Tricyclic Antidepressant

Sadiq Naveed

10/08/2010

Mechanism of action

• Early biochemical theories were based on knowledge of drug action of tricyclics.

• Observation regarding mechanism of action of tricylic agents suggested that depression is caused by deficiency of norepinephrine and serotonin.

• It stimulated interest to find out etiology of depression.

• Its still unclear whether these deficiencies play a central role in causing depression or are responsible of the vulnerability to become depressed.

• Recent challenge studies in depressed patients do confirm the action of antidepressant drugs are mediated by serotonin and norepinephrine.

• For example, tryptophan free diet rapidly depletes serotonin, and in depressed patients who have been successfully treated, causes depression.

• In addition, tryptophan depletion causes relapse in patients who were successfully treated with serotonergic agents, whereas those who were NE reuptake inhibitors remain unaffected.

• Alpha-methyl-p-tyrosine (AMPT) is a tyrosine hydroxylase enzyme inhibitor, which interrupts the synthesis of catecholamine, causes relapse in patients who were treated with Noradrenergic agents.

• It doesn’t affect the individual who were receiving serotonergic agents

• Tryptophan depletion in untreated depressed patients had no effect on patient’s depression

• It supported the evidence serotonin and norepinephrine mediate antidepressant effect.

• But it doesn’t necessarily imply that alteration in these neurotransmitter system are central to pathphysiology of depression.

• Early theories of depression that focused on depletion of serotonin and norepinephrine suggest that it might be helpful to identify serotonergic and noradrenergic depression. It will be helpful to select proper medication.

• A number of studies suggested investigated the predicative value of 3-Methoxy-4-hydroxyphenylglycol, a metabolite of norepinephrine, but a definite link with noradrenergic antidepressant was not established.

• Some of these studies were, in part, hampered by the use of agents such as amitriptyline and imipramine, which are not selective.

• Even with those studies that examined the ability of MHPG to predict response with more selective agents like Zimelidine, Fluoxetine, desipramine, failed to determine any relationship

• This data suggested that MHPG has no predictive value.

• However, it doesn’t rule out possibility that there are depressions in which serotonin or norepinephrine plays a relatively more important role.

• Recent research has shifted to include consideration of factors affecting postsynaptic signal transduction.

• These include coupling of G protein to adrenergic receptor or adenylyl cyclase, activity of membrane phospholipases and kinases.

• Other targets include glucocorticoid receptors, neurotropic factors and gene expression.

INDICATIONS AND EFFICACY

Major Depression

• Efficacy of tricyclics and tetracyclics agents is well established.

• Imipramine is most extensively studied tricyclic antidepressant, in part for many years it was the standard agent against which other drugs were compared.

• In 30 of 44 placebo controlled studies, Imipramine was more effective than placebo.

• If data from studies are combined, 65% of 1334 patients completing treatment with imipramine were substantially improved, whereas 30% of those on placebo improved.

• Intention-to-treat response rates for placebo controlled studies of imipramine were 51% for imipramine and 30% for placebo.

• In most comparison studies, the other tricyclic and tetracyclic antidepressant have been found to be comparable to imipramine in efficacy.

• Tricyclic agents are also effective when used for maintenance treatment.

• Early studies demonstrated that maintenance treatment with tricyclic would reduce the relapse rate associated with placebo by 50%.

• These studies employed lower doses.

• Subsequently, the Pittsburgh group found that imipramine, at full dose, effectively maintained nearly 80% of depressed patients for 3 years compared with 10% with placebo.

• In this study, maintenance psychotherapy had an intermediate effect, with about 30% of patients remaining well.

• Although this study reflected the impressive value of maintenance treatment with full dose with imipramine, the magnitude of findings may reflect the characteristic of the sample treated.

• The studies had patients with recurrent depression who might have been expected to do poor with placebo.

• In addition, the patient selected for study had a history of symptom free period between prior episodes suggesting that these patients will have more complete response to treatment then patients with residual symptoms.

