Antidepressants and Mood stabilizers Caldwell 2012 Handout learning objectives 1.

Describe the metabolite of fluoxetine and its significance for the half-life of fluoxetine. 2. Give the microsomal inhibitory hierarchy for fluoxetine, paroxetine, citalopram. 3. Apply two ways to avoid tricyclic overdose to a clinically-relevant case scenario. 4. Describe 3 dynamic systems upon which lithium is capable of acting. 5. Apply how lithium is metabolized and removed from the body to a clinicallyrelevant case scenario. The WHO estimates that, by 2020, major depression will represent the second most significant overall cause of disability and disease burden after ischaemic heart disease, and will be the leading cause of disability and disease in women (Murdoch and Keam, Drugs, 65(16):2379, 2005) Where are the selective norepinephrine reuptake inhibitors (SNRIs)? Some of the original antidepressants, that are called the tricyclics [the secondary amines: desipramine (Norpramin, Pertofrane), amoxapine (Asendin), maprotiline (Ludiomil), nortriptyline (Pamelor), and protriptyline (Vivactil)], are very selective for action at norepinephrine (NE) reuptake sites. Venlafaxine (Effexor) is often called an SNRI. However, pharmacological profiles typically show it having an equal or even greater inhibition of 5-HT pumps. Several drugs under study that have a specificity for NE amine pumps include: oxaprotiline, levoprotiline, lofepramine, reboxetine. Some pharmacokinetics of the SSRIs Fluoxetine is well-absorbed with peak plasma levels within 4-8 hours. Fluoxetines demethylated metabolite, norfluoxetine has a half-life of 7-9 days at steady state; Fluoxetines is slightly shorter. Fluoxetine inhibits a number of enzymes which means many drug-drug interactions. Sertraline and paroxetine have pharmacokinetics similar to the tricyclics. These two have shorter half-lives than fluoxetine.

Definition of myoclonus One or a series of shock-like contractions of a group of muscles, of variable regularity, synchrony, and symmetry, generally due to a central nervous system lesion. One important effect of many SSRIs is that they inhibit functioning of liver enzymes called microsomal oxidases. Here is a hierarchy of such action among several SSRIs:

paroxetine>norfluoxetine>fluoxetine=sertraline>>clomipramine (Anafranil)>citalopram Antidepressants in pediatric populations The FDA recently determined that the only SSRI approved for use in Pediatric populations was Prozac. Plus one should remember that most drug company sponsored research shows that if patients are taken off of anti-depressants, they will show a relapse of symptoms. This means that if an adolescent begins taking an antidepressant they will most likely continue taking it for life. Given the severity of this action, it is best left to trained psychiatrists rather than a general practioner. Non-compliance with anti-depressants. Some reasons for non-compliance (not taking the drug as prescribed) Patients need to be warned of the long latency to effect of anti-depressants so as not to get discouraged (not their fault). Inability to tolerate adverse effects and discouragement. SSRIs advantage is here. Better tolerated. Some pharmacokinetics for the tricyclics. Most are incompletely absorbed and much is metabolized in first pass. High protein binding and relatively high lipid solubility, thus volumes of distribution are large. Metabolism by transformation of the ring nucleus results in hydroxylation and conjugation to form glucuronides. Metabolism by demethylation of side chains can result in active metabolites such as desipramine and nortriptyline. Amitriptyline more active than metabolite nortriptyline; but imipramines metabolite, desipramine is often more active. Adverse effects of tricyclics Most normal people find that moderate doses of TAs cause such disagreeable side-effects that they wouldnt take them (not drugs of abuse). However, the more depressed one is the more likely they are to tolerate disagreeable side-effects. Tricyclics have anti-muscarinic actions. Here are some common symptoms resulting from treatment with anti-muscarinic agents: Blurred vision Dry mouth Epigastric distress Constipation Tachycardia Urinary retention

Tricyclics-adverse Reactions
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Agranulocytosis anorexia anxiety constipation leukopenia parkinsonism

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Orthostatic hypotension. Myocardial infarction. QT& RS prolongation.

