Depression - Treatment

Depression Treatment Algorithms

There are several approaches to treating a patient with depression. The following factors should be taken into account: the presence or absence of episodes of major depression in the anamnesis, the severity of the current episode, the degree of support for the patient from family and friends, comorbid mental or somatic disorders, the presence of suicidal intentions.

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Starting treatment for depression

The key to effective treatment is an accurate diagnosis of a major depressive episode, with the exclusion of other conditions that may present in a similar way, especially bipolar disorder. It is useful to quantify the initial state using rating scales. These are the Beck Depression Inventory, the Carroll Depression Inventory, the Zung Self-Rating Depression Scale, which are questionnaires filled out by patients, as well as clinical rating scales, which are used by the doctor to assess the patient's condition: the Hamilton Depression Inventory, the Montgomery-Asberg Depression Inventory. The use of these scales allows for a quantitative assessment of the effectiveness of therapy and helps to determine the state of complete euthymia, the ultimate goal of treatment.

Read also: 8 Things You Need to Know About Antidepressants

Pharmacotherapy is the main method of treating depression, but it can be combined with psychotherapy. Antidepressants are indicated for severe or moderate depression. Currently, there is a wide range of drugs that are quite safe and easy to use. Treatment is recommended to begin with new-generation drugs, while MAO inhibitors and TCAs are left in reserve - in case of ineffectiveness of first-line drugs.

Before prescribing a particular drug, it is necessary to confirm the diagnosis, exclude possible somatic or neurological causes of depression, discuss the diagnosis and treatment options with the patient, his family or close people. Every patient with an affective disorder should be examined for suicidal ideation. For this, for example, the patient can be asked: "Do things ever go so badly for you that you have a desire to commit suicide or harm yourself?" The frequency of re-examinations of the patient depends on the severity of the depressive episode and the effectiveness of the treatment.

The following factors influence the choice of antidepressant.

1. History of the effectiveness of previous therapy in the patient or his/her relatives. If any drug or class of drugs has been effective, then treatment should be started with them. The decision on maintenance therapy should be made depending on the number and severity of previous episodes.
2. Drug safety. Although modern antidepressants are much safer, including in case of overdose, than TCAs and MAO inhibitors, when choosing an antidepressant, one should take into account the possibility of drug interactions, as well as the presence of concomitant diseases that can increase the risk of side effects.
3. Spectrum of side effects. Most new generation drugs have the most favorable risk/efficacy ratio. It is important to inform the patient about possible side effects and available therapeutic options.
4. Compliance. Almost all new generation antidepressants are taken no more than twice a day, and most - once a day. Due to the ease of use and good tolerability, compliance with treatment with modern antidepressants is significantly higher than with traditional drugs.
5. Cost of drugs. Although the cost of therapy may seem high (often from 60 to 90 US dollars per month - depending on the dose), it is nevertheless less than the costs that are inevitable in the absence of treatment or in the case of low patient compliance when using generic TCAs, which are cheaper but more often cause side effects.
6. Possibility and necessity of monitoring the drug concentration in the blood. This applies only to some older generation TCAs, since the therapeutic concentration of the drug in plasma for new generation antidepressants has yet to be established.
7. Mechanism of action. The pharmacological effect of an antidepressant is important to consider when choosing not only the initial drug, but also the subsequent drug if the first one is ineffective.

In many patients, especially those with concomitant anxiety disorders and in the elderly, tolerability of the drug can be improved by starting treatment with a lower dose than recommended in the package insert. Tolerability of serotonin reuptake inhibitors at the beginning of treatment can be improved by taking the drug with food.

To begin treatment, it is convenient to use so-called "starter" packages, which are samples and are given out free of charge. This saves patients from having to buy a drug that may not be suitable due to intolerable side effects. If the drug has only a partial effect, then, in the absence of serious side effects, its dose can be increased to the upper limit of the therapeutic range.

As a rule, in outpatient treatment, 4-6 weeks of treatment are sufficient in most cases to evaluate the effectiveness of the drug. Individual patient response to antidepressants varies widely, and, unfortunately, it is impossible to determine in advance whether the effect will be rapid or slower. Scientists conducted a meta-analysis of the results of registration studies of drugs for the treatment of major depression to determine: if the patient did not respond to treatment during the first week, then what is the probability of improvement in the 6th week of therapy (6 weeks is the standard duration of treatment in clinical trials of antidepressants). In this group of studies, it was shown that if there was no improvement in the 5th week, then the probability of improvement in the 6th week was no higher than in the control group taking a placebo.

