How to choose Antidepressants for patients

Current guidelines recommend that choice of antidepressant should be based on superior tolerability, safety in overdose, and efficacy at prescribed doses.

The improved choice of treatment options offered by the newer antidepressants has meant that therapy is increasingly tailored to individual patient requirements.

In more recent years many newer drugs have been licensed and added to the original treatments for depression. The role of these drugs relative to the older drugs is established for some of the newer drug groups, particularly the SSRIs, and evidence suggests that efficacy is comparable. In addition, many new drugs have been promoted on the basis of superior tolerability and this is also supported by clinical studies.

 [An area of particular concern with regard to initial choice of an antidepressant is the most appropriate drug for patients considered to be a high suicide risk]

 

Suicide!!! It always attached with depression and antidepressant drugs too.

It is important to remember that suicide is an inherent risk in depression; it is generally accepted that with all antidepressant therapies the risk of suicide may increase in the early stages of recovery. Varying relative risks of toxicity in overdosage for different groups of antidepressant have been assessed.  

In practice, it is often difficult to identify patients at high risk for suicide, and it has therefore been suggested that a routine strategy should be to begin antidepressant therapy in all patients with drugs that have low toxicity in overdose.

However, whichever antidepressant is chosen, all patients should be closely monitored during early therapy until significant improvement in depression has been observed and limited quantities of antidepressants should be prescribed at any one time.

[No analyses cannot determine any Antideprresants on the data reflect prescribing patterns and patient selection as opposed to drug toxicity]

 

Why Trycylics Antidepressants are predominated over MAOIs and sometimes SSRIs too?

Tricyclic(TCA) antidepressants have long been preferred over MAOIs because of the problem of drug interactions and the need for strict dietary precautions with the latter group. Tricyclics(TCA) with sedative properties may be more suitable for agitated and anxious patients, whereas those with less sedative properties may be preferred for withdrawn and apathetic patients. Unfortunately, the traditional tricyclics(TCA) such as amitriptyline have antimuscarinic and cardiotoxic adverse effects that can limit their use.

Their cardiotoxicity also means that they are associated with a high risk of fatality in patients taking overdoses. Continuing development produced lofepramine and drugs related to the tricyclic(TCA) group such as mianserin that are less cardiotoxic than the earlier tricyclics(TCA). •

Older tricyclics are more appropriate in severely ill, hospitalised patients or in other situations where maximising efficacy is important.

*In general comparison of efficacy between tricyclics(TCAs) and SSRIs , the show no difference in efficacy although there is the suggestion of a greater efficacy for some tricyclics when given to inpatients.

 

Why SSRIs are better than trycyclics(TCAs)?

Drop-out rates due to adverse effects have generally been higher in patients receiving tricyclics(TCAs) than in those taking SSRIs. Older tricyclics(TCA) and the tetracyclic(TCA) maprotiline appear to be more toxic in overdosage than the tetracyclic mianserin and the SSRIs. Again Older tricyclics are more toxic in overdosage, and that the SSRIs and the newer tricyclic and related cyclic antidepressants are safer.

 

Why SSRIs are used for first line treatment?

Based on some current researches from health professionals, most of them recommend that an SSRI should be used as first-line treatment. In addition some consider that lofepramine, nortriptyline, or newer antidepressants such as mirtazapine or reboxetine are suitable alternatives. Bupropion, which is marketed as an antidepressant in the USA, is considered to be a firstline choice in US guidelines.

*In practice, SSRIs are often tried initially because of their more favorable adverse effects profile.

 

What are problems with SSRI Antideprssants?

The subsequent introduction of SSRIs such as fluoxetine provided a group of drugs with still fewer antimuscarinic and cardiotoxic adverse effects. However, the SSRIs themselves have characteristic adverse effects; gastrointestinal symptoms such as nausea and vomiting may be a problem, and sleep disturbances and anxiety may be exacerbated at the start of treatment. Moreover, those in current clinical use interact to varying degrees with cytochrome P450 isoenzymes, which carries a potential for interaction with a wide range of compounds.

 

Why SNRIs are developed?

More recently serotonin and noradrenaline reuptake inhibitors (SNRIs) such as duloxetine and venlafaxine have been developed, as well as reversible inhibitors of monoamine oxidase type A (RIMAs) such as moclobemide. RIMAs offer a safer alternative to the MAOIs and fewer dietary restrictions are necessary. Nefazodone, mirtazapine, and reboxetine, which have slightly different biochemical profiles from the major groups, are also more recent introductions.