• In practice, we have patients with chronic depression, with residual symptoms and with co morbid medical disorder.

• In these patient, drug treatment may be more effective than placebo but patients whose depression remains in remission may be lower

• FDA approved all of these agents for depression except clomipramine but it is used for depression. Some says its most potent antidepressant.

Melancholia or severe depression

• The efficacy tricyclic varies in different types of depression.

• When kuhn studied imipramine, it was essential to establish efficacy of an antidepressant in patients with endogenous depression or at least in those with severe depression.

• Early studies of imipramine and other tricyclics revealed that these agents are effective.

• Two studies of imipramine and desipramine found rates of response of 85% in severely depressed hospitalized patients with no refractory history and personality disorders.

• When SSRIs were introduced, it was suggested that they might be less effective than tricyclics in treating severe on melancholic depression.

• In a large meta-analysis of more than 100 studies comparing SSRIs and tricyclics, Anderson found that these agents have comparable efficacy.

• When individual agents and patient characteristics were considered, only amitriptyline appeared to be more effective than SSRIs.

• The only patient characteristic was inpatient status.

Anxious Depression

• Its not recognized in DSM IV TR as a subtype of depression.

• But it has been frequently studied.• Three of tricyclics and tetracyclics compounds

(Doxepin, amoxapine and meprotiline) has been FDA approved for use in patient with depression and anxiety.

• For many years, clinicians suggested that amitriptyline was the most effective for anxious depression.

• Direct comparison studies, however have found little indication that one compound is better than other for treatment of anxious depression.

• Depressed patient with anxiety may respond less than anxious patients.

• It has been observed with amitriptyline, imipramine and desipramine.

• Yet these drugs are still more effective than placebo in anxious depressed patients and it is not established that other classes are more effective than these agents in depressed patients,

Atypical depression

• A series of studies by Columbia university examined the efficacy of imipramine in patients with atypical depression.

• These patients had reactive mood and reversed vegetative symptoms, severe fatigue or rejection sensitivity.

• Imipramine was more effective than placebo but significantly less effective than Phenelzine.

• Validity and utility of atypical depression was supported by this observed difference

• Atypical depression hasn’t shown to be preferentially responsive to SSRIs, nor has any second generation antidepressant been shown to be superior to any other in treating atypical depression.

Psychotic depression

• In 1975, Glassman et al, found that imipramine was less effective in patients with major depression who had delusions.

• Later Chan et al, reviewed several studies addressing this question and involving more than 1000 patients.

• He found that usually tricyclics, given alone were effective in approximately two thirds of non psychotics patients but only about one third of those with psychotic features.

• Although the definition of psychosis has undergone several changes, currently it is defined in DSM as major depression with delusions or hallucinations

• Several open studies reviewed elsewhere and one prospective study found that the tricyclics, when combined with an antipsychotics are effective in psychotic depression.

• Anton and Burch suggested that because of its antipsychotic effects, Amoxapine might be effective for psychotic depression.

• In a double blind study, these researchers demonstrated that amoxapine was comparable in efficacy to the combination of Perphenazine and amitriptyline in treating psychotic depression

Bipolar Depression

• Thirty years ago, it was suggested that in MAOI antidepressant might be more effective than the tricyclics in treating bipolar depression.

• Later Himmelhoch et al demonstrated in a double blind study that tranylcypromine was more effective than imipramine for bipolar depression.

• In addition tricyclics are more likely agents to induce mania.

• As a result, the tricyclics are not recommended for monotherapy of bipolar depression

Chronic Major Depression and Dysthymia

• Imipramine appears to be more effective in treating chronic depression and Dysthymia and to be relatively comparable to Sertraline in efficacy.

• Imipramine and desipramine have both been studies in clinical trials and have been found to be more effective than placebo both for acute treatment and for maintenance treatment.

Late life depression

• Gerson et al reviewed the studies of tricyclic antidepressant reported prior to 1986.

