Less common approaches.

Many less commonly used antidepressant therapies are supported by anecdotal evidence only. They include light therapy (non-seasonal affective disorder), high-dose TCA or MAOI therapy (only if serum levels can be monitored), intravenous clomipramine or maprotiline (allows for rapid perfusion, avoids first pass liver metabolism), bromocriptine, high-dose selegiline, and psychosurgery. Modern stereotaxic psychosurgical procedures offer symptom relief with minimal risk, and reports of large trials indicate that up to 60% of truly treatment-resistant patients either recover or are considerably improved.

Absolute treatment resistance

Very few patients show absolute treatment resistance. In specialized clinics, only about 7% of patients remain depressed after 1 year of extensive investigations and treatment. Extensive treatment involves many drug trials singly and in combination as well as one or more courses of electroconvulsive therapy (ECT). Patients with absolute treatment-resistant depression (TRD) are older (mean age about 55), have been depressed longer, and usually have insoluble life problems.

Even patients with absolute TRD can be helped. Antidepressants often give some relief, and carefully prescribed psychostimulants can improve mood and psychoenergize.

Supportive psychotherapy and CBT can also be of benefit. Supportive psychotherapy helps depressed patients to carry on and CBT allows patients to view the world more positively. Regular exercise and reduction of alcohol consumption also help.

Common strategies for treatment resistance.

Electroconvulsive therapy

An important and effective treatment for depression, electroconvulsive therapy (ECT) is effective in about 90% of cases of major depression. The success rate drops when it is used for drug-refractory cases. Using ECT depends on patient-related factors: it clearly is the treatment of choice for depression with psychomotor slowing, stupor, psychotic symptoms, or depression requiring rapid response because of suicidal risk or malnutrition. Use of ECT should be considered whenever therapeutic management is being reviewed and revised.

Triiodothyronine (T₃) augmentation

Thyroid hormone potentiation of tricyclic antidepressants (TCAs) can be useful. The thyrotropin-releasing hormone stimulation test should be done first, if available and convenient, to rule out grade three (subclinical) hypo thy roidism. If hypo thy roidism is present, it should be treated with thyroid replacement therapy. If the patient is euthyroid, low doses of T₃ (25 to 50 µg/d) can be given with the antidepressant for 10 to 14 days. Up to a third of depressed patients, particularly women, respond. Most experience with this approach has involved tricyclic antidepressants (TCAs), and the effect on the selective serotonin reuptake inhibitors (SSRIs) or other new agents is not well studied.

Tricyclic-fluoxetine combination

Some reports indicate that fluoxetine, when added to a TCA such as desipramine, can produce a robust and rapid response in many patients. This augmentation effect could be a result of increased TCA levels due to fluoxetine inhibition of the cytochrome P 450 system. Because fluoxetine can raise blood levels of tricyclic antidepressants (TCAs), routine serum levels of TCAs are recommended. Other TCA-SSRI combinations can also be tried. All selective serotonin reuptake inhibitors (SSRIs), however, effect the cytochrome P 450 System by raising TCA levels.

Tricyclic-MAOI combination

Some evidence suggests that this combination is more effective than either drug used alone for some patients. Ideally both drugs should be started simultaneously or the MAOI added to a TCA regimen. The safest combination seems to be phenelzine with either amitriptyline or doxepin. Clomipramine, imipramine, and the new agents, such as fluoxetine, should be avoided. Give low doses initially and pay rigid attention to dietary restrictions.

The SSRI combinations

Although no literature supports the practice, clinical experience suggests that lower doses of two selective serotonin reuptake inhibitors (SSRIs) together might work better than either alone.

Augmentation with L-tryptophan

L-tryptophan is the dietary precursor of brain serotonin. Reports confirm that L-tryptophan can enhance the antidepressant effect of monoamine oxidase inhibitors (MAOIs) as well as tricyclic antidepressants (TCAs) and lithium. This might apply to the new antidepressant agents as well. The high doses required (more than 3 to 4 g/d) make this approach cumbersome because the tablets are quite large.

Psychostimulants

Dextroamphetamine, methylphenidate, and to a lesser degree magnesium pemoline all have mood-elevating, psychoenergizing properties and have a place in the management of mood disorders. These drugs can be used alone or combined with antidepressants. Apathetic, elderly, and medically ill depressed patients often respond to psychostimulants when they cannot tolerate the side effects of antidepressants or a rapid response is necessary.

