UK, but it is still considered to be an effective treatment for people suffering from life-threatening depression. ECT may be life-saving, but it can cause mild, temporary memory impairment.
Depression is often a recurrent disorder; up to three-quarters of people who have needed hospital treatment for depression will have another episode within 10 years. However, long-term antidepressant medication and psychological therapies can greatly reduce the risk of recurrence. Despite the effectiveness of drug treatment, suicide remains a serious risk; nearly half of all deaths in people with recurrent depression are due to suicide. This risk can, however, be substantially reduced by maintenance treatment with antidepressive drugs.
Depression and Anxiety in more detail - technical
Depression is common, with point prevalence in Western industrialized nations about 3% for men and 7% for women, and lifetime risk is about 10% for men and 20% for women. Depression is the leading cause of years lived with disability. Physicians fail to make an accurate diagnosis in at least half of those with depressive or anxiety disorders.
Pathophysiological hypotheses involve abnormalities in the hypothalamic–pituitary axis, levels of particular neurotransmitters (particularly noradrenaline, serotonin, and dopamine), and neuroanatomical changes.
Patients with depression or anxiety initially present with physical complaints 50 to 70% of the time, and these conditions are associated with an amplification of physical symptoms, additional functional impairment, and a decreased ability to adhere to medication and important lifestyle changes (exercise and diet) in patients with chronic medical illness.
Major depressive episodes—these last at least 2 weeks and are characterized by at least one of the two primary criteria—(1) depressed mood, or (2) loss of interest or pleasure in nearly all activities—together with at least five of nine other criteria.
Panic attacks—these are characterized by the sudden onset of intense apprehension, fear or terror, and by the abrupt development (within 10 min) of at least four of a number of symptoms.
Generalized anxiety disorder—this is characterized by constant, nonepisodic anxiety that affects patients for more than 6 months and interferes with normal function.
Patients should be reassured: (1) that they are not ‘crazy’, nor are their symptoms a manifestation of their own failure or shortcomings; (2) with proper treatment, these disorders almost always improve or remit, but relapses and recurrences can occur and so follow-up is essential; (3) a variety of treatments are available.
Psychosocial interventions—these are effective for ambulatory medical patients with psychiatric disorders, the three short-term psychotherapies used to specifically target the symptoms of major depression being cognitive behavioural therapy, interpersonal psychotherapy, and problem solving therapy.
Antidepressant therapy—the decision to prescribe should be based on the number of symptoms, the level of dysfunction, and previous episodes of depression or anxiety. The different classes of antidepressant drugs show virtually equivalent efficacy, hence the choice of medication should be made on issues such as side effects, cost, adherence, and physician familiarity and comfort with prescribing particular agents. The selective serotonin reuptake inhibitors (SSRIs) have become the first-line treatment for major depression, dysthymia, and panic disorder, primarily because their improved side effect profiles are associated with improved adherence to treatment. About 40 to 50% of patients with major depression respond to an antidepressant within 3 weeks after reaching a therapeutic plasma level, and up to 80% will respond if initial nonresponders are switched to another class of antidepressant, or with augmentation strategies using additional medication or psychotherapy. Treatment should be continued for between 6 and 9 months after a first major depressive episode. Pharmacotherapy should be discontinued slowly over a period of 7 to 21 days: if tapered too quickly, almost all antidepressants can produce withdrawal syndromes.
Electroconvulsive therapy (ECT)—this remains the most effective treatment available for depression: it can be life-saving in some cases, and in frail older patients it may be safer than antidepressants.
Many patients (30–40%) who respond to treatment remain at substantial risk of relapse during the subsequent 12 months, with risk factors for relapse being: (1) persistence of subthreshold depressive symptoms; (2) history of three or more previous episodes of major depression; and (3) chronic mood symptoms for more than 2 years.
Referral to a psychiatrist should be considered when: (1) the physician is confused about the primary diagnosis; (2) adequate treatment does not lead to an improvement in symptoms within 10 to 12 weeks, or several medication trials have failed; (3) there is suicidal behaviour.
Depression and anxiety are more commonly seen in primary care than any other condition except hypertension. Over half of all patients with mental health disorders are cared for solely by a primary care provider, and many seek help from their physician because they attribute symptoms of depression and anxiety to a physical problem. Physicians fail to make an accurate diagnosis in at least 50% of those with depressive or anxiety disorders. This failure occurs because of time limitations, lack of knowledge, focus on presenting physical symptoms, both the physician and patient perceiving depression as a ‘normal’ response to stressors, fear of opening ‘Pandora’s box’, and the stigma associated with psychiatric illness. Only about half of those patients who are accurately diagnosed with major depression receive the dose and duration of treatment with antidepressants that meets United States of America Agency for Health Care Policy and Research (AHCPR) guidelines. Fewer than half of patients with anxiety disorders in primary care are treated with specific medications or psychotherapy.
Early recognition of depressive and anxiety disorders is important because they can be treated effectively, often in primary care. The detection and treatment of anxiety and depression can prevent patient discomfort and unnecessary expensive diagnostic investigations, which are often ordered to investigate unexplained physical symptoms. More serious complications may also be prevented, such as the progression of psychiatric illness, loss of employment and impairment of social roles, decreased adherence to medical treatment, and suicide.