• They have found 13 placebo controlled studies but noted several problems in these studies like lack of diagnostic criteria, inclusion of younger patients and dosing issues.

• Although tricyclics were effective, overall drug and placebo response rates in these elder patients appeared to be lower than rates in non elderly patients.

• Katz et al performed one of the first placebo controlled studies in treatment of patients older than 80 years living in a residential care facility.

• Nortriptyline was more effective than placebo.

• The doses employed and levels achieved were similar to those in younger subjects.

• This study remains the only study to date showing an advantage for an antidepressant for an antidepressant over placebo in depressed patients older than 75 years.

Depression in Children : In children, the tricyclics antidepressant have not demonstrated superiority over placebo

Obsessive-compulsive disorder

• Unlike depression, which respond to variety of antidepressant agents, OCD appears to require treatment with a serotonergic agents.

• Clomipramine, the most serotonergic of tricyclics , is approved by FDA for use in OCD and its efficacy in this order is well established.

• Studies comparing its effectiveness with noradrenergic agents such as desipramine found that clomipramine was substantially superior.

• Although the SSRIs are effective in treating OCD, there is a suggestion that clomipramine may be superior.

• Whether this putative superiority is due to mechanism of clomipramine or to other factors is unclear.

Panic Disorder

• None of tricyclic or tetracyclic drugs are approved for use in panic disorder.

• Yet imipramine was the 1st drug described for use in this disorder.

• The efficacy of both tertiary and secondary tricyclics has been demonstrated in controlled trials.

• In treating this disorder, the drug is initiated at a low dose to avoid exacerbation of panic sympstoms

ADHD

• The efficacy of stimulant drug in treating ADHD is well established.

• The tricyclics, especially desipramine, also appears to be some value.

• In one study, desipramine, given at doses greater than 4 mg/kg for 3-4 weeks, was effective in two third of patients, whereas placebo was effective in only 10%.

• Desipramine was also found to be more effective than placebo in adults with ADHD.

• One of advantages of desipramine is its low potential for abuse.

• Unfortunately, five cases of sudden death were reported in early 1990s in children being treated with desipramine.

• All were under the age of 12 years.• As a result, desipramine is now

contraindicated in children younger than 12 years.

• Given that tricyclics as a group share same cardiac adverse effects, there is reason to be concerned that other tricyclics might have safety issues in young children

Pain Syndrome

• The tricyclics and maprotiline have been widely used in various chronic pain syndromes.

• In a review of literature, O’Malley et al (1999) identified 56 controlled studies involving tricyclic agents therapy for various pain syndromes headache (21 studies), fibromyalgia (18 studies), functional GIT syndromes (11 studies), idiopathic pain( 8 studies) and tinnitus ( 2 studies).

• Salerno et al indentified 7 more placebo controlled trials of tricyclics or maprotiline used for chronic back pain.

• These agents were quite effective, in fact, the mean effect size (0.87) and the drug-placebo difference in response rates (32%) observed in pain syndrome are more robust than those observed in placebo controlled studies in depression.

• In studies, in which depression was also assessed, improvement in pain appeared to be independent of improvement in depression.

• Thus , the analgesic effects of these compound were not simply result of their antidepressant effect.

• The mechanism of action of these agents appears to differ from that of antidepressant effect.

• The antinociceptive actions of the antidepressant result from action on descending norepinephrine and serotonin pathways in spinal cord.

• In animals, NE reuptake inhibitors and combined norepinephrine and serotonin reuptake inhibitors appear to be more potent than SSRIs.

• In humans, there is some evidence that combined agents amitriptyline and clomipramine are more effective than SSRI Fluoxetine or the norepinephrine selective agents maprotiline and nortriptyline

• In humans, antidepressant doing and timing effects for pain differ from those observed in depression.