Psychostimulants are also useful for patients who do not respond to any antidepressant and are truly treatment resistant. Non-response to one psychostimulant does not predict non-response to another. There is no evidence of addiction or dose escalation although clearly this class of drugs needs to be prescribed cautiously and monitored carefully. Using psychostimulants is somewhat similar to prescribing analgesics for chronic pain conditions and can be justified considering the morbidity associated with major depression.

Cognitive behavioural therapy (CBT)

This therapy can be very useful for treating chronic depression, such as dysthymia, and can be helpful as an augmentation strategy in conjunction with pharmacotherapy for treatment-resistant patients. Several studies have demonstrated the effectiveness of CBT, a technique that family physicians can easily learn.

If lithium augmentation is ineffective, it should be discontinued and the antidepressant changed (Table 5). A lack of response to one of the newer agents in a class, such as the selective serotonin reuptake inhibitors (SSRIs), does not predict lack of response to others in that class. If the first drug used was a reversible inhibitors of monoamine oxidase A (RIMA) with only one drug in the class, the switch should be to an SSRI. If the original drug was an SSRI, a second SSRI, a RIMA, or other newer agents should be tried. If a TCA or MAOI was used first, the switch should also be to one of the new classes of antidepressants.

The tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) should be kept as third-line antidepressants. Evidence shows that response to an SSRI does not determine response to a TCA. One study has shown that 60.5% of patients who failed to respond to SSRI monotherapy responded when switched to a noradrenergic TCA. Most tricyclic antidepressants (TCAs) have both serotonergic and noradrenergic properties. Desipramine and nortriptyline are somewhat more noradrenergic than the others. Venlafaxine, a new selective serotonin and noradrenaline reuptake inhibitor (SSNRI) might also be considered.

If atypical symptoms, such as panic attacks or anxiety, are present, an MAOI or reversible inhibitors of monoamine oxidase A (RIMA) should be considered after a suitable washout period for the previously used antidepressant (10 to 14 days for most antidepressants; up to 5 weeks for fluoxetine because of an active metabolite).

If the second antidepressant is not effective, lithium augmentation should be tried once more before the antidepressant is changed again.

Major depression is best managed through a treatment algorithm. The more resistant to treatment a patient’s illness is, the further treatment proceeds through the steps. As each trial of therapy is deemed ineffective, diagnosis should be reviewed and physical and psychosocial factors reassessed before making a decision about the next step. Psychotherapy is an essential accompaniment to any form of somatic treatment. Supportive psychotherapy offers reassurance and time for patients to talk about their pain and also provides support and education. Destructive lifestyles, guilt, low self-esteem, and anger are some of the issues that might need to be addressed. Some patients need to be referred for formal psychotherapy.

Strategies before changing antidepressants

Higher dose

For the new antidepressant compounds, most manufacturers recommend standard doses. If side effects are minimal, doses usually can be increased and tolerated well. Increasing the dose should be tried before adding other antidepressants or switching drugs.

Lithium augmentation

For patients who have failed to respond to an adequate course of an antidepressant, lithium augmentation is the most reasonable next step (Table 4 summarizes augmentation strategies). About 30% to 50% of patients respond to this technique, and it seems to work with all of the antidepressants (although less is known about how it works with the newer agents). Lithium, an antidepressant and mood stabilizer when used alone, appears to augment other drugs by enhancing postsynaptic receptor sensitivity.

To use this technique, the antidepressant should be continued at the current dose and lithium started at a dose of 300 mg three times a day. A positive response can occur in 5 to 12 days. If the response is positive, patients should continue to receive lithium for at least 6 months and in some cases for the duration of antidepressant therapy. Lithium levels should be monitored and kept within the therapeutic range of 0.6 to 1.0 mmol/L, and thyroid status should be closely followed.

Are there underlying physical factors?

Many physical diseases present with depressive symptoms or complicate depressive illness (Table 2). Some of these illnesses remain undetected for years and account for an apparent treatment-resistant depression (TRD). Normal thyroid function is particularly important; even mild or subclinical hypothyroidism can impair response to antidepressants. Hypothyroidism can be induced by lithium therapy, and many drugs, both medical and nonmedical, can cause depression or complicate treatment (Table 3).

