Frequently asked questions about Topiramate, used for treatment of mood disorders -mania and depression- and PTSD.

NOTE: Topiramate (Topamax) is only approved for the treatment of people with seizures. There are few systematic studies that establish the safety or efficacy of topiramate as a treatment for people with mood disorders or PTSD. While such studies are underway, what is currently known about the use of topiramate for the control of mood disorders and PTSD comes mostly from uncontrolled case reports.

1. What is topiramate (Topamax)?

Topiramate is an anticonvulsant that is chemically unrelated to any other anticonvulsant or mood regulating medication. The mechanism of action is unknown.

2. When was topiramate approved for marketing in the USA and for what indications may it be promoted?

Topiramate received final approval for marketing in the USDA on 24 December 1996 and is labeled for use as an anticonvulsant.

3. Is a generic version of topiramate available?

There is no generic topiramate as the manufacturer has patent protection.

4. How does topiramate differ from other mood stabilizing drugs?

Topiramate differs from other mood stabilizing drugs in two major ways:

1. topiramate's frequent effectiveness for patients who have failed to respond to antidepressants or mood stabilizers;
2. topiramate's unique side-effect profile.

5. What, if anything, uniquely distinguishes topiramate from carbamazepine and valproate?

Topiramate has been successful in controlling rapid cycling and mixed bipolar states in people who have not received adequate relief from carbamazepine and/or valproate.

6. People with what sorts of disorders are candidates for treatment with topiramate?

It is too early to be very specific about which mood disorders are most likely to respond to treatment with topiramate. There are just about no published reports on topiramate's use in psychiatry. Patients with hard-to-treat bipolar syndromes have been treated more often than patients with "treatment-resistant" unipolar disorders.

Topiramate seems especially useful when it comes to treating people who have become manic as the result treatment with lamotrigine.

There has recently been a report regarding the control of the symptoms of PTSD by topiramate.

7. Is topiramate useful for the treatment of acute depressed, manic and mixed states, and can it also be used to prevent future episodes of mania and/or depression?

The initial use of topiramate was to treat people with depressed, manic rapid-cycling, and mixed states that did not respond to existing medications. Some patients are now being maintained on topiramate on a long term basis in an attempt to prevent future episodes. The effectiveness of topiramate as a long-term prophylactic agent is currently being established.

8. Are there any laboratory tests that should precede the start of topiramate therapy?

Before topiramate is prescribed the patient should have a thorough medical evaluation, including blood and urine tests, to rule out any medical condition, such as thyroid disorders, that may cause or exacerbate a mood disorder.

9. How is treatment with topiramate initiated?

Topiramate is usually initially prescribed at an initial dose of 12.5 -25 mg once or twice a day and the total daily dose is increased by 12.5 - 25 mg every week. When prescribed in addition to other anticonvulsants being used as mood stabilizers, the final dose is often between 100 and 200 mg per day. Some patient with Bipolar Disorder do well on as little as a total daily dose of 50 mg/day. When used for the control of the symptoms of PTSD the average final dose is about 175 mg/day (with a range of 25 - 500 mg/day).

10. Are there any special problems prescribing topiramate for people taking lithium, carbamazepine (Tegretol), or valproate (Depakene, Depakote)?

An interaction between lithium and topiramate has not been reported.

Carbamazepine and valproate both have the ability to lower plasma levels of topiramate . . . carbamazepine by about 50% and valproate by about 15%. Topiramate has no effect on the plasma level of carbamazepine but can reduce the plasma level of valproate by about 10%. Pharmacokinetic interactions between topiramate and either lamotrigine (Lamictal) or gabapentin (Neurotin) have not been reported.

11. What is the usual final dose of topiramate?

When used as a mood-stabilizing agent the final dose of topiramate is most often between 50 and 200 mg/day. Some people require doses as high as 400 mg/day to achieve a good mood stabilizing effect . . . especially when topiramate is being used as a monotherapy . . . while others do fine on 25 mg/day.

12. How long does it take for topiramate to 'kick-in?'

While some people notice the antimanic and antidepressant effects early in treatment, others have to take a therapeutic amount of topiramate for up to a month before being aware of a significant amount of improvement.

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13. What are the side-effects of topiramate?

Here is a listing of topiramate's side effects that affected 10% or more of the 711 people taking the drug during clinical trials and the frequency of those side effects in the 419 people treated with placebo in those trials:

Common Adverse Reactions (%)
(Topiramate = 200 mg/day)

Side-effects are most noticeable the few days after an increase in dose and then often fade.

14. Which side-effects are severe enough to force people to discontinue topiramate?

The side-effects that most frequently caused people to discontinue therapy with topiramate were: psychomotor slowing (4.1%), memory problems ( (3.3%), fatigue (3.3%), confusion (3.2%), and somnolence (3.2%).

Much less frequently happening but more serious side-effects that force people to stop topiramate therapy include kidney stones, which affect about 1% of people taking the drug, and acute glaucoma, which to date had been reported in about one person in 35,000 taking topiramate. The sudden onset of back pain may indicate the presence of a kidney stone, while eye pain, changes in vision or the the develpment of redness in the eye may indicate glaucoma. Most cases of glaucoma have devdeloped within the first two months of therapy with topiramate.

Information from the FDA on topiramate and glaucoma.

15. Does topiramate have any psychiatric side effects?

Among the reported side effects of topiramate are sedation, psychomotor slowing, agitation, anxiety, concentration problems, forgetfulness, confusion, depression, and depersonalization. As with other anticonvulsants, psychosis has rarely been reported as a side-effect.

16. How does topiramate interact with prescription and over-the-counter medications?

Only a few interactions between topiramate and other drugs have been identified. Topiramate may increase the plasma level of phenytoin (Dilantin). Phenytoin lowers the concentration of topiramate in the blood by about 50%. While topiramate has little effect on the plasma level of carbamazepine, the latter may decrease the plasma level of topiramate by about 50%. Valproate lowers the plasma level of topiramate by about 15%. Topiramate may lead to decreased effectiveness of some oral anticontraceptives.