Bupropion, another unrelated antidepressant, is also available in some countries. With the exception of nefazodone, which causes hepatotoxicity and venlafaxine, which is cardiotoxic, most of these newer drugs seem to be associated with fewer severe adverse effects; their efficacy is also comparable to that of the tricyclics(TCA) and SSRIs.

[Toxicity of the SNRI venlafaxine in overdose appears to be greater than other new serotonergic antidepressants and comparable to some of the less toxic tricyclics]

 

Which drugs used for Atypical Depression?

Other drugs used in the treatment of depression include flupentixol, the antidepressant dose of which is lower than that used for the treatment of psychoses. Ademetionine, the active derivative of methionine, has been tried in depressive disorders, and extracts of the plant St John’s wort are widely used in some countries for depression.

Transdermal patches containing selegiline, an irreversible inhibitor of monoamine oxidase type B, are available in the USA for the treatment of depression. * The use of an MAOI may be considered in patients with atypical depression.

 

Why Lithium is the most standard antidepressant drug?

Lithium may be used for the prophylaxis of recurrent unipolar depression as an alternative to standard antidepressants, although it is more commonly used in the management of bipolar disorder (see above); its role in unipolar depression is more usually to augment the effect of standard antidepressants in treatment-resistant disease.

 

What is the use of Sedative Antidepressants?

One of the less sedative antidepressants should be used where appropriate, although care is needed with all psychotropic drugs, especially at the start of treatment. Regardless of antidepressant choice, certain principles of management apply when starting antidepressant therapy.

*The sedative properties of some of the antidepressants may adversely affect the performance of potentially hazardous tasks such as driving and the operation of machinery.

 

How to start treatment and change drugs for newer patients?

Antidepressants often causes toxic effects like antimuscarinic and cardiotoxic effects and no analysis can tell us the actual about starting antidepressant therapy for newer or older patients. However the following method is recommended before starting any antidepressant therapy:

• A low initial dose will minimise adverse effects; this is then increased until an adequate response is observed. When this is done with the newer antidepressants, including the SSRIs, the dose can generally be increased after a few days; for the tricyclics the increase should be more gradual. Gradual introduction of treatment is of particular importance in the elderly who may be more susceptible to adverse effects.

• Although some adverse effects of antidepressant drugs appear soon after treatment is started, there is a delay of about 2 weeks before any therapeutic benefit is observed, and at least 6 weeks before maximum improvement in depressive symptoms occurs. Claims of a fast onset of action have been made for several antidepressants, but in a review of data relating to onset of action with currently available antidepressants, none have been shown conclusively to work faster than any other. This delay in benefit may relate to a combination of pharmacokinetic and neuro-chemical factors.

• Patients should not be considered resistant to the chosen drug until they have been maintained at an adequate dose for at least 4 weeks (the BNF and NICE2 have recommended 6 weeks in the elderly). Patients with a partial response should continue for a further 2 weeks (6 weeks in the elderly) before being considered resistant. Treatment failure is often due to subtherapeutic doses, particularly with the older tricyclics whose adverse effects limit maximum tolerable doses in many patients. Where lack of compliance leads to sub-therapeutic doses therapeutic drug monitoring may be of value.

 

How to use Antidepressants for those who are already failed in first-line treatment (treatment-resistance problem)?

• Switching to an alternative antidepressant

• Adding another drug (augmentation), particularly if there has been a partial response

• Introducing psychological treatments such as cognitive behavioral therapy guidelines generally consider it preferable to try an alternative single antidepressant before giving combinations of drugs (augmentation).

It has been suggested that for practical purposes a patient should not be considered to have treatment-resistant depression until 2 or more consecutive antidepressants at adequate doses have been tried without response. If switching antidepressants the choice is between a drug from the same pharmacological group or one from a different group.

In the UK, venlafaxine is usually reserved for patients with treatment-resistant depression because of its adverse cardiovascular effects and toxicity in overdose. MAOIs can also be tried in patients who are refractory to or intolerant of treatment with other antidepressants.

Pindolol has also been studied as an augmentation agent with several SSRIs and other serotonergic antidepressants. Another method is to combine different classes of antidepressants. Although this has been used successfully in the treatment of drug-resistant depression, it may result in enhanced adverse reactions or interactions and the BNF considers it hardly ever justified; it should only ever be done under expert supervision.

If the response to treatment is good, the patient should continue with the same treatment for at least 4 to 6 months, and perhaps 12 months in the elderly; symptoms are likely to recur if treatment is stopped too soon.