Depression and anxiety are very common and frequently follow a recurrent or a chronic course. The National Comorbidity Survey (NCS) found using structured psychiatric interviews that almost 50% of community respondents in the United States had at least one lifetime DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders, third edition, revised) psychiatric disorder. Major depression was the most common of these, with a lifetime prevalence of 17.3% and a 12-month prevalence rate of 10.3%. The point prevalence of depression in western industrialized nations is from 2.3 to 3.2% for men and 4.5 to 9.3% for women; lifetime risk is 7 to 12% for men and 20 to 25% women. The reasons for gender differences are poorly understood but are thought to include endocrine, biological, and sociocultural factors: women have been found to have experienced higher rates of childhood (especially sexual) abuse.
The prevalence rates of depression are higher for medical patients than for the general population: 6 to 10% of primary care patients and 10 to 14% medical inpatients meet the criteria for major depression. In patients with at least two chronic physical illnesses, the 12-month prevalence rate of major depression was 12.5%. Major depression is commonly associated with cardiovascular disease (prevalence rate of 15–23%), diabetes (prevalence rate of 11–15%), chronic obstructive pulmonary disease (prevalence rate of 10–20%), cancer (15–30%), cerebrovascular accidents (12–34%), chronic pain (33–35%), and Parkinson’s disease (40%). Depression and panic disorder are also common in patients with ‘medically unexplained’ syndromes (Table 1).
About 16% of people experience an anxiety disorder sometime during their lifetime. These are more common in women, with a lifetime prevalence of panic disorder in 5%, compared to 2% in men. Only one-quarter to one-third of patients with panic disorder or post-traumatic stress disorder (PTSD) present to a mental health setting, with one-third presenting to an emergency room and over a third to their primary physician.
Most patients (80%) meeting criteria for a psychiatric disorder also have one or more comorbid psychiatric disorders: almost half the cases of depression and anxiety occur in the same patients at the same time. About 25% of patients with major depression, dysthymia, and anxiety disorders also have a history of substance abuse.
Depression is the leading cause of years lived with disability. In the United States of America, the estimated total annual cost of major depression was 83.1 billion dollars in 2000, of which 31% were direct medical costs, 7% were suicide-related mortality costs, and 62% were workplace costs. This increase in medical costs is secondary to the many medically unexplained symptoms these patients experience as well as the adverse effect of depression on self-care (adherence to diet, exercise, cessation of smoking and taking medications) in those with comorbid, chronic medical illness. Patients with anxiety and depression make more emergency visits, primary care visits, and more telephone calls to their physicians, have more medical tests and evaluations, take more medications, and are more likely to be admitted to hospital for a medical disorder than patients who do not have these disorders. As many as 50% of ‘high utilizers’ of medical care services have a current depressive or anxiety disorder. Even after controlling for age and pre-existing medical comorbidity, patients with depression receive two to four times as much nonpsychiatric medical care as patients without depression, and those with panic disorder and PTSD use two to three times as many services as other primary care patients.
|Table 1 Prevalence of depression and panic disorder|
|Panic disorder||Major depression|
|High utilizers of primary care||22||25|
|Chest pain and negative angiography||33–43||40|
|Irritable bowel syndrome||29||35|
Depressive and anxiety disorders are associated with an amplification of physical symptoms, additional functional impairment, and a decreased ability to adhere to medication and important lifestyle changes (exercise and diet) in patients with chronic medical illness. Depression reduces the effectiveness of rehabilitation in older patients with stroke, Parkinson’s disease, heart disease, fractures, and pulmonary disease. Effective treatment of major depression reduces physical symptom burden and functional impairment in patients with chronic medical illness. In patients with depression and diabetes, effective treatment of depression was associated with savings in total medical costs.
The indirect costs of depression and anxiety include absenteeism from work, adverse effects on family roles, and shortened lifespan. In the WHO study in primary care, depression was associated with 6.1 disability days per month—as much or more than eight chronic illnesses, including coronary artery disease and arthritis. Anxiety disorders usually strike people at the beginning of their working lives and may last for many years. Some studies report that over half of those with panic disorder or PTSD are not working, with others forced to take lower-paying or part-time jobs near their homes. The lost economic productivity is easier to quantify than the other indirect costs: lost earning time of family or friends bringing patients to treatment, decreased efficiency at work, the toll on families, the future costs to society of children reared by an unemployed or housebound parent. The role functioning of patients with panic disorder and PTSD has been found to be substantially lower than that of patients with chronic medical illnesses, but higher than that of depressed patients.
Depressive and anxiety disorders are complex syndromes that are diagnosed based on clinical criteria. Pathophysiological hypotheses for these disorders involve abnormalities in the hypothalamic–pituitary axis, levels of particular neurotransmitters, and neuroanatomical changes.
Data support an underlying genetic component for major depression, panic disorder, generalized anxiety disorder, and obsessive–compulsive disorder. There are significantly higher rates of depression and panic disorder in first-degree relatives of patients with these disorders. Twin studies have shown a higher rate of concordance for monozygotic compared to dizygotic twins in patients with panic disorder and major depression.