Interactions with other prescription and over-the-counter drugs are not known at this time.

17. Is there an interaction between topiramate and alcohol?

Alcohol may increase the severity of the side-effects of topiramate.

18. Is topiramate safe for a woman who is about to become pregnant, pregnant or nursing an infant?

Topiramate is has been placed in the FDA pregnancy Category C:

"Animal studies have shown an adverse effect on the fetus but there are no adequate studies in humans; The benefits from the use of the drug in pregnant women may be acceptable despite its potential risks . . . ."

19. Is topiramate safe for children and adolescents?

The FDA has recently approved the use of topiramate in children.

20. Can topiramate be used in elderly people?

Older people seem to handle topiramate similarly to younger ones. There is little experience using topiramate for the treatment of psychiatric disorders in the elderly.

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21. Do symptoms develop if topiramate is suddenly discontinued?

There are no specific symptoms that have been described following the abrupt discontinuation of topiramate, other than the seizures that sometimes follow the rapid discontinuation of any anticonvulsant. Only when necessary because of a serious side effect, should topiramate be suddenly discontinued.

22. Is topiramate toxic if taken in overdose?

There is only limited data on the effects of overdoses of topiramate. There have been no reports of deaths following an overdose.

23. Can topiramate be taken along with MAO inhibitors?

Yes, the combination has been used without any special problems.

24. What does topiramate cost?

As of 21 March 04, an on-line pharmacy (Drugstore.com) was selling topiramate for the following amounts per tablet (when bought in lots of 100 tablets):

25 mg - $1.45
100 mg - $2.06
200 mg - $2.6725. Might topiramate be effective in people who have failed to receive benefit from other psychopharmacologic agents?

The major use of topiramate in psychiatry is with people who have mood disorders that have not been adequately controlled by other medications at times including lamotrigine and gabapentin. A developing use is for people with PTSD.

Topiramate has also been shown to decrease craving for alcohol in people with alcoholism, and to prevent migraine headaches.

26. What are the advantages of topiramate?

Topiramate seems to be effective in some people with bipolar mood disorders that have not responded to lithium and/or other mood-stabilizers. Some people who have not been able to tolerate any antidepressant because of switches to mania or increased speed or intensity of cycling, or because of the development of mixed states, have been able to tolerate therapeutic doses of anti- depressants when taking topiramate.

For most people, topiramate has tolerable side effects and it can be taken twice a day.

The weight loss that accompanies topiramate therapy in some instances is useful for those individuals who have gained weight while taking other mood stabilizing drugs. In some studies 20-50% of people taking topiramate lost weight.

27. What are the disadvantages of topiramate?

As topiramate has only been available for a relatively short time, it was first marketed in 1996, there is no information about long term side-effects. As its use with people with mood disorders started even more recently, it is not known if people who initially do well on topiramate continue to do so after many years of treatment.

Topiramate increases the probability of kidney stones. the development of kidney stones may be prevented by increasing one's intake of water.

28. Why should physicians prescribe, and patients take, topiramate, when there are mood regulating medications that have been available for many years and which have been shown to be effective in double-blind placebo- controlled studies?

There are two major reasons why physicians prescribe and patients take topiramate rather than conventional, better established drugs. They are that not everyone benefits from treatment with the older, better known drugs, and that some patients find the side effects of the established drugs to be unacceptable.

As there has not been a good psychopharmacologic treatment for people with PTSD, topiramate offers such people the possibility of medically -induced relief.

29. Is topiramate available in countries other than the USA?

Topiramate is available in many countries throughout the world.

30. Has anything been published on the use of topiramate as a therapeutic agent for people with mood disorders and/or PTSD?

While reports on the use of topiramate as a treatment for people with mood disorders and PTSD have been presented at various psychiatric meetings, little is in print about the psychiatric uses of this medication.

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The following publications are relevant to the psychiatric uses of topiramate:

Alao AO, Dewan MJ.
J Nerv Ment Dis. 2001 Jan;189(1):60-3.
Evaluating the tolerability of the newer mood stabilizers.
[No MEDLINE abstract available]

American Journal of Ophthalmology 2001, 132, 112-114
Presumed topiramate-induced bilateral acute angle-closure glaucoma.
[MEDLINE abstract]

Andrade C.
Bipolar Disord. 2001 Aug;3(4):211-212.
Confusion and dysphoria with low-dose topiramate in a patient with bipolar disorder.
[MEDLINE abstract]

Barbee JG.
Intwenational Journal of Eating Disorders, 2003, 33, 468-472. Topiramate in the treatment of severe bulimia nervosa with comorbid mood disorders: A case series. [MEDLINE abstract]

Berlant JL.
Journal of Clinical Psychiatry 2001, 62 (Suppl 17), 60-63.
Topiramate in posttraumatic stress disorder: preliminary clinical observations.
[MEDLINE abstract]

Berlant J.
Poster, presented at 39th Annual Meeting New Clinical Drug Evaluation Program (NIMH) Boca Raton, Florida, June 1-4, 1999.
Open-lable topiramate treatment of post-traumatic stress disorder.

Berlant J.
Journal of Clinica Psychiatry 2002, 63, 15-20.
Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: a preliminary report.
[MEDLINE abstract]

Besag FM.
Drug Safety 2001, 24, 513-536.
Behavioral effects of the new anticonvulsants.
[MEDLINE abstract]

Bowden CL.
Expert Opin Investig Drugs. 2001, 10, 661-671.
Novel treatments for bipolar disorder.
[MEDLINE abstract]

Brandes JL, Saper JR, Diamond M, et al.
Journal of the Americcan Medical Associagtion, 2004, 291,965-973.
Topiramate for migraine prevention: A randomized controlled trial.
[MEDLINE abstract]

Calabrese JR, Keck PE Jr, McElroy SL, Shelton MD.
Journal of Clinical Psychopharmacology 2001, 21, 340-342.
A pilot study of topiramate as monotherapy in the treatment of acute mania.
[MEDLINE abstract]

Calabrese JR, van Kammen DP, Shelton MD, et al
American Psychiatric Association Annual Meeting 1, New Research Abstracts NR680
Topiramate in severe treatment-refractory mania.
[No MEDLINE abstract available]
[MEDLINE abstract]

Calabrese JR, Shelton MD, Rapport DJ, Kimmel SE.
Journal of Clinical Psychiatry 2002, 63 (Suppl 3),5-9.
Bipolar disorders and the effectiveness of novel anticonvulsants.