Other researchers have found similar results. An open-label study of fluoxetine in major depression sought to determine whether the response at weeks 2, 4, and 6 of treatment could predict the degree of improvement after week 8 of therapy.

If the antidepressant is ineffective within 6-8 weeks, the following tactics are preferable.

1. Try another antidepressant (not an MAO inhibitor) that has different pharmacological properties from the previous one.
2. Add lithium or thyroid hormone to the original antidepressant.
3. Add a second antidepressant.

Other guidelines provide similar recommendations, which also assume that lack of effect requires a change in therapy. According to the APA recommendations, if treatment is unsuccessful, a switch to another antidepressant with different pharmacological properties or the addition of a second antidepressant to the original one should be made. The decision to intensify the therapy or change the drug depends on the patient's characteristics, the effectiveness of the previous therapy, and the physician's experience.

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Duration of treatment for depression

After the first episode of major depression, antidepressant treatment should generally be continued for 6 to 12 months, after which the drug is slowly withdrawn over 4 to 12 weeks or more (depending on the type of drug and the dose used). During the continuation phase, the same dose that was effective at the beginning of treatment is used. After three or more episodes of major depression or two severe episodes, long-term maintenance therapy is indicated, which also involves prescribing an effective dose of antidepressant.

If there is no effect, the first step is to ensure that the treatment is adequate. The diagnosis should be revisited, with particular attention to the possibility of comorbid disorders (anxiety disorders, substance abuse), unrecognized bipolar disorder, or a general (somatic or neurological) disease. In elderly patients with a first episode of major depression, it is especially important to carefully exclude a somatic disease or iatrogenic conditions (e.g., a complication of drug therapy), which may be the underlying cause of affective symptoms. The ineffectiveness of therapy may also be explained by poor patient compliance, failure to follow the prescribed treatment regimen, or incorrect use of the drug (low dose or too short duration of treatment).

As recommended above, if the initially chosen treatment method is ineffective, it is either replaced by a new treatment method or enhanced by adding additional agents. In the first case, instead of one antidepressant, another one is prescribed, belonging to the same or another class, or ECT is performed. Strengthening the effect of the initially prescribed agent involves adding a drug with a different mechanism of action.

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Changing Depression Therapy

When replacing an antidepressant, the first decision to be made is whether to select a drug from the same class or family or not. Substitution of one TCA for another is successful in 10-30% of cases. When switching from a TCA to a heterocyclic antidepressant (usually high doses of trazodone or buspirone), improvement is achieved in 20-50% of cases. Prescribing MAO inhibitors after unsuccessful treatment with TCAs causes improvement in 65% of patients. When replacing an MAO inhibitor with a serotonin reuptake inhibitor (or vice versa), an adequate washout period is necessary, the duration of which depends on the half-life of the drug. ECT in patients resistant to TCAs or substitution of SSRIs for TCAs lead to improvement in 50-70% of cases. Placebo-controlled studies of the effectiveness of substituting one SSRI for another have not been conducted, but in open studies, the effect was obtained in 26-88% of cases.

When stopping taking a serotonin reuptake inhibitor, a specific “serotonin withdrawal syndrome” may develop. It manifests itself as malaise, gastrointestinal disorders, anxiety, irritability, and sometimes a sensation of electric current running through the arms and legs. This syndrome may develop when taking the drug abruptly or when one or more doses are missed (due to inattention). The likelihood of developing the syndrome is inversely proportional to the half-elimination period. Thus, it occurs more often when treating with drugs with a short half-elimination period (for example, paroxetine or venlafaxine) than with drugs with a long half-elimination period (for example, fluoxetine). Substitution of one SSRI for another is usually carried out within 3-4 days, but if signs of “serotonin withdrawal syndrome” appear, it is done more slowly. When replacing an SSRI with a drug with a different mechanism of action, the transition should always be gradual, since the new drug does not prevent the development of “serotonin withdrawal syndrome”.

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Adjuvants for the treatment of depression

In case of resistance to treatment or incomplete effect, therapy can be enhanced with various means. To enhance the effect of an antidepressant, lithium preparations, thyroid hormone (T3), buspirone, psychostimulants, pindolol can be added to it. If the effect of SSRI is insufficient, TCAs are added to it. The two most studied auxiliary means are lithium and T3 preparations.