Mood disorders are associated with dysregulation of the biogenic amines: noradrenaline (norepinephrine), serotonin, and dopamine are the three neurotransmitters most implicated. In animal models, long-term treatment with virtually all antidepressants is associated with a decrease in the sensitivity of postsynaptic β-adrenergic and serotonin-2 receptors. Anxiety disorders are associated with abnormalities of the same neurotransmitters as well as in receptors of the neurotransmitter γ-aminobutyric acid (GABA), an inhibitory neurotransmitter found mainly in the cerebral cortex.
A variety of neuroendocrine abnormalities have been reported in patients with mood disorders, but it is unclear whether these are the cause of the mood disorder, or reflect an underlying brain disorder. Among the more consistent observations in patients with major depression is dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis, presenting as elevation of basal cortisol, dexamethasone-mediated negative feedback resistance, increased cerebrospinal fluid levels of corticotropin-releasing factor (CRF), and an ACTH response to challenge with exogenous CRF. These features appear to be markers of state rather than trait: they usually normalize after successful treatment.
There is evidence suggesting that panic disorder is associated with specific biological abnormalities in the central nervous system. It may result from an abnormally sensitive fear network, which includes the prefrontal cortex, insula, thalamus, amygdala, and projections to the locus coeruleus, hypothalamus, periaqueductal grey substance, and peribrachial nucleus. Selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and benzodiazepines all decrease the firing rates of selected neurons in this fear network, such as those in the locus coeruleus. Studies of patients with PTSD have shown increased central noradrenaline levels, down-regulated central adrenergic receptors, and chronically decreased glucocorticoid levels.
Diagnosis and clinical manifestations
Patients with depression or anxiety initially present with physical complaints 50 to 70% of the time. They often complain of vague symptoms or report multiple somatic symptoms in a variety of anatomical locations, or experience greater dysfunction than can be attributed to their known medical disorders. Patients with panic disorder and PTSD often selectively focus on the somatic components of anxiety, such as chest pain or palpitations, attributing their increased anxiety and tension to the frightening nature of somatic symptoms.
When depression or anxiety is suspected, simple screening questions may be helpful: ‘Are you feeling sad, blue, or depressed?’; ‘Have you lost interest and pleasure in most things you usually enjoy?’; ‘Do you have sudden episodes or attacks where your heart beats fast, your chest is tight, it feels hard to breathe and you feel shaky?’ For PTSD, inquiry about persistent nightmares or flashbacks (daytime memories of trauma) after a traumatic event is an effective screen. The physician should enquire about the patient’s explanatory model for his or her symptoms: ‘Why do you think you get these symptoms?’
History is the single best diagnostic tool. The physician should elicit the patient’s concerns and fears, current life situation, family and other support systems, and concurrent medical problems. A family history of psychiatric problems (depression, anxiety, substance use disorders) should also be obtained. In the United States of America, the Patient Health Questionnaire-9 (PHQ-9) has been the depression tool recommended to screen for depressives as well as monitor progress of depression treatment. Screening questions about a childhood or adult history of physical or sexual abuse, or of domestic violence, are important and can be woven into the usual questions about family medical history. Adverse childhood and adult traumatic experiences are associated with an increased risk of anxiety and affective disorders in adulthood. Over half of the depressed women in one primary care study reported experiencing physical abuse as adults.
The physician should explain carefully that anxiety and depression reflect a biological predisposition that is provoked during a period of life stress. Risk factors that predispose patients to anxiety or depression include a personal or family history of depression or substance abuse, serious medical illness, lack of social support, or a history of early childhood trauma or neglect. Risk factors that can precipitate an acute episode or perpetuate the disorder include poor physical health, divorce, poor interpersonal relationships, illness or death in a family member, trauma, low socioeconomic status, or a stressful work situation.
Depression and dysthymia
Major depressive episodes last at least 2 weeks and are characterized by at least five of nine criteria, including at least one of the two primary criteria of depressed mood and loss of interest or pleasure in nearly all activities (Table 2). There are two to three times as many people with ‘minor’ depressive symptoms that fall short of major depression criteria: these have a higher rate of spontaneous recovery.
Physical symptoms of depression are predictive of a good response to treatment: those with middle insomnia (awakening between 02.00 and 04.00 h) or a diurnal variation in mood are more likely to respond to antidepressant medications.
Several dimensions of depression severity should be assessed: the frequency and chronicity of depressive symptoms, the impact of depression on the patient’s ability to function, the potential for suicide, and the presence of psychotic or manic symptoms. Dysthymic disorder is characterized by a chronically depressed mood that occurs most of the day, more days than not, for at least 2 years. It is associated with many features of major depression but differs in its onset, duration, persistence, and severity of symptoms. Dysthymia is associated with impaired functioning and may not remit spontaneously, and most patients with this condition have also experienced recurrent major depressive episodes.