• For example, usual dosage of amitriptyline required for pain management (<75mg/kg) are lower than required for depression (15-300 mg/day) and response usually occur within 1st or 2nd week

• Nocturnal enuresisNocturnal enuresis : Imipramine is FDA approved for nocturnal enuresis in children and it is clearly effective in clinical trials.

• The dose of imipramine is 25-50 mg/day at bedtime

• The mechanism of action is played by anticholinergic effect.

• It has not been shown clearly but the risk of cardiac side effects is lower than other tricyclics in children younger than 12 years.

SIDE EFFECTS AND TOXICOLOGY

• The delineation of side effects during the treatment of depressed patients is complicated because depression itself has somatic symptoms.

• For example, headache, constipation and drowsiness, symptoms usually seen as side effects, have been observed in 50% untreated patients with major depression if these symptoms were each directly assessed.

• During treatment, patient may be quick to label these somatic symptoms as side effects even if these symptoms were pre-existing

• Clinical trial data for recently marketed antidepressant indicate that the rate of headache on placebo in depressed patients ranges from 17% to 24%.

• For Fluoxetine, Sertraline, paroxetine and bupropion, the rate of drug was only 1-2% higher than placebo.

• For venlafaxine XR and citalopram, the rate of headache was higher for placebo than drugs.

• A strong argument can be made headache is symptom of depression

• In group of patients, however, the strongest predictor of overall somatic symptom severity is the severity of depression at time of assessment.

• Another general factor contributing to side effects is the patient’s vulnerability

• For example, one of the best predictor of orthostatic hypotension during treatment is the presence of orthostatic hypotension prior to treatment.

• Seizures are more likely in a patient with history of seizures.

• Cardiac conduction problems are most likely occur in patient with cardiac conduction delay

• The final manifestation of somatic symptom during treatment is the net result of interaction of direct effect of medication on specific organs, indirect effect of medication on depression, symptoms of depression and patient’s vulnerability to certain symptoms

Central Nervous System effects

• The principal action of tricyclic and tetracyclics agents in CNS is to alleviate depression

• In particular, they reduce the symptom of depression rather than simply elevating mood

• The anticholinergic and antihistaminic effects of tricyclics and tetracyclics can produce confusion or delirium.

• The incidence of delirium is dose-dependent and increases at blood level above 300 ng/ml.

• One study reported that 67% of patients with blood level above 450 ng/ml developed delirium with tertiary amine including amitriptyline.

• The clinician should be careful in treating patient with severe depression

• This can be problematic in patients with psychotic depression.

• Patient with concurrent dementia are particularly to development of dementia and the more anticholinergic should be avoided in these patients

• IM or IV physostigamine can be used to reverse or reduce the symptom of delirium

• Its short duration of action makes the continued use of this agent difficult.

• Seizures can occur with all of tricyclics and tetracyclics agents and are dosage and blood level related.

• For clomipramine the risk of seizures if reported up to 0.5% at dosage up to 250 mg/day.

• At dosage above 250 mg/ day, risk of seizures increases to 1.67%

• For maprotiline, the overall risk of 0.4% but it increases above the maximum recommended dosage of 225 mg/day.

• The risk of seizures for older agents is not well established

• A retrospective meta-analysis of imipramine found an estimated rate of 1 per 1000 patients receiving dose less than 200 mg/day.

• Another larger review for amitriptyline and Doxepin found 1-4% risk at doses between 250-450mg/day.

• But the sample in studies was very small and confidence interval was too large.

• Seizures risk for secondary amine hasn’t been well established.

• Mechanism of action is not well established.• It is thought that seizures are induced by GABA

receptor ionophore complex, which decreases chloride conductance

• Risk of tremors has been associated with increased dosage and reduction of dosage results in improvement.

• Because amoxapine has 7-hydroxy metabolite with neuroleptic properties, these agents can rarely cause neuroleptic malignant syndrome and tradiv dyskinesia.