Carpenter LL, Leon Z, Yasmin S, Price LH
Journal of Affective Disorders 2002 May; 69, 251-255.
Do obese depressed patients respond to topiramate? a retrospective chart review.
[MEDLINE abstract]

Cassano P, Lattanzi L, Pini S, et al.
Bipolar Disorders 2001, 3, 161.
Topiramate for self-mutilation in a patient with borderline personality disorder.
[No MEDLINE abstract available]

Chengappa K N, Gershon S, Levine J. Bipolar Disorders 2001, 3,215-232
The evolving role of topiramate among other mood stabilizers in the management of bipolar disorder.
[MEDLINE abstract

Chengappa KN, Rathore D, Levine J, et al.
Bipolar Disorder. 1999 Sep;1(1):42-53.
Topiramate as add-on treatment for patients with bipolar mania.
[MEDLINE Abstract]

Chengappa KN, Levine J, Rathore D, Parepally H, Atzert R.
European Psychiatry 2001, 16, 186-190.
Long-term effects of topiramate on bipolar mood instability, weight change and glycemic control: a case-series.
[MEDLINE abstract]

Colom F, Vieta E, Benaberra A, et al
Journal of Clinical Psychiatry 2001, 62, 475-476.
Topiramate abuse in a bipolar patient with an eating disorder.
[MEDLINE abstract]

Davanzo P, Cantwell E, Kleiner J, et al.
Journal of the American Academy of Child and Adolescent Psychiatry 2001, 40, 262-263.
Cognitive changes during topiramate therapy.
[No MEDLINE abstract available]

De Leon OA. Harvard Review of Psychiatry. 2001, 9, 209-222.
Antiepileptic drugs for the acute and maintenance treatment of bipolar disorder.
[MEDLINE abstract]

DelBello MP, Kowatch RA, Warner J, et al.
Journal of Child and Adolescent Psychopharmacology, 2002, 12, 323-330.
Adjunctive topiramate treatment for pediatric bipolar disorder: a retrospective chart review.
[MEDLINE abstract]

Deutsch SI, Schwartz BL, Rosse RB, et al.
Clinical Neuropharmacology, 2003, 26, 199-206.
Adjuvant topiramate administration: a pharmacologic strategy for addressing NMDA receptor hypofunction in schizophrenia.
[MEDLINE abstract]

Doan RJ, Clendenning M.
Canadian Journal of Psychiatry 2000, 45, 937-938.
Topiramate and hepatotoxicity.
[No MEDLINE abstract available]

Drapalski AL, Rosse RB, Peebles RR, Schwartz BL, Marvel CL, Deutsch SI.
Clinical Neuropharmacology 2001, 24, 290-294.
Topiramate improves deficit symptoms in a patient with schizophrenia when added to a stable regimen of antipsychotic medication.
[MEDLINE abstract]

Dursun SM, Deakin JF.
J Psychopharmacol 2001 Dec;15(4):297-301.
Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia: A naturalistic case-series outcome study.
[MEDLINE Abstract]

Dursun SM, Devarajan S.
Canadian Journal of Psychiatry 2001, 46, 287-288.
Accelerated weight loss after treating refractory depression with fluoxetine plus topiramate: possible mechanisms of action?
[No MEDLINE abstract available]

Erfurth A, Kuhn G.
Neuropsychobiology 2000, 42 (Suppl 1), 50-51.
Topiramate monotherapy in the maintenance treatment of bipolar I disorder: Effects on mood, weight and serum lipids.
[MEDLINE abstract]

Felstrom A, Blackshaw S.
American Journal of Psychiatry, 2002, 159, 1246-1247 .
Topiramate for bulimia nervosa with bipolar II disorder. [No MEDLINE abstract available]

Gareri P, Falconi U, de Fazio P et al.
Progress in Neurobiology 2000, 61, 353-396.
Conventional and new antidepressants drugs in the elderly.
[MEDLINE abstract]

Ghaemi S N, Manwani S G, Katzow J J, Ko J Y, Goodwin F K.
Annals of Clinical Psychiatry 2001, 13, :185-189.
Topiramate treatment of bipolar spectrum disorders: A retrospective chart review.
[MEDLINE abstract]

Gitlin MJ.
Bulliten of the Menninger Clinic 2001 65, 26-40.
Treatment-resistant bipolar disorder.
[MEDLINE abstract]

Goldberg JF, Burdick KE.
Journal of Clinical Psychiatry 2001, 62 Suppl 14, 27-33.
Cognitive side effects of anticonvulsants.
[MEDLINE abstract]

Gordon A, Price LH
American Journal of Psychiatry 1, 156, 968-969.
Mood stabilization and weight loss with topiramate.
[No MEDLINE abstract available]

Grunze HC, Normann C, Langosh J et al.
Journal of Clinical Psychiatry 2001,62, 464-468.
Antimanic effacacy of topiramate in 11 patients in an open trial with an on-off-on design.
[MEDLINE abstract]

Jochum T, Bar KJ, Sauer H. J Neurology Neurosurgery and Psychiatry, 2002, 73, 208-209
Topiramate induced manic episode.
[No MEDLINE abstract available]

Khan A, Faught E, Gelliam F. et al.
Seizure 1, 8, 235-237.
Acute psychotic symptoms induced by topiramate.
[MEDLINE abstract]