Patients with anxiety have cognitive, affective, and somatic symptoms. The key feature distinguishing panic disorder from other anxiety disorders is the episodic nature of the attacks. Panic attacks are characterized by the sudden onset of intense apprehension, fear or terror, and by the abrupt development of at least four of the symptoms listed in Table 3, reaching a peak within 10 min. Panic disorder is diagnosed when attacks are recurrent, produce persistent fear, or become significantly disruptive to the patient’s life. Post-traumatic stress disorder (PTSD) is associated with exposure to a traumatic event and persistent re-experiencing of the event in dreams and flashbacks, persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness, and persistent symptoms of increased arousal (i.e. startling easily, sleep problems).
|Table 2 DSM-IV criteria for major depressive episode|
|Five (or more) of the following symptoms, present most of the time for the past 2 weeks; at least one of the symptoms is either depressed mood or loss of interest or pleasure:|
|◆ Depressed mood|
|◆ Loss of interest or pleasure in activities|
|◆ Weight loss or gain (change of >5% per cent of body weight in a month)|
|◆ Sleep disorder (insomnia or hypersomnia)|
|◆ Psychomotor agitation or retardation|
|◆ Fatigue or loss of energy|
|◆ Feelings of worthlessness, or excessive or inappropriate guilt|
|◆ Diminished ability to concentrate or make decisions|
|◆ Recurrent thoughts of death or suicidal ideation, plan or attempt|
Diagnostic and statistical manual of mental disorder, third edition, revised (1987).
|Table 3 DSM-IV criteria for panic disorder|
|Both 1 and 2:|
|1. Recurrent unexpected panic attacks: discrete period of intense fear or discomfort, in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 min:|
|Sweating||Derealization or depersonalization|
|Trembling or shaking||Fear of losing control or going crazy|
|Shortness of breath or choking||Fear of dying|
|Chest pain||Chills or hot flushes|
|Nausea or abdominal distress|
|2. At least one of the attacks has been followed by 1 month (or more) of one (or more) of the following:|
|Persistent concern about having additional attacks|
|Worry about the implications of the attack or its consequences|
|A significant change in behaviour related to the attacks|
Diagnostic and statistical manual of mental disorder, third edition, revised (1987).
The risk of suicide should be evaluated in all patients with depressive and anxiety disorders. The risk of suicide attempts and suicidal ideation more than doubles in depressed patients with comorbid anxiety or physical illness. Other risk factors for suicide include gender (older white males are at highest risk), alcoholism, severe medical illness, psychosis, and lack of social support. The topic of suicidal ideation can be approached gradually with a nonspecific question such as, ‘Do you ever feel so discouraged that life does not seem worth living?’
Asking about suicide will not increase a patient’s risk. Enquiries about suicide can reassure the patient and enable the physician and patient together to make a plan to prevent suicide, including deciding together whether emergency psychiatric consultation or hospitalization is necessary. Physicians should consider using a ‘no harm contract’, meaning that patients are simply asked to contract with the physician in writing that they will contact the physician if they think that they are losing control of a suicidal impulse. Although data on the effectiveness of this technique are not available, it seems sensible and is standard clinical practice in many centres.
An adequate diagnostic workup for anxiety or depression may include a complete blood screen, urinalysis, and routine laboratory tests of renal and liver function. Selected patients should receive an electrocardiogram or chest radiograph. Thyroid function studies are recommended in perimenopausal or postmenopausal women. Given the sizeable differential diagnosis for a patient presenting with anxiety or depression, the extent of workup must be tailored for each case.
While depression and anxiety are usually recurrent or chronic disorders, their clinical course can be markedly improved with timely, evidence-based treatments. Many patients can be treated successfully by primary care or general physicians.
Physicians should educate patients about the nature of depression or anxiety and how symptoms can be managed. They should explore background problems, define treatment goals, and dispel negative perceptions (e.g. that antidepressant therapy is addictive). Patients should be reassured that they are not ‘crazy’, nor are their symptoms a manifestation of their own failure or shortcomings.
There are several important educational points to cover. Depression and anxiety are common and are associated with important physiological changes. With proper treatment these disorders almost always improve or remit, but relapses and recurrences can occur and so follow-up is essential. Physicians should enquire about the patient’s concerns regarding a diagnosis of depression or anxiety, also their worries about medical disorders. Raising the possibility of referral to a psychiatrist or other mental health professional early may make it easier to accept later.
Patients should be educated about the types of available treatments. Identifying the patient’s desires and goals for treatment can provide a focus for the management of problems that can otherwise seem to be poorly defined and overwhelming. This can also increase patients’ sense of participation in their care. Successful disease management programmes developed for asthma and diabetes that have emphasized educating patients to be partners in their medical care have resulted in significant improvements in adherence to treatment and in outcomes: similar approaches have been shown to be successful in managing those with depression and panic disorder.
The decision to prescribe antidepressant therapy should be based on the number of symptoms, the level of dysfunction, and previous episodes of depression or anxiety. Before initiating antidepressant therapy the physician should educate the patient regarding potential side effects, the need to take medication regularly, and the usual time period and course to recovery.
The different classes of antidepressant drugs show virtually equivalent efficacy in the treatment of outpatients with major depressive disorder. The consensus on the pharmacotherapy of panic disorder also described equivalent efficacy of SSRIs, tricyclic antidepressants (TCAs), serotonin noradrenaline reuptake inhibitors (SNRIs), MAOIs, and high potency benzodiazepines. For other forms of anxiety (social phobia and PTSD) there is more evidence of the efficacy of SSRIs and MAOIs compared to TCAs.