Tricyclics extremely dangerous in overdose quantities

Overdoses appear as: Danger of suicide coma with acidosis. attempts. respiratory depression Prescription < 1.25 agitation when conscious. g or 50 dose units of seizures. 25 mg, no refill. bowel and bladder entrust drug to paralysis. relative. cardiac arrythmias.

Other Indications for all ADs

Attention Deficit Disorder Panic and anxiety disorders OCD (not Bupropion) Post-traumatic Stress Disorder

Enuresis (tricyclics) Anorexia nervosa Chronic pain (tricyclics??) Cataplexy of narcolepsy.

*definition of cataplexy A transient attack of extreme generalized muscular weakness, often precipitated by an emotional state such as laughing, surprise, fear, or anger.

Mood stabilizers
Lithium Evidence that lithium acts on neurotransmitters: Some evidence that lithium enhances 5-HT action. May decrease DA and NE turnover (needs study) which agrees with increased NE turnover in mania. Blocks DA receptor supersensitivity that develops with anti-psychotics.

Thoughts on treating with lithium Tricyclics and SSRIs often precipitate mania (accelerate cycling?) Lithium is used prophylactically, to prevent mania and depression. Alcoholism is often associated with bipolar, and lithium reduces drinking when the conditions coexist.

Pharmacokinetics of lithium As a small inorganic ion it is distributed in body water and is not metabolized.

Excreted by kidneys (reduce dose if creatinine clearance is impaired).

Because of the adverse effects of lithium and the difficulty removing it if it is overdosed, it needs to be carefully monitored, particularly when first dosed. Monitoring Complete blood count, urinalysis and blood tests, ECG in older pts as baseline measures (sinus node effect). 5 days after beginning read steady state Li+ levels. Every 5 days until desired level has been achieved and then can increase intervals of monitoring. The patient should be kept on lithium once the manic symptoms disappear (called Maintenance Therapy): If pt has had only one cycle or is unreliable stop Lithium after one course with gradual discontinuation. If cycles are worsening or more frequent or > once/year then maintain them on Lithium after remission, with approval of patient. Some adverse effects of lithium Polyuria and polydipsia are problems. Tremor (can use propranolol to alleviate). mental confusion, withdrawal and bizarre movements. Stop the Lithium and monitor serum levels. With overdose can use hemodialysis to remove. Bradycardia-tachyardia (sick sinus) syndrome is a definite contraindication to use of lithium because Li further depresses the sinus node. Lithium is transferred into breast milk. Li overdose in infants appears as lethargy, cyanosis, poor suck response and Moro reflexes. Other indications for lithium Schizoaffective disorders are mixed mania and schizophrenia; anti-psychotics and lithium used in the manic phase. Adding lithium to anti-psychotics may salvage otherwise treatment-resistant schizophrenics. Here is a warning for use of depakote in pediatric populations. HEPATIC FAILURE RESULTING IN FATALITIES HAS OCCURRED IN PATIENTS RECEIVING VALPROIC ACID AND ITS DERIVATIVES. EXPERIENCE HAS INDICATED THAT CHILDREN UNDER THE AGE OF TWO YEARS ARE AT A CONSIDERABLY INCREASED RISK OF DEVELOPING FATAL HEPATOTOXICITY, ESPECIALLY THOSE ON MULTIPLE ANTICONVULSANTS, THOSE WITH CONGENITAL METABOLIC DISORDERS, THOSE WITH SEVERE SEIZURE DISORDERS ACCOMPANIED BY MENTALRETARDATION, AND THOSE WITH ORGANIC BRAIN DISEASE. WHEN DIVALPROEXSODIUM IS

USED IN THIS PATIENT GROUP, IT SHOULD BE USED WITH EXTREME CAUTION AND AS A SOLE AGENT. THE BENEFITS OF THERAPY SHOULD BE WEIGHED AGAINST THE RISKS. ABOVE THIS AGE GROUP, EXPERIENCE IN EPILEPSY HAS INDICATED THAT THE INCIDENCE OF FATAL HEPATOTOXICITY DECREASES CONSIDERABLY IN PROGRESSIVELY OLDER PATIENT GROUPS.