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Are there underlying psychosocial factors?

Psychological and social factors, such as unresolved neurotic conflicts, a history of sexual abuse, current marital or work conflicts, unemployment, and poverty, can exacerbate mood disorders. Psychotherapy must be part of the treatment plan.

Is the current course of treatment adequate?

The most frequent reason for patients not responding to treatment is inadequate use of antidepressants. Surveys have shown that two thirds of correctly diagnosed patients do not receive adequate treatment, even under specialist care. Inadequate dose is the most common reason for treatment failure. One third of patients do not respond to the first course of antidepressants; this proportion decreases with use of consecutive antidepressant trials.

The dose and duration of an antidepressant drug trial must be adequate. For most antidepressants, this means the maximum recommended daily dose for at least 3 to 5 weeks. Unpleasant side effects sometimes lead to noncompliance, and serum levels are sometimes subtherapeutic despite what seems to be an adequate dose. Other factors, such as alcohol or drug use or abuse, might affect serum levels.

If the antidepressant is a tricyclic (TCA), determining serum levels could be important for management; tests are readily available at most centres. Nortriptyline has a therapeutic range of 50 to 140 ng/mL (178 to 499 nmol/L). Other tricyclic antidepressants (TCAs) have a less precise range (about 150 to 200 ng/mL or 535 to 1070 nmol/L). Establishing serum levels can help to ensure compliance; ensure adequate absorption; and assist in dose adjustment for special groups such as the elderly or medically ill, when severe or unusual side effects are present or during apparent treatment failure. Serum levels unfortunately have not been established for other classes of antidepressants.

The most common causes of noncompliance are disabling or unpleasant side effects, particularly those that cause sexual dysfunction. Most side effects are transient; if persistent, they usually can be easily managed.

Many patients are reluctant to take antidepressants. They sometimes feel they are relying on a pharmacologic “crutch,” or that they are unworthy of receiving help. They fear addiction, worry about side effects, or could have delusional beliefs about being poisoned.

Inadequate response to therapy can be iatrogenic. Lack of understanding of the biologic basis of depression, failure to educate patients and families, failure to conduct adequate treatment trials, or reluctance to prescribe the newer antidepressants, monoamine oxidase inhibitors (MAOIs), or electroconvulsive therapy (ECT) are factors.

More than 20% of patients with major depression have not recovered after 2 years and, of those who do initially recover, 20% suffer a relapse 1 year later. Most studies have shown that 60% to 70% of patients respond to the first antidepressant used and a further 10% to 15% respond either to a second antidepressant or to electroconvulsive therapy (ECT). About 15% of patients fail to recover even with multiple therapeutic trials and can be called treatment resistant. However, even these patients can be helped by supportive psychotherapy and lifestyle changes. The terms absolute and relative are used to describe treatment-resistant depression (TRD). Patients with absolute TRD have been correctly diagnosed, have received adequate treatment, but have failed to improve. Patients with relative treatment-resistant depression (TRD) have not been adequately assessed, have not received adequate treatment, or have reached the limit of the expertise of their attending physicians.

Factors involved in treatment failure

Several questions should be considered when assessing patients with mood disorders who have not responded to treatment (Table 1).

Is the diagnosis correct?

Several psychiatric illnesses present with depressive symptoms or with comorbid or secondary depression and are mistakenly diagnosed as a primary depression. These include obsessive compulsive disorder; panic disorder or generalized anxiety disorder with demoralization; posttraumatic stress disorder, particularly in adults who have been sexually abused as children; schizophrenic defect state with apathy; uncomplicated grief; and dementia, such as early Alzheimer’s disease with cognitive decline. Although anti-depressants might benefit some of these patients, the treatment approach to each of these disorders is quite different.

Can the depression be subtyped?

For several subtypes of depression, a standard approach to treatment likely will be ineffective, and patients will appear treatment resistant. More information on these subtypes is available elsewhere.

Bipolar affective disorder, depressed phase

The depressed phase of bipolar disorder clinically resembles an episode of major depression. Introducing lithium or other anticycling drugs and avoiding drugs that might induce cycling becomes important. Rapid onset of symptoms, hypersomnia, a postpartum trigger, a history of manic or hypomanic episodes, or a positive family history are clues to bipolarity.