 

What is time intervals required when changing antidepressant drugs?

When changing a patient from one type of antidepressant to another an appropriate drug-free interval may be needed. An MAOI (including a RIMA and selegiline) should not be started until at least one week after stopping a tricyclic antidepressant, an SSRI, or any related antidepressant; in the case of bupropion, mirtazapine, and the SSRI sertraline the drug-free interval is extended to 2 weeks, and for fluoxetine, to 5 weeks because of their longer half-lives.

For the tricyclics clomipramine and imipramine a drugfree interval of 3 weeks should be allowed. Conversely, 2 weeks should elapse between stopping MAOI (including selegiline) therapy and starting patients on a tricyclic antidepressant (3 weeks in the case of clomipramine or imipramine), an SSRI, or any related antidepressant.

No treatment-free period is necessary between stopping a reversible inhibitor of monoamine oxidase type A (RIMA) and starting an SSRI or another antidepressant. Drugs that have been used in augmentation strategies for resistant depression include lithium, thyroid hormones (liothyronine), and central stimulants such as methylphenidate.

 

What is treatment management when reducing and stopping antidepressant drugs?

In general, the dose should not be reduced for this continuation phase. Continuing therapy beyond this phase is a matter of clinical judgement and should take into account the number of prior episodes, any residual symptoms, and the severity of the episode. 

Maintenance therapy should be considered for recurrent depressive disorders, and may be necessary for several years, if not indefinitely, in some cases.

Again, full therapeutic doses are recommended for prophylaxis rather than reduced doses. Suddenly stopping antidepressant therapy after regular use for 8 weeks or more may precipitate withdrawal symptoms.

Common symptoms seen after antidepressant withdrawal include headache, anorexia, nausea, insomnia, and anxiety; the SSRIs have also been associated with episodes of dizziness and paraesthesia which are rarely seen with the tricyclics.

Withdrawal reactions may be more severe with the MAOIs especially tranylcypromine. To minimise symptoms, most guidelines and authorities such as the BNF recommend reducing the dose over a period of about 4 weeks, although considerably longer periods (6 months) may be required when withdrawing maintenance therapy. Depressive disorders may arise in childhood and adolescence, the prevalence increasing with age.

Concerns about a possible increased risk of suicide with antidepressant treatment, have led to considerable uncertainty about appropriate management in young patients.

In the UK, guidelines state that the mainstay of treatment for this patient group should be psychological therapy; treatment with antidepressants should only be offered alongside psychological therapy.

 

How to use Antidepressants for children?

For children and adolescents with mild depression, as for adults, a period of watchful waiting may be appropriate before starting any treatment. If symptoms have not resolved after several weeks, patients should be started on an appropriate course of psychological therapy such as group cognitive behavioural therapy or guided self-help which should be continued for 2 to 3 months.

Antidepressants should not be used for the initial treatment of mild depression. Children or adolescents with moderate to severe depression (or those with mild depression unresponsive to the above measures) should be given more specific psychological treatment such as individual cognitive behavioural therapy, interpersonal therapy, or short term family therapy. Combined treatment with an antidepressant (which, as in adults, appears more effective than either alone) should only be considered if there is a lack of response to psychotherapy alone.

The SSRI fluoxetine is considered the first-choice antidepressant in children aged and over because of proven efficacy and low toxicity in overdose; although the evidence for its efficacy in younger children has been questioned, a review by the EMEA concluded that studies showed a positive effect and allowed its use throughout the EU in children from 8 years of age. The other SSRIs should not be used in children because of a lack of demonstrated efficacy and/or an increased risk of a harmful outcome.

Similar recommendations have been made for the SNRI venlafaxine. Patients who remain unresponsive to combined treatment should be initially tried on an alternative psychological therapy.

How to change antidepressant drugs (for children)?

A change in antidepressant may also be warranted and guidelines issued in the UK have suggested that citalopram and sertraline may be appropriate, provided certain criteria have been met. (Paroxetine and venlafaxine should not be used.) Lithium has also been tried and ECT may be considered for older children with severe, unresponsive depression.

Tricyclics may have a modest effect in the treatment of depression in adolescents; however, they are not effective in the treatment of younger children. In practice they have often been reserved for refractory cases in adolescents although evidence to support this role is lacking recent UK guidelines do not recommend their use.

There have also been reports of death due to cardiotoxicity in children taking tricyclic antidepressants, in particular desipramine and imipramine. Following the concerns raised about the possible increased risk of suicide in children and adolescents treated with antidepressants, the FDA undertook a meta-analysis of 372 studies in adults. From 295 studies in psychiatric patients, the overall risk of suicide was not increased, but there was a trend toward increased risk with younger age.