Ketter TA et al.
Neurology 1, 53, (5, Suppl 2), S53-S67.
Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders.
[MEDLINE abstract]

Ketter TA et al.
Cell Mol Neurobiology 1, 19, 511-532.
Metabolism and excretion of mood stabilizers and new anticonvulsants.
[MEDLINE abstract]

Klufas A, Thompson D.
American Journal of Psychiatry. 2001, 158, 1736.
Topiramate-induced depression.
[No MEDLINE abstract available]

Komanduri R.
Journal of Clinical Psychiatry, 2003, 64, 612.
Two cases of alcohol craving curbed by topiramate.
[No MEDLINE abstract available]

Kupka RW, Nolen WA, Altshuler LL et al.
British Journal of Psychiatry, Suppliment 2001, 41, s177-s183.
The Stabley Foundation Bipolar Network. 2. Preliminary ssummary of demographics, ccourse of illness and response to novel treatments.
[MEDLINE abstract]

Kusumakar V, Yatham LN, O'Donovan CA, et al
American Psychiatric Association Annual Meeting 1, New Research Abstracts NR477
Topiramate in rapid-cycling bipolar women.
[No MEDLINE abstract available]

Letmaier M, Schreinzer D, Wolf R, Kasper S.
International Clinical Psychopharmacology. 2001, 16, 295-298.
Topiramate as a mood stabilizer.
[MEDLINE abstract]

Li X, Ketter TA, Frye MA
Journal of Affective Disorders 2002, May;69, 1-14.
Synaptic, intracellular, and neuroprotective mechanisms of anticonvulsants: are they relevant for the treatment and course of bipolar disorders?
[MEDLINE abstract]

McElroy SL, Suppes T, Keck PE, et al
Biological Psychiatry, 2000, 47, 1025-1033.
Open-label adjunctive topiramate in the treatment of bipolar disorders.
[MEDLINE abstract]

McIntyre RS, Mancini DA, McCann S, Srinivasan J, Sagman D, Kennedy SH.
Bipolar Disorders. 2002, 4, 207-213.
Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study.
[MEDLINE abstract]

Maidment ID
Annals of Pharmacotherapy, 2002, 36(7):1277-1281 .
The use of topiramate in mood stabilization.
[MEDLINE abstract]

Marcotte D
Journal of Affective Disorders 1998, 50, 245-251.
Use of topiramate, a new anti-epileptic as a mood stabilizer.
[MEDLINE abstract]

Martin R, Kuzniecky R, Ho S, et al.
Neurology, 1, 15, 321-327.
Cognitive side effects of topiramate, gabapentin, and lamotrigine in healthy young adults.
[MEDLINE abstract]

Millson RC, Owen JA, Lorberg GW, Tackaberry L.
American Journal of Psychiatry 2002, 159, 675.
Topiramate for refractory schizophrenia.
[No MEDLINE abstract available]

Normann C, Langosch J, Schaerer LO et al.
American Journal of Psychiatry, 1, 156, 2014.
Treatment of acute mania with topiramate.
[No MEDLINE abstract available]

Pavuluri MN, Janicak PG, Carbray J.
Journal of Child and Adolesc Psychopharmacology, 2002, 12, 271-273.
Topiramate plus risperidone for controlling weight gain and symptoms in preschool mania.
[No MEDLINE abstract available]

Pecuch PW, Erfurth A.
Journal of Clinical Psychopharmacology 2001 21, 243-244.
Topiramate in the treatment of acute mania.
[ No MEDLINE abstract available]

Pinninti NR, Zelinski G.
Journal of Clinicsl Psychopharmacology, 2002, 22, 340 .
Does topiramate elevate serum lithium levels?
[No MEDLINE abstract available]

Post RM
Schizophrenia Research 1, 39, 153-158.
Comparative pharmacology or bipolar disorder and schizophrenia.
[MEDLINE abstract]

Post RM, Frye MA, Denicoff KD, et al.
Neuropsychopharmacology 1998 Sep;19(3):206-219
Beyond lithium in the treatment of bipolar illness.
[MEDLINE abstract]

Post RM, Frye MA, Denicoff KD et al.
Bipolar Disorders 2000, 2, 305-315. Emerging trends in the treatment of rapid cycling bipolar disorder: a selected review.
[MEDLINE abstract]

Schlatter FJ, Soutullo CA, Cervera-Enguix S.
Journal of Clinical Psychopharmacology 2001 21, 464-466.
First break of mania associated with topiramate treatment.
[No MEDLINE abstract available]

Tondo L, Hennen J, Baldessarini RJ.
Acta Psychiatr Scand. 2003 Jul;108(1):4-14.
Rapid-cycling bipolar disorder: effects of long-term treatments.
[MEDLINE abstract]

Vieta E, Gilabert A, Rodriguez A, et al.
Actas Esp Psiquiatr 2001, 29, 148-152.
Effectiveness and safety of topiramate in treatment-resistant bipolar disorder
[MEDLINE abstract]

Vieta E, Goikolea JM, OLivares JM, et al.
Journal of Clinical Psychiatry, 2003, 64, 834-839.
1-year follow-up of patients treated with risperidone and topiramate for a manic episode.

Vieta E, Sanchez-Moreno J, Goikolea JM, et al.
World Journal of Biological Psychiatry, 2003, 4, :172-176.>/I>
Adjunctive Topiramate in Bipolar II Disorder.
[MEDLINE abstract]

Vieta E, Torrent C, Garcia-Ribas G, Gilabert A, et al.
Journal of Clinical Psychopharmacolpgy, 2002, 22, 431-435
Use of topiramate in treatment-resistant bipolar spectrum disorders.
[MEDLINE abstract]

 

Winkelman JW.
Sleep Medicine, 2003, 4, 243-266.