Anticholinergic effects

• Tricyclics can block muscarinic receptors and can cause dry mouth, blurry vision, urinary hesitancy and ocular crisis in patient with narrow angle glaucoma.

• Amitriptyline is most potent, followed by clomipramine.• Desipramine is least anticholinergic.• Amoxapine and maprotiline also have minimal

anticholinergic effects• Anticholinergic effects can contribute to tachycardia but it

can be as a result of stimulation of B-adrenergic receptors.

• Thus tachycardia rapidly occur in patient receiving desipramine

• An ocular crisis in patient with narrow angle glaucoma can cause severe pain

• Urinary retention can be associated with severe stretch injuries to bladder.

• Constipation can progress to obstipation• In these patients, medications should be

discontinued and supportive measures should be given.

• Elderly population is at greater risk for more severe side effects,

• Neuroleptic agents can precipitate these problems

• Tricyclics doesn’t effect patients with chronic angle glaucoma.

• Patient with narrow angle glaucoma who are receiving pilocarpine eye drops can be treated with tricyclics, as can those with iridectomy.

• Bethanecol at dosage of 25 mg, three or four times a day may be helpful in urinary hesitancy.

• Regular use of stool softener can be used for constipation

Antihistaminic effects

• Central H1 blockade can contribute to sedation and delirium.

• It can cause problems of increase appetite and weight gain in patients with chronic treatment.

• Doxepin is most potent H1 blocker, more than diphenhydramine.

• It has been surpassed by mirtazapine and olanzapine, which are even more potent.

• Tricyclics have been used as hypnotics because of its sedating effects

• Because of its cardiac effects and lethal overdose, practice should be discouraged

Cardiovascular effects

• Orthostatic hypotension is the most common reason for discontinuation.

• It can occur with all tricyclics but is less pronounced with Nortriptyline.

• Apha-1 adrenergic blockade contribute to orthostatic hypotension, however its postural reflex which is primarily affected.

• It is more likely to occur in patients with pre-existing orthostatic hypotension, patients who are getting volume depleting diuretics and in elderly population.

• Orthostatic hypotension can occur at low doses.• Gradual dose adjustment may allow to

accommodate to feeling of light-headedness but blood pressure take 4 weeks to accommodate.

• Fludrocortisones have been used to rise blood pressure but its not very effective.

• Doses of antihypertensive should be reduced.• Desipramine has been reported to raise supine

pressure in younger patients, although its not clear this effect is limited to this age group

• This effect may be reported similar to venlafaxine

Tachycardia

• Tachycardia can occur with all tricyclics, not only with more anticholinergic agents.

• There can be changes in both supine and postural pulse, and the standing pulses can be markedly elevated.

• A relatively recent study of Nortriptyline with therapeutic plasma concentration, found a means pulse rise of 11%( 8 beats per minute).

• Patient, don’t accommodate to pulse rise and it can persist for months.

• Tachycardia is more prominent in younger patients, who are more sensitive to sympathomimetic effect.

• It is one of the most common reasons for drug continuation in adolescents.

• A persistent pulse rise in older patients increases cardiac work and can lead to clinical significant effects in patients with IHD.

Effects on cardiac conduction

• Cardiac arrhythmia is principal cause of death following overdose.

• It has been a concern regarding use of TCA in patients with and without heart disease.

• They cause inhibition of Na/K – ATPase which stabilize the electrically excitable membrane and delay conduction particularly ventricular conduction.

• So, TCA has type 1 antiarrythmatic qualities or quinidine like effects.

• In patients with pre-existing conduction delay, TCA can further delay conduction and cause heart block.

• A pretreatment QTc interval of 450 msec or greater indicates that cardiac conduction is already delayed. TCA can aggravate this condition and patient is not a candidate for TCAs.

• High doses can further increase risk of cardiac toxicity.

• For example, first degree AV heart block is increased with plasma concentration of imipramine above 350 ng/ml.

• TCA can have beneficial effects on ventricular excitability at therapeutic levels.