Although the effect was not statistically significant, the FDA considered the trend sufficiently convincing to warn that, like children and adolescents, young adults (aged 18 to 24 years) treated with antidepressants of any type may be at increased risk of suicidal thinking and behaviour. In the UK, an Expert Working Group of the CSM found no clear evidence that use of SSRIs in young adults increased the risk of self-harm or suicidal thoughts. However, it was noted that such patients have a higher background risk of suicidal behavior than older adults and consequently should be closely monitored during treatment.

 

What are the appropriate Antidepressants for Geriatric patients?

Depression in the elderly is not uncommon and may affect up to 4% of this population.57 Suicide is also more frequent in the elderly than in the general population and depressive symptoms are present in about 80% of patients aged over 74 years who commit suicide.

Depression in the elderly is often undertreated and prognosis is poor; treatment is also often complicated by co-existing medical conditions. SSRIs are often the first choice of treatment in the elderly because of their favorable adverse effect profile and low toxicity in overdose. They may be especially appropriate in patients with an existing cardiovascular disease or in those taking other medications that may lower the blood pressure.

Tricyclics such as amitriptyline and imipramine are probably best avoided in the elderly as their cardiotoxic, antimuscarinic, and sedative effects may be particularly troublesome. However, the tricyclics desipramine and nortriptyline are considered by some to be an alternative first-choice as they are less cardiotoxic and have fewer antimuscarinic and sedative actions compared with amitriptyline or imipramine.

Other newer antidepressants may also be useful in specific situations; bupropion, which has the advantage of a relative lack of cardiotoxicity and drug interactions, may be an appropriate option. Lower initial doses of antidepressant drugs are often recommended in the elderly to minimise adverse effects but individual differences in metabolism and excretion may mean that some patients are undertreated.

The elderly tend to respond more slowly to antidepressants than younger patients nd additional psychosocial or psychotherapeutic management is often warranted. The treatment of resistant depression in elderly patients should follow the same principles as in younger patients. ECT is also safe and effective in the elderly, and should be considered in those at high risk for suicide or who are refractory to or intolerant of antidepressant drugs.

Depression late in life may require long-term antidepressant treatment beyond the recovery phase, even after first episodes of depression and should be a continuation of the treatment that was successful in the initial acute phase.

 

What are the usages of antidepressants for pregnant mothers?

Treatment of women with depressive disorders during and after pregnancy raises concerns about the risk of teratogenicity, fetal growth retardation, or perinatal problems (see also individual drug monographs); the ratio of risk to the child versus the benefit to the mother must therefore be considered very carefully. It should also be remembered that untreated depression during pregnancy has been associated with poor neonatal outcomes such as low birthweight.

In some cases starting treatment with an antidepressant will be appropriate although psychotherapy and ECT should also be considered as alternatives. Treatment should not be stopped as a matter of routine in early pregnancy in women who become pregnant while taking an antidepressant. Maternal mood disorders in the immediate postpartum period are related to hormonal changes, particularly falling progesterone levels; the symptoms are mild and resolve spontaneously after several days, therefore no treatment is required.

Of greater concern are major depressive episodes that occur beyond this initial phase, which are clinically identical to depressive disorders in general and call for the same principles of management (although there are few studies to support this). These depressive episodes have been found to be related to the presence of immediate postpartum mood disorders, although no hormonal basis to this association has been identified.

Nevertheless, there has been interest in the use of estrogen as a treatment. As with use of any medication in breast-feeding mothers, the risks to the infant from drugs distributed into breast milk must be considered. The American Academy of Pediatrics considers that all antidepressants are drugs whose effect on nursing infants could be of concern.

 

What to do when Anxiety and Depression present at the same time?

Symptoms of anxiety and depression often coexist, and although it may be difficult to distinguish which is the predominant disorder, especially in milder forms, patients usually require an antidepressant. Anxiolytics and antipsychotics can be useful adjuncts in agitated depression, but a sedative antidepressant might be preferable. Combination preparations of antidepressants with antipsychotics or anxiolytics should not be used because the dosage of the individual components should be adjusted separately.

Also, anxiolytics should only be prescribed on a short term basis whereas antidepressants are given for longer periods. The efficacy of antidepressants in chronic fatigue syndrome in clinical studies have been equivocal although it has been suggested that antidepressant therapy should be tried in patients with co-existing depression. Cognitive therapy may also be useful.