Some tricycle anti-depressants have been successfully used to lessen the problems associated with depression. This paper addresses information available about Clozapine (a tricyclic dibenzodiazepine), Protriptyline (a dibenzocycloheptene derivative), and Clomipramine (a dibenzazepine). Tricyclic antidepressants work by inhibiting the reuptake of norepinephrine and serotonin into nerve terminals. Clomipramine is prescribed to control obsessional behaviour (an antiobsessional drug); it is a very strong drug which must be used with care. The strong sedative properties of Clomipramine require careful observation of patients during the treatment. It was found the Clozapine is commonly taken by oral dosage to lessen effects of depression. Protriptyline which was marketed as Vivactil® has been taken off the market due to the severe side effects and risky drug interactions. Clomipramine is marketed as Anafranil®. Clozapine has the most information in the literature and of the three is the safest to use.
(Clozapine, Protriptyline, Clomipramine, Vivactil®, Anafranil®, tricyclic antidepressants)
Tricyclic Anti-depressants: Clozapine, Protriptyline, and Clomipramine
Tricyclic drugs are one of the three classes of medicine used in the treatment of depression and related illnesses. The first class includes both tricyclic antidepressants and the Selective Serotonin Reuptake Inhibitors (SSRIs). The mechanism in both is to stop (inhibit) the reuptake of serotonin and/or noradrenalin.
Absorpitivity of the tricyclic antidepressants into the blood stream is rapid. The therapeutic response in the patient takes four to six weeks after the start of dosing.
The first change to brain processes by the tricylics is to stop neurotransmission of serotonin and/or noradrenalin. It has been hypothesized that the secondary processes are responsible for helping the patient (Cowen, 146). The tricyclics are generally divided into two groups; the secondary and tertiary; “tertiary have a terminal methyl group on the side chain, . . . secondary amines do not” (Cowen, 146). Clinically the tertiary amine group has been found to be stronger as the prevention mechanism.
The tricyclics can be identified by their three-ring molecular structure from which other groups are attached. The development of tricyclics has produced derivatives of those originally designed (see Appendices). For example Clozapine is a derivative and has a very unusual configuration compared to Protriptyline.
Possible side effects that the drugs have in common are drowsiness, weight gain, hypoglycemia, dry mouth or low fever. Other side effects might include dizziness, loss of concentration, some problems with memory, or an arrhythmic heartbeat. Clomipramine is a particularly strong medication so if a patient has a tendency to any of the above side effects they would probably be worsened with Clomipramine. I would cut the dosage for Clomipramine if it was the best choice for the particular patient’s obsessional behavior or depression. The recommended way to control the dosage for the pharmaceuticals, especially Clomipramine is to start with a small dosage. During the first weeks the doctor must observe the patient carefully. Increments of increased dosage can be added (for example each day or each week) until the patient shows signs of improvement. It is expected that 4 to 6 weeks are necessary before behavioral or mood changes become evident.
Clozapine has a very concerning side effect that requires blood tests while it is being used for treatment. The drug can have the side effect of decreased production of white blood cells so special precaution needs to be taken; the white blood cells are needed to fight off infections. During therapy with Clozapine blood tests must be taken frequently.
Regular Blood testing is required. Dosing should be based on whether or not the patient can take a White Blood Cell (WBC) count and Absolute Neutrophil Count (ANC). So if patient can take these tests every 2 weeks than a 2 weeks dose can be given; if every 4 weeks than a 4 week dose. (Clozapine, Novartis, Clinical use instructions)
Adverse effects of Clozapine have included: ‘Agranulocytosis, seizures, myocarditis, Orthost hypotension’ and there is an increased risk of death in elderly patients having dementia or dementia related psychosis. (Clozapine, Novartis, Clinical use instructions)
Protriptyline The US FDA discontinued the use of Protriptyline. It has dangerous side effects involving the cardiovascular system, the neurological system and may cause psychotic symptoms. It can also make the illness worse instead of better. Older patients must be monitored for heart rate and urination frequency if medicated with Protriptyline. Protriptyline was available in tablets at two concentrations 5-mg and 10-mg. The daily doses ranged from 15 to 40 mg/day.
When the drug regime is ending the dosage should be decreased gradually and constant observation of the patient is very important during this time.
Clomipramine is suggested for situations where sedation is required such as “depressive states, phobias and cataplexy associated with narcolepsy” (emc/Novartis, Heading 4.1). This drug should not be used by children or adolescents. A very small starting dose of 10 mg is recommended for elderly patients with increases to only 30-75 mg daily (can be increased over a 10-day time period). The elderly patient can stay at the peak rate until the end of treatment. It should be emphasized that Clomipramine should only be used in severe cases where sedation is required.
The mechanisms for the drugs discussed above are the same as tricyclic antidepressants in general, they block serotonin and noradrenalin.
How the Pharmacokinetics Related to the Recommended Dosage Regimes
The characteristics of absorption, distribution, metabolism and elimination are very important to know in order to evaluate the correct dose. Some drugs like Clozapine must be started at a low dose until a safe level is reached in the blood stream. That level can be maintained depending on the patient’s response. Other antidepressants like Protriptyline may be better with the dose/day taken in increments throughout the day. Clomipramine is a very strong drug that has high sedative properties. Starting doses and peak doses should be smaller than for Clozapine in general. The symptoms of patients requiring Clozapine are different than those requiring Clomipramine. Clomipramine is necessary for severe cases and should be used with great care.