The choice of medication should therefore be made on issues other than efficacy, such as side effects (Table 4), cost, adherence, and physician familiarity and comfort with prescribing particular agents. Primary care providers should become familiar with one or two medications with minimal side effects from each of the major classes of antidepressants: SSRIs, TCAs, and newer atypical antidepressants. In each case, the aim is to optimize treatment benefit and lower risk. Factors to be considered include the possibility of side effects, history of response or a failure to respond, possible drug interactions, the presence of other psychiatric or medical conditions, familial response to a specific agent, and patient age.
Randomized controlled trials have failed to show efficacy for antidepressant medication in patients with minor depression, largely because the placebo response rate is so high. Watchful waiting is appropriate for these patients, although the physician should recognize that they are at a higher risk of developing a major depressive episode.
Classes of medications
The SSRIs have become the first-line treatment for major depression, dysthymia, and panic disorder, primarily because their improved side effect profiles are associated with improved adherence to treatment. In the primary care setting patients are significantly more likely to discontinue TCAs than SSRIs, with those started on an SSRI being 7.5 times more likely to take medication consistent in dosage and duration with treatment guideline recommendations. The initial prescription of fluoxetine results in fewer side effects, a lower rate of medication switching, and no difference in clinical outcomes, quality of life outcomes, or overall treatment costs when compared to TCAs. Given that most SSRIs are now sold as generics, the costs compared to TCAs are comparable.
The advent of the SSRIs (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram) and the newer atypical antidepressants (bupropion (previously called amfebutanone), venlafaxine, and duloxetine) has significantly increased the number of patients receiving pharmacological treatment for depression and anxiety in a primary care setting. These new agents have fewer, adverse side effects and are safer for treating older patients and those with comorbid medical illnesses. SSRIs are also much safer than the tricyclic antidepressants if taken in overdose. They do not cause postural hypotension or cardiac conduction delay.
These agents have the advantage that the starting dose may also be an effective treating dose. This is most clearly the case for fluoxetine (20 mg), but may also be true for paroxetine (20 mg), sertraline (50 mg), and citalopram (20 mg). The frail older patients and those with liver disease require smaller starting doses (generally one-half of the usual recommended starting dose). Fluoxetine has the longest half-life (24–27 h) and a long-acting active metabolite (half-life of 7 days). The other SSRIs and duloxetine have half-lives of about 24 h and have no active metabolites with longer half-lives. This allows once-daily dosing and rapid washout. Bupropion, venlafaxine, and nefazodone have shorter half-lives (14 h), so must be given at least twice a day; sustained release forms of amfebutanone and venlafaxine can be taken once daily.
Table 4 describes common side effects of these medications: those such as anxiety, insomnia, nausea, headache, and agitation occur in fewer than 20% of patients. When they do occur, they are usually mild and may respond to a reduction in the dose of medication. Sexual dysfunction (decreased libido and anorgasmia) occurs in up to one-third of patients treated with SSRIs and may be alleviated by the addition of bupropion (100–200 mg per day in divided doses) or buspirone (30–60 mg). Strategies for the management of other common side effects are listed in Table 5.
|Table 4 Side effects of medications used to treat depression and anxiety|
|Sedation, fatigue||Anticholinergic||Dizziness||Insomnia; Agitation||Headache||Weight gain||GI||Anorgasmia|
GI, gastrointestinal; TCA, tricyclic antidepressant; SSRIs, selective serotonin-reuptake inhibitors; * buproprion
GI, gastrointestinal; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
a Previously known as amfebutanone.
Patients with anxiety disorders are especially sensitive to the SSRI side effects of jitteriness, restlessness, agitation, and insomnia. Low doses should be prescribed initially (5–10 mg paroxetine; 12.5–25 mg of sertraline; 25 mg fluvoxamine; 5 mg fluoxetine) for approximately 1 week, then gradually increasing to full therapeutic doses. To completely alleviate panic attacks in most cases requires: 20 to 50 mg paroxetine, citalopram, or fluoxetine; 50 to 200 mg of sertraline; and 100 to 300 mg of fluvoxamine and 150 to 300 mg of venlafaxine. Similar schedules and dosages are used to treat patients with social phobia, PTSD, and generalized anxiety disorder.
Most SSRIs (but not bupropion) inhibit the cytochrome P450 system in the liver, thus potentially leading to drug interactions. Amfebutamone is an effective antidepressant that may be especially useful because it does not cause the sexual side effects common to the SSRIs, but it has been associated with a slight increase in prevalence of seizures compared to other antidepressants. The medication should not be given to individuals at risk for seizures (those with a history of seizures or head injury, or—for reasons that are unclear—bulimia), and should never be administered in a single dose greater than 200 mg. The starting dose of 75 mg twice per day should be increased every week to achieve a therapeutic dose of between 300 and 450 mg/day. The sustained-release form of bupropion may have a decreased risk of seizures due to being associated with lower peak serum levels.