Treatment of nocturnal eating syndrome and sleep-related eating disorder with topiramate.
[MEDLINE abstract]

Source: Ivan K. Goldberg, M.D.

 

 

next: Lithium for Maintenance Treatment of Mood Disorders
~ bipolar disorder library
~ all bipolar disorder articles

Lithium, Carbamazepine (Tegretol), and Valproic Acid (Depakote) have been used when mood disorders co-exist with ADHD. One frequently sees bipolar patients with supposed comorbid ADHD or diagnosed solely with ADHD. This is becoming increasingly common in adults as well as kids thanks to the popularity of the ADHD diagnosis. The problem is that just about all bipolar patients have a disorder of attention. To differentiate between the two, it is sometimes helpful to look for symptoms that are seen in bipolar disorders but not usually in ADHD, for example:

• racing thoughts
• not needing to sleep or hypersomnia
• changes in energy parallel to the above
• tangential thinking
• overspending, overcommitting
• grandiosity
• grandiose thrill seeking (eg, jumping off of high places)
• psychosis.

When ADHD and Bipolar Disorder are comorbid, starting treatment with a stimulant in these patients will often exacerbate the hyperactivity, flatten affect, and greatly decrease appetite. Some doctors start instead with either clonidine or guanfacine plus one of the following mood stabilizers: lithium, carbamazepine, valproic acid, or lamotrigine.

Once the patient is stable on therapeutic doses, a stimulant can be added if ADHD symptoms remain; if necessary, an antidepressant is sometimes added as well.

The boundary between persistent hypomania and ADHD is unclear. The usual practice is to treat such cases with stimulants before puberty and with mood-stabilizing agents in adulthood.

Drug Monographs -
Selected Medications Mentioned in this Section:

• Lithium Carbonate (Eskalith, Lithobisd, Lithonate, etc.)
• Divalproex Sodium / Sodium Valproate + Valproic Acid (Depakote )
• Carbamazepine (Tegretol)
• Lamotrigine (Lamictal)
• Guanfacine HCL (Tenex)
• Clonidine (Catapres)

 

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next: Side Effects of ADD - ADHD Medication
~ adhd library articles
~ all add/adhd articles

Clonidine (Catapres), another alternative to stimulants for treating ADHD, has been receiving widespread anectdotal support from parents with ADHD children, and is now considered a reasonable and increasingly popular pharmaecuetical treatment for ADHD. It seems to work best in decreasing hyperactivity, but does not always improve distractibility (as stimulants do). Some physicians have found benefits in using this medication with children who have ADHD and conduct problems.

Clonidine can be useful in alleviating the hyperactivity and fidgetiness of ADHD, without having any clear affect on the attentional part. It is often used in conjunction with methylphenidate, which helps the learning and attentiveness. Methylphenidate in higher doses, ie, those necessary to control the hyperactivity in some kids, will begin to have a negative effect on learning. Thus the combination, which enables specific treatment of attention with one drug and activity with another. Clonidine may be used with Group One or Two medications to increase their effectiveness.

Warnings: Only 10 children total have been studied in double blind placebo controlled clonidine trials. Possible sudden death may be related to clonidine/stimulant combination.

Robert Renichel and Charles Popper have a review, in the Journal of Child and Adolescent Psychopharmacology, of cases of sudden death in children taking the combination of clonidine and methylphenidate. This came in response to a July, 1995, National Public Radio news piece about three deaths in children being treated with the combination. Their conclusion was that none of the fatalities support the conclusion that the combination played any role in the children's deaths.

The most common presenting symptom of clonidine poisoning in children is lethargy. Other toxic effects include bradycardia; early transient hypertension followed by hypotension; respiratory depression and apnea; miosis; and hypothermia.

Among the 285 clonidine toxicity cases among children reported to the Kentucky poison center since 1990, 55% involved the child's own medication; 106 cases were the result of therapeutic error, usually a double dose. A common scenario was for one parent to dose their child and then the second parent to unknowingly give the child a second dose, he said. Ninety-nine children were 1-3 years old, the most common age range for accidental poisonings; 81 children were 7-10 years old, most of whom took their own medication in excess.

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next: Medication Treatments for ADHD - Mood Stabilizers (for ADHD with Mood and Behavior Problems)
~ adhd library articles
~ all add/adhd articles

Busiprone (BuSpar) is a relatively new anti-anxiety medication which shows some promise in treating ADHD when psychostimulant medications are not effective or their side effects cannot be tolerated. It can also "potentiate" benefits of the serotonergic antidepressants. The side-effects of Busoprone are often better tolerated than those of other medications used for ADHD. It should always be remembered, that for reasons still not fully understood, every individual responds differently and uniquely to a specific medication. The effective administration of a specific medication for any psycho-neurological condition will still - and most likely will for quite some time - remain an art, rather than a science.

For adults with ADHD, it has been noted that women with ADHD often report especially severe PMS, and their spouses and children may be very troubled by their exceptional irritability and impatience during this time of the month. Medications such as BuSpar are often extremely effective in relieving PMS symptoms.

RELATED STUDIES:

Transdermal Patch Formulation of Anti-Anxiety Medication Holds Promise For Treating Hyperactive Children
C. Keith Conners, Ph.D.
Professor of Medical Psychology
Duke University Medical Center

Administration through a skin patch developed by Sano Corporation of a widely used anti-anxiety medication may provide a safe and effective treatment alternative for children with attention deficit hyperactivity disorder (ADHD), according to the results of a pilot study presented at a National Institute of Mental Health conference by Duke University researchers.

The drug buspirone (BuSpar) was administered to a group of 32 children with ADHD using a new transdermal (through the skin) delivery technology. The transdermal buspirone patch is not yet commercially available and will require completion of current trials as well as the necessary FDA review and approvals.

Following the eight-week, open-label study, 70-80% of patients treated were rated by parents and teachers as "much improved or very much improved," according to study-leader C. Keith Conners, Ph.D., Professor of Medical Psychology at Duke University Medical Center. "The treatment was well liked by parents and well tolerated by the patients in the study - important considerations in evaluating prospective therapies for ADHD," said Dr. Conners.