Delusional (psychotic) depression

A major depressive episode with psychotic features, such as mood-congruent delusions or auditory hallucinations, usually responds poorly to antidepressant monotherapy and requires an antipsychotic agent as well. Electroconvulsive therapy, however, is the treatment of choice.

Major depression with obsessional features

Major depression presenting clinically with obsessions and compulsions responds better to antidepressants that are strong inhibitors of the serotonin transport system, such as the tricyclic clomipramine or any of the selective serotonin reuptake inhibitors (SSRIs).

Atypical depression

Atypical depression is characterized by symptoms such as panic attacks, severe generalized anxiety, agoraphobia, or social phobia. Vegetative features are also atypical and include initial insomnia, increased appetite, hypersensitivity to rejection, and attention-seeking behaviours. Monoamine oxidase inhibitors (MAOIs) or the reversible inhibitors of monoamine oxidase A (RIMA) are probably the agents of choice.

Postpartum depression

About 80% of depressions that begin for the first time postpartum are bipolar. Postpartum depression often resists treatment. Psychosocial issues, such as bonding with the infant and the marital relationship, are very important and need to be addressed as part of the treatment plan. If the mother is hospitalized, physicians should consider admitting the infant once the mother has improved enough to show interest in and look after the baby, even if assistance from nursing staff is needed.

Double depression

Double depression, as the name suggests, is a major depression superimposed on chronic dysthymia. Chronic dysthymia usually requires psychotherapy and lifestyle changes, although pharmacotherapy can help. A major depression that responds to antidepressants might seem unresolved if the dysthymia continues untreated.

Seasonal affective disorder

In this disorder, probably a variant of bipolar disorder, patients suffer from a winter-onset depression for at least 2 consecutive years and have either a normal mood or mild hypomania during the summer. Seasonal affective disorder (SAD) is further characterized by carbohydrate craving, decreased energy, and increased need for sleep during the winter depressive phases. Some patients with SAD respond to traditional antidepressants or lithium, but the treatment that seems most effective is light therapy. Patients with variants of seasonal affective disorder (SAD), such as summer depression (and winter highs), sometimes respond to temperature manipulation rather than light.

Diagnosis of uncomplicated anxiety disorders may be made by competent physicians in many specialties who have a thorough understanding of the etiology, signs and symptoms, impact and treatment of anxiety disorders. The accepted guidebook in making a diagnosis is the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). However, as mentioned earlier, psychiatrists have the most expertise in diagnosing and treating anxiety disorders, and in some cases may be the best professional for the patient to consult.

Treatment for anxiety disorders often involves a combination of pharmacologic and psychological approaches. Nonpharmacologic interventions and therapies are essential at some point of treatment, and pharmacists need to be familiar with these approaches. Once an accurate diagnosis of the anxiety disorder is made by physical and/or laboratory assessment, any drugs or substances that the patient may be taking that exacerbates the anxiety disorder need to be identified and stopped. Treatment should start with bibliotherapy–essentially giving large doses of information about the nature, etiology, presentation, and treatment of the anxiety disorder. (See TABLE 5.)

This patient education should be followed by effective pharmacologic treatment to stop the panic attacks and to help with anticipatory anxiety around having another panic attack or anxiety symptoms. Once the actual physical anxiety events are eliminated, a wide variety of cognitive, behavioral and supportive psychotherapies are available to help reshape the behavioral effects of the disorder. This will allow patients to make changes in their lives and resume the social, occupational, and day-to-day activities that have been impaired by the anxiety disorder.

Post-traumatic Stress Disorder (PTSD)

Post-traumatic Stress Disorder (PTSD) has become much more recognized and appreciated following the traumatic events of September 11th. The estimated lifetime prevalence for PTSD is almost 8%. This anxiety disorder centers on a person re-experiencing an extremely traumatic event, such as a natural disaster, war, crime, rape, or abuse, whether the abuse is physical, mental or sexual in nature. Because of this experience, a person may have recurrent thoughts about the event or actually re-experience some of the same feelings and reactions that occurred during the initial exposure. A person with Post-traumatic Stress Disorder (PTSD) will try to avoid activities or thoughts associated with the initial traumatic event. In addition, the person will usually experience autonomic arousal or panic symptoms when encountering or thinking about the triggering situation.