The heterocyclic medications include the tricyclic antidepressants and several other agents that are similar in structure, including maprotiline, amoxapine, and trazodone. These medications are similar in their side effects and dosing strategies. Low starting doses are required, with a gradual increase to a therapeutic level. For treating depression, panic disorder, or PTSD, physicians should begin at 10 to 25 mg of imipramine, gradually increasing the dose by 10 to 25 mg every 4 or 5 days. The ultimate dosage is variable, with some patients responding at a low dosage (50–100 mg), and others needing up to 300 mg. Plasma levels can be measured, but these function primarily as indicators of whether or not the patient is taking the medication: clinicians should treat the patient and not the blood level, since many with high or low blood levels may do very well clinically. Nortriptyline is an exception: it has a therapeutic window (50–150 ng/ml)—levels below or above this are less likely to lead to remission of depression.
|Table 5 Managing the side-effects of pharmacotherapy|
|Insomnia||Move dose to early part of the day|
|Add trazodone 50–100 mg at bedtime or nortriptyline 25 mg at bedtime|
|Switch to paroxetine or fluvoxamine|
|Nausea or diarrhoea||Take medication with food|
|Reduce dose for 4–7 days, then reintroduce higher dose|
|Add H2 blocker|
|Switch to nortriptyline|
|Sedation||Move dose to bedtime|
|Switch to fluoxetine or sertraline|
|Anorgasmia||Add buproprion 100 mg once or twice per day|
|Weekend drug holidays (not fluoxetine)|
|Switch to buproprion|
For the few patients with anxiety disorders who do not tolerate SSRIs or TCAs, high-potency benzodiazepines may be an effective second-line treatment. Alprazolam, lorazepam, and clonazepam have all been shown to be more effective than placebo for the treatment of panic disorder. Patients can be started at 0.25 mg clonazepam three times per day, gradually increasing by 0.25 mg every 2 to 3 days until the attacks stop. Symptoms of generalized anxiety disorder can be alleviated in most cases with a clonazepam dose between 0.25 and 0.5 mg twice daily and 1 mg two or three times daily, or lorazepam 0.5 to 1 mg three times daily. These agents are best used in conjunction with an SSRI or TCA at the beginning of treatment. After 6 to 8 weeks, when the antidepressant begins to have its optimal effects in treating anxiety symptoms, the benzodiazepine can usually be tapered with a 10% dose reduction per week.
Buspirone is an azapirone with affinity for 5-HT1A and dopamine receptors that has been approved for the treatment of patients with generalized anxiety disorder. It is nonsedating, and there are no withdrawal symptoms with abrupt discontinuation. There are also no synergistic effects with alcohol. Buspirone is typically effective at doses of 30 to 60 mg, divided two or three times daily. Common side effects include dizziness, nausea, headache, and nervousness. These can be reduced by using lower starting doses of 5 mg two or three times daily and advancing as tolerated.
β-Adrenergic blockers may be useful for treating performance anxiety. Propranolol is used at doses of 10 to 80 mg per day (ideally taken 2 h before the anticipated exposure). Atenolol at 25 to 100 mg may be preferred since it has fewer CNS side effects (exacerbating depression). The α-blocker prazosin h as been found to be more effective than placebo in treating nightmares in patients with PTSD.
MAOIs are potentially the most effective class of medication for panic or certain types of depression. However, their regular use in primary care or by general physicians is precluded by the lack of familiarity with these agents, and the potential for hypertensive crisis that can ensue from not following a low tyramine diet or taking an over-the-counter stimulant medication (like pseudoephedrine).
Clinicians need to ask patients in a routine and nonjudgemental manner about their use of alternative treatments, and should know enough about the more common ones to assess for deleterious effects or interactions. St John’s wort has been widely used in Europe. A recent meta-analysis found it to be more effective than placebo and of similar effectiveness to low dose TCAs in the short-term treatment of mild depression. However, a recent study comparing treatment with an SSRI versus St John’s wort found that St John’s wort was less effective in treating major depression. Gastrointestinal effects including nausea, pain, loss of appetite, and diarrhoea occurred at a rate of 0.55% in a German study of 3250 patients taking 300 mg three times a day. It may cause a sunburn-like reaction, mucosal inflammation, pruritus, and can lead to significant depression of the blood level of ciclosporin (or tacrolimus) in organ transplant recipients, even leading to rejection.
Special issues in pregnancy
Mild post-partum ‘blues’ occur in 30 to 75% of women immediately after delivery. Symptoms include labile mood, tearfulness, irritability, anxiety, and sleep and appetite disturbances lasting 4 to 10 days. Patients should be evaluated for post-partum major depression if physical symptoms and depressed mood persist for 2 weeks, which occurs in about 10%. Symptoms usually begin during the third trimester. A history of depression, limited social support, marital conflict, and ambivalence about the pregnancy increase the risk of depression during pregnancy and in the post-partum period.
Pharmacotherapy for depression during pregnancy requires an assessment of the risks and benefits of treatment for both mother and fetus. The risks of not treating major depression may include suicide, poor maternal and fetal nutrition, low birth weight and preterm labour, obstetric complications, and the continuation of depression into the post-partum period, with effects on mother and child bonding. Interpersonal psychotherapy has been shown to be effective in decreasing depression and helpful in resolving interpersonal and psychosocial conflicts without exposing the mother or fetus to medications. Although psychotherapy is the first-line treatment for mild to moderate depression during pregnancy or after the birth of a child, antidepressant treatment may be warranted in severe major depression.