He noted that the results of transdermal buspirone evaluated in the phase II trial suggest that the therapy may offer several benefits for treatment of ADHD in children. Unlike oral medications that must be taken repeatedly at home and school, the transdermal patch is applied once each morning, relieving children and their caregivers of the daily responsibility and stigma of pill-taking.

Oral medications are frequently metabolized in the liver. In the drugs currently used to treat hyperactivity and attention deficit disorder this so-called "first-pass metabolism" releases active drug components erratically, creating fluctuations which increase the risk of inconsistent control of symptoms.

"The main difference is that oral drugs' side effects are associated with their peak level in thebloodstream, which is higher than their therapeutic level," Dr. Conners noted. "If you can reduce these peak levels, you can avoid a lot of adverse effects." He said that this may help account for the tolerability of the transdermal buspirone noted in the study.

The study looked at boys and girls aged 8-12 years who were physically healthy and had been diagnosed with ADHD. Two eight-child groups wore low- dose skin patches measuring either 2.5 cm2 or 5 cm2. Two high-dose groups of eight children began the treatment period with skin patches measuring 10 cm2 or 20 cm2. Patches were replaced daily. The high-dose skin patches were increased in size every 10 days.

According to Dr. Conners, the study demonstrated a relationship between dose and effect. That is, the two high-dose groups showed improvement in terms of clinical global impairment ratings by parents and teachers, while the low-dose groups showed less improvement. He characterized the side effect profile as mild and well tolerated.
The adverse effects reported were mild or moderate in severity and included insomnia (15.6%), reaction at the site of the patch (12.5%), headache (9.4%), and increased activity level (9.4%). There was one severe headache. The next steps in evaluating the therapy will be the analysis of placebo-controlled efficacy studies currently underway.

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(Pemoline (Cylert) is no longer available in the U.S.)

Cylert ranks third in sales for the treatment of ADHD. Cylert is manufactured by Abbott; no generic is available.

Unlike other stimulant medications Cylert has an onset of action of about an hour and must be taken for 1-2 weeks before improvement occurs. It is recommended that the dosage of this medication be increased in increments of 18.75mg every 2-3 days over several weeks. Cylert is more expensive than Ritalin or Dexedrine.

Important points about Cylert:

1. Liver enzyme changes have occasionally been noted on patients taking Cylert. Baseline liver enzymes are recommended with follow ups at 3-6 months.
2. Persons using alcohol are at higher risk with this medication. Patients with either liver or kidney compromise should not take this medication.
3. SSRI's affect the use of Cylert due to their effects on the liver P450 isoenzymes.
4. Cylert is a useful alternative for patients with cardiovascular disease as it has no effect on this system.
5. Cylert may cause insomnia, appetite suppression, and tics.

Summary Drug Monograph:

Clinical Pharmacology:

Cylert (pemoline) has a pharmacological activity similar to that of other known central nervous system stimulants; however, it has minimal sympathomimetic effects. Although studies indicate that pemoline may act in animals through dopaminergic mechanisms, the exact mechanism and site of action of the drug in man is not known.

There is neither specific evidence which clearly establishes the mechanism whereby Cylert produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system.

Pemoline is rapidly absorbed from the gastrointestinal tract, Approximately 50% is bound to plasma proteins. The serum half-life of pemoline is approximately 12 hours. Peak serum levels of the drug occur within 2 to 4 hours after ingestion of a single dose. Multiple dose studies in adults at several dose levels indicate that steady state is reached in approximately 2 to 3 days. In animals given radiolabeled pemoline, the drug was widely and uniformly distributed throughout the tissues, including the brain.

Pemoline is metabolized by the liver. Metabolites of pemoline include pemoline conjugate, pemoline dione, mandelic acid, and unidentified polar compounds. Cylert is excreted primarily by the kidneys with approximately 50% excretedunchanged and only minor fractions present as metabolites.

Cylert (pemoline) has a gradual onset of action. Using the recommended schedule of dosage titration, significant clinical benefit may not be evident until the third or fourth week of drug administration.

Dosage and Aministration:

Cylert (pemoline) is administered as a single oral dose each morning. The recommended starting dose is 37.5 mg/day. This daily dose should be gradually increased by 18.75 mg at one week intervals until the desired clinical response is obtained. The effective daily dose for most patients will range from 56.25 to 75 mg. The maximum recommended daily dose of pemoline is 112.5 mg.

Clinical improvement with Cylert is gradual. Using the recommended schedule of dosage titration, significant benefit may not be evident until the third or fourth week of drug administration.

Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy. ufficient to require continued therapy.

Warnings:

Because of its association with life threatening hepatic failure, Cylert should not ordinarily be considered as first line drug therapy for ADHD.

Since Cylerts's marketing in 1975, 13 cases of acute hepatic failure have been reported to the FDA. While the absolute number of reported cases is not large. the rate of reporting ranges from 4 to 17 times the rate expected in the general population. This estimate may be conservative because of under reporting and because the long latency between initiation of Cylert treatment and the occurrence of hepatic failure may limit recognition of the association. If only a portion of actual cases were recognized and reported, the risk could be substantially higher.

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Of the 13 cases reported as of May 1996, 11 resulted in death or liver transplantation, usually within four weeks of the onset of signs and symptoms of liver failure. The ear-liest onset of hepatic abnormalities occurred six months after initiation of Cylert. Although some reports described dark urine and nonspecific prodromal symptoms (e.g., anorexia, malaise, and gastrointestinal symp-toms), in other reports it was not clear if any prodromal symptoms preceded the onset of jaundice. It is also not clear if the recom-mended baseline and periodic liver function testing are predictive of these instances of acute liver failure. Cylert should be dis-continued if clinically significant hepatic dysfunction is observed during its use.