Cardiac Output

• TCA don’t reduce cardiac contractility or cardiac output.

• Studies using radionuclide angiography indicate no adverse effect of imipramine or Doxepin on cardiac output, even in patients with diminished left ventricular ejection fraction.

• But orthostatic hypotension was common and can be severe in these patients.

• Glassman, noting that the type 1 antiarrhythmic drugs given following MI increases the risk of cardiac death.

• It suggested that tricyclics may pose similar risk.

• The risk of sudden death is also increased when heart variability is reduced and TCA reduces heart variability.

Sudden death

• Sudden death has been reported in five children under age of 12 who are receiving desipramine.

• It was suggested that immature conduction system in some children might render them more vulnerable to cardiac effects of desipramine.

• Subsequently, a study was conducted in 71 children with 24-hour cardiac monitoring.

• No cardiac abnormalities were observed.

• Wilens et al, examined the possibility that hydroxydesipramine might reach high levels in children and adolescent but such levels were not reported.

• A study of electrocardiographic parameters failed to show a relationship between those parameters and concentration of desipramine and hydroxydesipramine.

• These studies failed to reveal a mechanism of sudden death but they suggested these events are not predictable and dose dependent.

• So, blood levels or ECG monitoring doesn’t identify risk

Important points

• Considering clinical implications of cardiac side effects, it was suggested that in adults without with cardiac disease, orthostatic hypotension may occur but cardiac conduction problems are unlikely.

• In patients with preexisting cardiac conduction delay, the tricyclics may cause heart block.

• In patients with IHD, continued use of tricyclics will increase cardiac work and reduce heart rate variability, possibly increase risk of cardiac death

• Children younger than 12 years also appear vulnerable to the risk of sudden death during administration of tricyclics, possibly because of cardiac conduction effects or reduced heart variability.

• Cardiac arrhythmia is the most common cause of death with TCA overdose.

• These cardiac safety issues, coupled with recently reported safety of SSRIs Sertraline when administrated for depression following MI.

• It indicated tricyclics are relatively contraindicated in patients with IHD and there use be reserved for patients with treatment refractory depression

Hepatic Effects

• Acute hepatitis has been associated with administration of imipramine and desipramine.

• Mild increases of liver enzymes (less than three times of normal) are not uncommon and usually can be monitored safely over a period of seven days or weeks without potential harmful consequences.

• Acute hepatitis is relatively uncommon. • Etiology is not well established but in some

cases it appears because of hypersensitivity reaction

• It is characterized by AST levels> 800 which develop in few days.

• If a random blood test indicates mildly elevated liver enzyme, enzyme levels can be followed with in few days.

• Because of rapid rise in liver enzyme levels in acute hepatitis, that condition will be evident clinically quickly and can be distinguished from mild, persistent elevated liver enzymes.

• It is fatal and TCA should be stopped

Other side effects

• Increased sweating

• Weight gain

• Sexual dysfunction

• Allergic skin rashes

• Various rare blood dyscrasias

Overdose

• Antidepressant are used for depressed patients who are at risk for overdose, lethality of antidepressant is of great concern.

• A tricyclics overdose of 10 times the total daily dose can be fatal.

• Death, usually occur as a result of cardiac arrhythmias.

• However, Seizures and CNS depression can occur.

• Although they have not been used widely, Amitriptyline is still used for pain.

• Total number of death because of overdose associated with amitriptyline is comparable to all other tricyclics and tetracyclics.

• Mortality rate for TCA was 257/100000 and for SSRIs was 15.3/ 100000.

Teratogenicity

• Long history of TCA use without significant birth defects argues for safety of these agents.

• Dose adjustment is required if they will be used.• Drug withdrawal following delivery can cause

tachypnea, cyanosis, irritability and poor sucking reflex.

• The drug in this class should be discontinued one week before delivery.

• Tricyclics are excreted in breast milk similar to those in plasma,

• The actual delivered quantity, however, is small