The use of selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors for the treatment of depression during pregnancy should be individualized based on their respective risks and benefits. Although the majority of early reports of SSRI treatment during pregnancy did not identify an increased risk for birth defects, in 2005 the Food and Drug Administration (FDA) issued an advisory indicating that early exposure to paroxetine may increase the risk for cardiac defects. In response, two large-scale case- control studies were published, and overall, SSRI exposure was not associated with congenital heart problems in these studies, suggesting that SSRI exposure is associated with a small absolute risk for major defects. Findings on the relationship of minor physical anomalies to SSRI exposure, however, have been inconsistent. Although a higher risk for three or more minor anomalies in fluoxetine-exposed infants has been reported, no increased risk has been found in newborns exposed to sertraline or SSRIs generally, compared to unexposed newborns. Studies of SSRI use later in pregnancy have suggested significantly lower maternal weight gain and infant birth weight after exposure to fluoxetine after 25 weeks’ gestation. Exposure to SSRIs late in pregnancy has been associated with short-term complications in newborns including jitteriness, mild respiratory distress, excessively rapid respiration, weak cry, poor muscle tone, and admission to the neonatal intensive care unit. There have also been several reports of less favorable Apgar scores associated with third-trimester SSRI exposure, and a specific association between late-pregnancy fluoxetine exposure and persistent pulmonary hypertension of the newborn.
Data regarding the excretion of antidepressants in breast milk are limited. The American Academy of Pediatrics Committee on Drugs concluded: ‘antidepressants are drugs whose effect on nursing infants is unknown but may be of concern’. Several studies have shown only small amounts of SSRIs in breast milk and infant serum samples. Children have been followed through their enrolment in kindergarten with no evidence of negative effects on global intelligence, language, or behaviour.
Regular visits are essential for patients with depression and anxiety. Brief visits every 2 weeks are usually indicated during the first 6 weeks of treatment to evaluate the dosage and side effects of medications, and any changes in the patient’s condition. With appropriate counselling beforehand and a regular discussion of side effects, patients are more likely to adhere to a full medication trial, which can also be encouraged by telephone monitoring. The physician should record the main symptoms that the patient presents at the beginning of treatment, and review these at each follow-up visit. The treatment response should be evaluated after they have been on a therapeutic dose of medication for 4 weeks. Simply asking the patient to note the degree of progress on a scale of 1 to 5 can be helpful in assessing either an improvement or worsening of the target symptoms, e.g. by using empirically validated, self-rating scales, such as the PHQ-9, administered at initial diagnosis and at each follow-up. A 25% or greater reduction in baseline symptoms constitutes a reasonable basis for extending the initial treatment. If there has been no response or only a partial response in symptoms, the dose of the medication should be increased to the upper therapeutic range.
Because only 40% of patients with major depression improve over 4 to 6 months during treatment in usual primary care, researchers have developed health care models to improve quality of depression care in primary care systems. A recent meta-analysis of 37 studies reported that collaborative care models were twice as effective as usual care in achieving adherence to antidepressant medication at 6 months and were associated with improved depression outcomes for as long as 2 to 5 years. Collaborative care has two core components: (1) designation of allied health professionals or mental health professionals (called depression care managers) to support primary care providers by helping educate patients about depression, providing close patient follow-up, tracking depression outcomes, side effects and treatment adherence, and facilitating additional visits or treatments with the primary care physician for patients with persistent symptoms; and (2) consultation focusing on patients whose depression is not improving as expected by a designated psychiatrist, who provides backup and case load supervision for the depression care manager and clinical advice/decision support to primary care doctors.
About 40 to 50% of patients with major depression respond to an antidepressant within 3 weeks after reaching a therapeutic plasma level. This success rate can be as high as 80% by switching initial nonresponders to another class of antidepressant, or by augmentation strategies using additional medication or psychotherapy. However, if a patient fails to improve adequately with first-line therapy, the diagnosis and the treatment plan must be reassessed. There may be unrecognized comorbid anxiety or substance abuse, and treatment failure is commonly due to inadequate dosing or lack of adherence to medication.
Once the patient is stabilized on a medication (usually 6–12 weeks), monthly visits are important for support. If chronic prophylactic treatment is necessary, visits every 3 months are usually appropriate. Consensus statements recommend a treatment period of between 6 and 9 months after a first major depressive episode. Pharmacotherapy should be discontinued slowly over a period of 7 to 21 days. If tapered too quickly almost all antidepressants (except fluoxetine) can produce withdrawal syndromes that include sleep disturbance, mood changes, anxiety, sensory disturbance, malaise, muscle aches, vertigo, sweating, fatigue, and gastrointestinal upset.
Patients who have remitted during the acute phase of pharmacotherapy for anxiety and depressive disorders remain at substantial risk of relapse during the subsequent 12 months: 37.1% of depressed primary care patients experience further depressive symptoms during this time. There are three main risk factors associated with relapse: (1) persistence of subthreshold depressive symptoms; (2) history of three or more previous episodes of major depression; and (3) chronic mood symptoms for more than 2 years. Patients with two of these risk factors are approximately three times more likely to relapse than those without. Between 50 and 60% of patients who have had a single major depressive episode will have a second one; 70% of those who have two episodes will have a third; and 90% of those who have had three episodes will have a fourth. For patients with three or more depressive episodes or dysthymia and major depression, the AHCPR guidelines recommend treatment for 2 years or more.