Drug Interactions:

The interaction of Cylert (pemoline) with other drugs has not been studied in humans. Patients who are receiving Cylert concurrently with other drugs, especially drugs with CNS activity, should be monitored carefully.
Decreased seizure threshold has been reported in patients receiving Cylert concomitantly with antiepileptic medications

Precautions:

Clinical experience suggests that in psychotic children administration of Cylert may exacerbate symptoms of behavior disturbance and thought disorder.

Cylert should be administered with caution to patients with significantly impaired renal function.

Since Cylert's market introduction. there have been reports of elevated liver enzymes associated with its use. Many of these patients had this increase detected several months after starting Cylert. Most patients were asymptomatic, with the increase in liver enzymes returning to normal after Cylert was discontinued. Liver function tests should be performed prior to and periodically during therapy with Cylert. Treatment with Ctlert should be initiated only in individual without liver disease and with normal baseline liver function tests.

The relationship, if any, between reversible elevations in liver function tests and the occurrence of life threatening hepatic failure in patients on long-term therapy with Cylert is not known. Liver function testing may not predict the onset of acute liver failure. Nonetheless, Cylert should be discontinued if clinically significant liver function test abnormalities are revealed at any time during therapy with this drug

Adverse Reactions:

The following are adverse reactions in decreasing order of severity within each category associated with Cylert:

Hepatic: There have been reports of hepatic dysfunction, ranging from asymptomatic reversible increases in liver enzymes to hepatitis, jaundice and life- threatening hepatic failure, in patients taking Cylert.

Hematopoietic: There have been isolated reports of aplastic anemia.

Central Nervous System: The following CNS effects have been reported with the use of Cylert: convulsive seizures: literature reports indicate that Cylert may precipitate attacks of Gilles de la Tourette syndrome; hallucinations; dyskinetic movements of the tongue, lips, face and extremities: abnorrnal oculomotor function including nystagmus and oculogyric crisis; mild depression; dizziness; increased irritability; headache; and drowsiness.

Insomnia is the most frequently reported side effect of Cylert, it usually occurs early in therapy prior to an optimum therapeutic response. In the majority of cases it is transient in nature or responds to a reduction in dosage.

Gastrointestinal: Anorexia and weight loss may occur during the first weeks of therapy. In the majority of cases it is transient in nature; weight gain usually resumes within three to six months.

Nausea and stomach ache have also been reported.

Miscellaneous: Suppression of growth has been reported with the long- term use of stimulants in children. Skin rash has been reported with Cylert.

Mild adverse reactions appearing early during the course of treatment with Cylert often remit with continuing therapy. If adverse reactions are of a significant or protracted nature, dosage should be reduced or the drug discontinued.

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Desoxyn is rarely used in the treatment of ADHD. There is no generic available. Desoxyn is made by Abbott and the dosage is comparable to Dexedrine. However, Desoxyn is about 2-3 times more expensive than Dexedrine.

Important points to remember when prescribing or taking Desoxyn:

1. Desoxyn is apparently effective for the Inattentive form of ADHD.
2. Onset of action is 20-30 minutes, lasting 3 to 4 hours where the drop-off in effect is more similar to Dexedrine than Ritalin.
3. Desoxyn is contraindicated in patients with glaucoma.

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Dextroamphetamine saccharate/Dextroamphetamine sulfate (Dexedrine) in treating ADHD:

Dexedrine is one of the better known stimulant medications and is second only to Ritalin in the treatment of ADHD. The generic equivalent of Dexedrine is Dextroamphetamine Sulfate. Because the PDR continues to list Dexedrine under "Diet Control" medications, some insurance companies will not cover Dexedrine for the treatment of ADHD.

Important things to bear in mind when prescribing or taking Dexedrine:

1. The onset of action is 30 minutes, slower than Ritalin.
2. The coverage provided by Dexedrine is 3 1/2 to 4 1/2 hours; about an hour longer than Ritalin, especially with adult administration.
3. Dexedrine purportedly has a "smoother" onset of action and "drop-off" than Ritalin. It is usually almost completely absorbed and therefore one does not usually see the variation in onset of action that one sees with the use of Ritalin.
4. Dexedrine 5mg is about equivalent to 10mg of Ritalin. In other words it is about twice as potent as Ritalin.
5. Ingestion of Vitamin C and Dexedrine simultaneously, e.g., taking medication with orange juice, may significantly reduce Dexedrine absorption.
6. Because Dexedrine in the SR form is long acting, it is very useful for Middle and High school students who forget to take their second or third dose.
7. Dexedrine, however, has the potential side effect of reduced appetite.

Summary Drug Monograph for Dexedrine:

Clinical Pharmacology:

Amphetamines are non-catecholamine, sympathomimetic amines with CNS stimulant activity. Peripheral actions include elevations of systolic and diastolic blood pressures and weak bronchodilator and respiratory stimulant action.

There is neither specific evidence which clearly establishes the mechanism whereby Amphetamines produce mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system

Dexedrine (dextroamphetamine sulfate) Spansule capsules are formulated to release the active drug substance in vivo in a more gradual fashion than the standard formulation, as demonstrated by blood levels. The formulation has not been shown superior in effectiveness over the same dosage of the standard, noncontrolled-release formulations given in divided doses.

Dosage and Aministration:

Attention Deficit Disorder with Hyperactivity:

Not recommended for pediatric patients under 3 years of age.

In pediatric patients from 3 to 5 years of age, start with 2.5 mg daily, by tablet daily dosage may be raised in increments of 2.5 mg at weekly intervals until optimal response is obtained.

In pediatric patients 6 years of age and older, start with 5 mg once or twice daily, daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day.

Spansule capsules may be used for once-a-day dosage wherever appropriate. With tablets, give first dose on awakening additional doses (1 or 2) at intervals of 4 to 6 hours.

Where possible drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.