The addition of lithium to TCAs is successful in 40% to 60% of cases. Improvement may be seen within 2 to 42 days, but most patients show efficacy within 3 to 4 weeks. A recent double-blind, placebo-controlled study evaluated the efficacy of lithium addition in 62 patients whose Hamilton Depression Rating Scale scores had decreased by less than 50% after 6 weeks of treatment with fluoxetine (20 mg/day) or lofepramine (70 to 210 mg/day). Patients were given lithium at a dose that maintained plasma lithium levels at 0.6 to 1.0 mEq/L. After 10 weeks, improvement was seen in 15 of 29 (52%) patients taking lithium and antidepressants, compared with 8 of 32 (25%) patients taking placebo and antidepressants.

In elderly patients, lithium appears to be less effective as an adjuvant therapy than in younger patients. Zimmer et al. (1991) evaluated the efficacy of lithium as an adjuvant in 15 patients aged 59 to 89 years who had either failed (n = 14) or had only a partial effect (n = 2) on 4-week nortriptyline therapy. In the study, restoration of euthymia was observed in 20% of patients, and partial improvement was seen in 47%.

Predictors of the effectiveness of adjuvant therapy with lithium include bipolar disorder, less severe depression, younger age of patients, and rapid improvement after lithium administration. Patients who responded to lithium treatment were less likely to have a recurrent episode of depression than patients who were resistant to lithium.

Lithium therapy is usually started at a dose of 300-600 mg/day, then titrated to maintain plasma lithium levels at 0.6-1.0 mEq/L. Slow-release lithium preparations are less likely to cause side effects. Laboratory testing is necessary before lithium is prescribed, as discussed later in the discussion of bipolar disorder.

The potential of thyroid hormones has been studied particularly well when added to TCAs. However, there are reports that they can also enhance the effects of SSRIs and MAO inhibitors. The effectiveness of T3 as an adjunctive therapy has been proven in open and double-blind controlled studies. Adding T3 to TCAs brings improvement in 50-60% of cases. It should be emphasized that T3, not T4, is used as an adjunctive therapy for major depression, since T3 is much more effective. Taking T4 for hypothyroidism does not interfere with the use of T3 for the treatment of depression. In a study, five out of seven patients with depression who did not respond to antidepressant treatment for 5 weeks had their Hamilton Depression Rating Scale scores reduced by more than 50% after adding T3 at a dose of 15-50 mcg/day. Adjunctive therapy with T3 is generally well tolerated. Treatment with T3 usually begins with a dose of 12.5-25 mcg/day, with severe anxiety the initial dose should be lower. The therapeutic dose ranges from 25 to 50 mcg/day. During treatment, it is necessary to monitor thyroid function, the dose of T3 should be selected so as not to suppress the secretion of thyroid-stimulating hormone.

A number of other drugs are also used as adjuvant therapy in treatment-resistant patients. Most of these have only been tested in small, open-label studies.

Buspirone, a partial 5-HT1D receptor agonist, is used in generalized anxiety disorder. In a study, buspirone was used as an adjunctive agent in 25 patients with major depression who had failed to respond to 5 weeks of SSRI therapy (fluvoxamine or fluoxetine) and two or more previous courses of antidepressant treatment. Addition of buspirone at a dose of 20-50 mg/day to the treatment regimen resulted in complete or partial recovery (according to the Clinical Global Impression scale) in 32% and 36% of patients, respectively.

Pindolol is a beta-adrenergic receptor antagonist used to treat hypertension. It also effectively blocks 5-HT1A receptors. Researchers administered pindolol 2.5 mg three times daily to eight patients who had not responded to antidepressant treatment for 6 weeks. Five of the eight patients showed rapid improvement within 1 week, with their Hamilton Depression Rating Scale scores dropping below 7. However, it should be noted that drugs from different companies may have different potencies, as they differ in the ratio of racemates in the mixture.

Other drugs used as adjuvant treatment include psychostimulants (such as methylphenidate, amphetamines, dexedrine), which are used in combination with SSRIs, TCAs, and MAO inhibitors. However, caution should be exercised when adding a psychostimulant to an MAO inhibitor due to the risk of increasing blood pressure. When adding a TCA to an SSRI, the possibility of interaction between the TCA, on the one hand, and paroxetine, sertraline, or fluoxetine, on the other hand, should be taken into account. With such a combination, a significant increase in the concentration of TCAs in the blood is possible. There is also data on the use of bupropion to enhance the effect of SSRIs. In bipolar affective disorder type II (BAD II), the addition of normothymic agents is effective during an episode of major depression.

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