Social Phobia (SP)

Social phobia affects between 3% and 13% of the adult population and can occur in patients as young as in early childhood. Social phobia is not about being shy, bashful, or not liking people; instead it is a disorder in which patients experience intense feelings of humiliation and/or scrutiny when in a social situation. This situation can be specific, such as giving a talk in a class, or generalized to almost every encounter with any person throughout the day, whether this involves one person or many people. Social phobia is a chronic, unremitting anxiety disorder that has a significant genetic component and a biological basis. Social Phobia (SP) has high comorbidity with other anxiety disorders, as well as depression and alcohol and substance use disorders. The impairment can have extreme ramifications, ranging from not ever applying for a job or a school to quickly quitting because of the intense discomfort experienced when the patient is forced to talk or interact with others. Common symptoms include flushing, blushing, tachycardia, sweating, stuttering, and tremor. In essence, the patient has panic-attack symptoms when he or she is only placed in social situations. The person can experience either limited symptoms or a full-blown attack that affects every body system. TABLE 4 lists some situations in which people with social phobia experience extreme anxiety and thus make every effort to avoid.

Once thought to be a rather uncomplicated and mild form of anxiety, generalized anxiety disorder (GAD) has been found to be a much more significant psychiatric disorder. An effective analogy to illustrate the severity uses a respiratory disease model in which GAD is akin not to the common cold, which is mild, inconveniencing and will shortly go away. Instead, generalized anxiety disorder (GAD) is more like chronic obstructive pulmonary disease, which is chronic in nature and associated with a high morbidity and mortality. In GAD, there is constant and excessive worry and anxiety for greater than six months along with marked chronic physical symptoms of anxiety. The person has no or little control of this excessive anxiety, which greatly affects a person’s capacity for work and enjoyment of life. This anxiety does not have to be rational or be associated with a known precipitating event or stressor. Generalized anxiety disorder (GAD) appears to have a genetic component. Its occurrence, which can affect up to 5%-8% of the adult population over a lifetime, can have profound effects on a person’s life. Some of these effects are listed in TABLE 3, which shows some of the findings of the Harvard/ Brown Anxiety Research Program.

Comorbidity of other anxiety disorders such as panic disorder, social phobia and obsessive compulsive disorder (OCD) is common, as well as of other psychiatric disorders such as depression and substance use disorders. Patients with untreated generalized anxiety disorder (GAD) are high users of medical services as they attempt to understand and treat their excessive anxiety.

Obsessions are recurrent, distressing thoughts that a person experiences without the ability to control the frequency and intensity of these intrusive thoughts. These thoughts cause marked anxiety and distress (panic symptoms) when they occur and occupy a marked amount of the patient’s day. A common example concerns the possibility of contamination or having a disturbing aggressive thought. A compulsion is a behavior or action that the patient believes he or she cannot stop doing or put off without experiencing a tremendous amount of anxiety. An example would be excessive washing of a part of the body or checking to make sure that one did the right thing or did not make a mistake. Obsessions and compulsions often occur together; frequently, the compulsion is a way to reduce the panic-like symptoms that follow an obsessive thought. These obsessions and compulsions cause marked distress to the individual and are time consuming, taking over one hour a day. Obsessive compulsive disorder (OCD) was initially reported to occur in up to 2.6% of the adult population. There is considerable comorbidity in anxiety disorders, and as many as 15% of anxiety disorder patients may meet criteria for OCD.

Patients with obsessive compulsive disorder (OCD) experience these thoughts as ridiculous, absurd, repugnant, and quite illogical; the thoughts may even be quite foreign to the person’s core values and beliefs. Given these characteristics, one begins to understand why many patients do not report these symptoms or seek treatment for fear of ridicule and embarrassment.

Many patients experience an early onset of symptoms, with 30% of patients developing the disorder by adolescence. Strong evidence exists for a definite neuroanatomical abnormality, with hyperactivity found in the basal ganglia, claudate nucleus and orbital frontal cortex. Concomitant neurological syndromes such as Tourette’s add further evidence for a biological etiology for obsessive compulsive disorder (OCD). Comorbid psychiatric disorders such as depression and alcoholism have a high likelihood of occurring in individuals with untreated OCD. Common obsessions and compulsions that manifest in obsessive compulsive disorder (OCD) are shown in TABLE 2.