Prescribing to children and elderly people probably isn’t a good idea. Some references seemed to indicate that these age groups could handle antidepressants and gain help from them. I did not find data to support that assumption.
Compare and contrast the side effect profiles. How can this be used in the selection of appropriate drug for an individual patient?
Although Clozapine has some real risks if all the protocols are followed for blood testing and negative interaction with other drugs, the efficacy is very good. It was also reported by Merck that Clozapine works for schizophrenia when other pharmaceuticals have failed. Due to the dangerous risk to systems in the human body I would not use Protriptyline. A severely depressed person should not have a drug with such a low-dose/high-toxicity easily available to them. The side effects of Clomipramine include the risk in all antidepressants given to patients with suicidal tendencies: the risk of death by suicide before the adequate dosage can be reached. With Clomipramine anxiety may be increased at the start of the pharmaceutical regime; episodes of hypomanic or manic may occur requiring lessening of dose or withdrawal completely of Clomipramine. Some incidents with patients with schizophrenic induced’ activation of psychosis’ (emc/Novartis, Heading 4.4).
References
Clorazil Novartis Clinical description http://www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf
Cowes , P. J. Pyschopharmacology. Chapt. 6, (eds.) Alan s. Bellack & Michel Hersen. Comprehensive Clinical Psychology, Volume 6. New York, NY: Pergamon (1998) pp. 135-162.
Discontinuation of the drug. Vivactil®.Tablts (protriptyline HCL, USP) FDA.gov. http://www.fda.gov/downloads/Drugs/DrugSafety/ucm089820.pdf
Drug Bank http://www.drugbank.ca/drugs/DB00344
Kim K-H, Lee S-M, Paik J-W, Kim N-S. (2011) The effects of continuous antidepressant treatment during the first 6 months on relapse or recurrence of depression. Journal of Affective Disorders. 132: 121-129.
Kirchheiner, J., Nickchen, K., Bauer, M., Wong, M-L, Licinio, J., Roots, I., & Brockmoller, J. (2004). Pharmacogenetics of antidepressants and antipsychotics: The contribution of allelic variations to the phenotype of drug response. Molecular Psychiatry. (9) 442, 473 J. Med. Chem. 11 (2): 325–32. doi:10.1021/jm00308a031
Kovachich, G. B., Aronson, C. E., & Brunswick, D. J.: Effect of repeated administration of antidepressants on serotonin uptake sites in limbic and neocortical structures of rat brain determined by quantitative autoradiography. Neuropsychopharmacology. 1992 Dec;7(4):317-24.
Vivactil – protriptylinehydrochloride tablet, film coated, Duramed Pharmaceuticals, Inc.http://www.pharmgkb.org/download.action?filename=Protriptyline_8_8_11.pdf
emc/Novartis informational website http://www.medicines.org.uk/emc/medicine/4091/SPC/anafranil%20capsules/#CLINICAL_PARTS
Appendices
CLOZARIL®
IUPAC name: (clozapine), an atypical antipsychotic drug, is a tricyclic dibenzodiazepine
derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine. CLOZARIL is available in pale yellow tablets of 25 mg and 100 mg for oral administration.
25 mg and 100 mg Tablets
Active Ingredient: clozapine is a yellow, crystalline powder, very slightly soluble in water.
Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch
DESCRIPTION
IUPAC name, HCl is N-methyl-5H dibenzo[a,d]-cycloheptene-5-propanamine hydrochloride. Its molecular formula is C19H21N•HCl
and its structural formula is:
Protriptyline HCl, a dibenzocycloheptene derivative, has a molecular weight of 299.84. It is a white to yellowish powder that is freely
soluble in water and soluble in dilute HCl. Protriptyline HCl is supplied as 5 mg or 10 mg film-coated tablets. Inactive ingredients
are anhydrous lactose, carnauba wax, corn starch, dibasic calcium phosphate, hydroxypropyl cellulose, hypromellose, magnesium
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, propylene glycol, sodium starch glycolate, titanium dioxide,
and the 5 mg tablets contain FD&C Yellow #6 and FD&C Red #40; the 10 mg tablets contain D&C Yellow #10 and D&C Red #30.
Reference Vivactil – protriptylinehydrochloride tablet, film coated, Duramed Pharmaceuticals, Inc.
Clomipramine.
IUPAC Clomipramine hydrochloride USP is 3-Chloro-5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine monohydrochloride,
Clomipramine hydrochloride USP is a white to off-white crystalline powder. It is freely soluble in water, in methanol, and in methylene chloride, and insoluble in ethyl ether and in hexane.
Inactive Ingredients. D&C Red No. 33 (25-mg capsules only), D&C Yellow No. 10, FD&C Blue No. 1 (50-mg capsules only), FD&C Yellow No. 6, gelatin, magnesium stearate, methylparaben, propylparaben, starch (corn), and titanium dioxide.
Anafranil®, (clomipramine hydrochloride capsules USP), is an antiobsessional drug that belongs to the class (dibenzazepine) of pharmacologic agents known as tricyclic antidepressants. Anafranil (clomipramine hcl) is available as capsules of 25, 50, and 75 mg for oral administration. (Novartis) http://www.rxlist.com/anafranil-drug.htm Informational website emc/Novartis