The optimal duration of treatment for anxiety disorders has not been as well established by controlled studies. Treatment is recommended for 6 to 9 months after the first episode. Maintenance therapy should be considered for those with either a chronic history since adolescence, or three or more recurrences. Panic disorder and PTSD are recurrent or chronic diseases in most cases. In a review of 16 studies, most patients with panic disorder had improvement in symptoms with treatment, but few experienced complete resolution. As panic disorder progresses, attacks become more frequent and are preceded by anticipatory anxiety. Patients may begin to associate environmental events with anxiety, leading to avoidance behaviour. The disorder may culminate in agoraphobia: being afraid to leave the house because of the association with panic attacks.
Electroconvulsive therapy (ECT)
ECT remains the most effective treatment available for depression: it can be life-saving in some cases, and in the frail older patient it may be safer than antidepressants. Some reversible short-term memory loss is a common side effect, but this reverts to normal in almost all cases. Patients with recurrent depression who receive effective ECT treatment should be treated with prophylactic medication or maintenance ECT once the acute course of the treatment has finished.
Randomized controlled trials support the efficacy of psychosocial interventions provided to ambulatory medical patients with psychiatric disorders. Problem solving skills and other behavioural techniques, most of which can be provided as simple self-help materials, are part of the psychosocial support that general physicians can provide in a disease management programme for depressive or anxiety disorders. As in all chronic illnesses, lifestyle changes should be reinforced: good sleep habits, adequate exercise, and minimization of caffeine and alcohol intake.
There are three short-term psychotherapies used to specifically target the symptoms of major depression: cognitive behavioural therapy (CBT), interpersonal psychotherapy (IPT), and problem solving therapy (PST). CBT is directed at the negative and distorted thinking patterns and subsequent maladaptive behaviours that often accompany depressive episodes. IPT helps the patient learn to manage the current interpersonal relationship difficulties that are sometimes related to the development and maintenance of depressive symptoms. PST helps activate patients to break down global problems to smaller units that they can begin to attempt to solve.
Patients with major depression treated with CBT and IPT experience as much relief from symptoms by 16 weeks, and those with PST by 11 weeks, as those taking medication alone. Given these findings, physicians need not rely as heavily on drug treatments as they typically have, and should consider psychosocial interventions if the patient prefers them and they are available.
In a meta-analysis of studies on panic disorder and PTSD, psychological coping strategies involving relaxation training, cognitive restructuring, and exposure worked comparably with both antidepressant and benzodiazepine medications. The combined somatic exposure and cognitive therapy (or exposure to traumatic memories in patients with PTSD) helps patients confront and alter maladaptive cognitions (e.g. catastrophic thoughts of a heart attack or stroke when experiencing rapid heartbeat). A meta-analysis of the treatment of generalized anxiety disorder concluded that CBT is more efficacious than control treatments and at least equal in efficacy to anxiolytics.
Referral to a psychiatrist should be considered when the physician is confused about the primary diagnosis, as in distinguishing an anxiety disorder from depression with anxiety or substance abuse disorder. Referrals should also be made when adequate treatment does not lead to an improvement in symptoms within 10 to 12 weeks, or several medication trials have failed. Patients with suicidal behaviour also require specialty care.
Generalized anxiety disorder
Generalized anxiety disorder is characterized by constant, nonepisodic anxiety that affects patients for more than 6 months and interferes with normal function. Lifetime prevalence rates are 5.1% in community samples. Medical problems such as hyperthyroidism should be ruled out as the cause of the symptoms of motor tension and autonomic hyperactivity. This disorder can be treated effectively with SSRIs, TCAs, SNRIs, buspirone, and benzodiazepines; the first four classes should be tried first, given their lower potential for habituation and dependence.
Specific phobias are characterized by episodic anxiety in response to a specific precipitant, with intense excessive fear making patients avoid the situation. Examples of stimuli for simple phobias are airplanes, heights, and insects, although most patients with simple phobias do not seek care for the condition. Social phobia is the fear of humiliation or failure in public situations (such as public speaking, meeting strangers, and eating in restaurants), and many with this condition also have major depression (58.3% of cases of social phobia), or other anxiety disorders (panic disorder, 27.8%; generalized anxiety disorder, 30.6%). Since social phobia usually begins in childhood or adolescence, patients often consider marked social anxiety and avoidance as part of their personality.
Recent studies have shown that SSRIs are more effective than placebo in the treatment of social phobia; effective cognitive behavioural techniques have also been developed. Propranolol (10–80 mg) may be useful for treating nongeneralized social phobia that occurs in one situation, such as public speaking.
Obsessive–compulsive disorder (OCD) is characterized by regular intrusive thoughts or obsessions about aggression, sex, religion, theft, or loss—or other covering mental rituals such as counting objects or letters. Patients may also have persistent rituals or compulsions that are so frequent or complex that they interfere with normal function. They experience these obsessions and compulsions as intrusive, silly, and upsetting. Most patients with OCD have experienced major depressive episodes. Pharmacological treatment is indicated: although clomipramine has been the first-line treatment for many years, recent randomized controlled trials have shown SSRIs to be as effective. Treatment with SSRIs should continue for at least 10 weeks before it is considered ineffective. Randomized trials have shown behavioural treatments to be effective; these focus on exposure to feared activities and prevention of compulsive responses.