Warnings:

Amphetamines have a high potential for abuse. Admimistration of Amphetamines for prolonged periods of time may lead to drug dependence and should be avoided. Particular attention should be paid to patients obtaining Amphetamines for nontherapeutic use or distribution to others.

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Contraindications:

Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma.

Agitated states.

Patients with a history of drug abuse.

During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crises may result).

Drug Interactions:

Acidifying Agents: Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, fruit juices, etc.) lower absorption of amphetamines, Urinary acidifying agents (ammonium chloride, sodium acid phosphate, etc.) increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines.

Adrenergic Blockers: Adrenergic blockers are inhibited by amphetamines.

Alkalinizing Agents: Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase absorption of amphetamines. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups by agents increase blood levels and therefore potentiate the action of amphetamines.

Antidepressants tricyclic: Amphetamines may enhance the activity of tricyclic or sympathometic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.

MAO Inhibitors: MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of neurological toxic effects and malignant hyperpyrexia can occur, sometimes with fatal results.

Antihistamines: Amphetamines may counteract the sedative effect of antihistamines.

Antihypertensives: Amphetamines may antagonize the hypotensive effects of antihypertensives.

Chlorpromazine: Chlorpromazine blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning.

Ethosuximide: Amphetamines may delay intestinal absorption of ethosuximide.

Haloperidol: Haloperidol blocks dopamine and norepinephrins reuptake, thus inhibiting the central stimulant effects of amphetamines.

Lithium Carbonate: The stimulatory effects of amphetamines may be inhibited by Lithium Carbonate.

Meperidine: Amphetamines potentiate the analgesic effect of meperidine.

Methenamine Therapy: Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy.

Norepinephrine: Amphetamines enhance the adrenergic effect of norepinephrine.

Phenobarbital: Amphetamines may delay administration of phenobarbital and may produce an intestinal absorption of phenobarbital; coadministration of phenobarbital may produce a co-synergistic anticonvulsant action.

Phenytoin: Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action.

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Propoxyphene: In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur.

Veratrum Alkaloids: Amphetamines inhibit the hypotensive effect of veratrum alkaloids.

Precautions:

Long-term effects of amphetamines in pediatric patients have not been well established.

Amphetamines are not recommended for use in pediatric patients under 3 years of age with Attention Deficit Disorder with Hyperactivity. Clinical experience suggests that in psychotic children, administration of amphetamines may exacerbate symptoms of behavior disturbance and thought disorder.

Amphetamines have been reported to exacerbate motor and phonic tics and Tourette's syndrome. Therefore, clinical evaluation for tics and Tourette's syndrome in children and their families should precede use of stimulant medications.

Data are inadequate to determine whether chronic administration of amphetamines may be associated with growth inhibition; therefore growth should be monitored during treatment.

Drug treatment is not indicated in all cases of Attention Deficit Disorder with Hyperactivity and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe amphetamines should depend on the physician's assessment of the chronicity and severity of the child's symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics.

When these symptoms are associated with acute stress reactions treatment with amphetamines is usually not indicated.

Adverse Reactions:

Cardiovascular: Palpitations, tachycardia, elevation of blood pressure. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use.

Central Nervous System: Psychotic episodes at recommended doses (rare), overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, tremor, headache, exacerbation of motor and phonic tics and Tourette's syndrome.

Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects.

Allergic: Urticaria.

Endocrine: Impotence, changes in libido.

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Adderall for ADHD

Adderall is made by Richwood Pharmaceuticals, and was previously known as 'Obetral'. The dosage of Adderall is roughly equivalent to a comparable dose of Dexedrine.

Adderall tablets consist of equal amounts of Amphetamine and Dextroamphetamine, with both short and long-acting preparations. The therapeutic effect is apparently more subtle and smooth than other preparations and the length of action is 6-9 hours.

Important points to note when prescribing or taking Adderall:

1. It provides therapeutic cover for a full school or working day.
2. Adderall has been used for 'impulse-control.
3. Adderall has a distinct anorexic effect and therefore management of diet, especially in children, is essential.
4. Because Adderall has a slow onset of action and a sloped drop-off of action, anxiety induced at the onset of action and rebound at drop-off is reduced over other stimulants

Summary Drug Monograph for Adderall:

Clinical Pharmacology:

Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. Peripheral actions include elevation of systolic and diastolic blood pressures and weak bronchodilator and respiratory stimulant action.

There is neither specific evidence which clearly establishes the mechanism whereby amphetamine produces mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system.

Dosage and Aministration:

Regard less of indication, amphetamines should be administered at the lowest effective dosage and dosage should be individually adjusted. Late evening doses should be avoided because of the resulting insomnia.

Attention Deficit Disorder with Hyperactivity; Not recommended for children under 3 years of age. In children from 3 to 5 years of age, start with 2.5 mg daily; daily dosage may be raised in increments of 2.5 mg at weekly intervals until optimal response is obtained.

In children 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.

Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.

Warnings:

Clinical experience suggests that in psychotic children, administration of amphetamine may exacerbate symptoms of behavior disturbance and thought disorder. Data are inadequate to determine whether chronic administration of amphetamine may be associated with growth inhibition; therefore, growth should be monitored during treatment.

Drug Interactions:

Acidifying agents - Gastrointestinal acidifying agents (guanethidine,reserpine, glutamic acid HCl,ascorbic acid, fruit juices, etc.) lower absorption of amphetamines.

Urinary acidifying agents -(ammonium chloride, sodium acid phosphate, etc.) Increase the concentration of the ionized species of the amphetamine.

Primary excretion - Both Groups of agents lower blood levels and efficacy of amphetamines.

Adrenergic blockers - Adrenergic blockers are inhibited by amphetamines.

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Alkalinizing agents -Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.)increase absorption of amphetamines. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentate the actions of amphetamines.

Antidepressants, tricyclic - Amphetamines may enhance the activity of tricyclic or sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.

MAO inhibitors - M.O. antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings, this can cause headaches and other signs of hypertensive crisis. A variety of neurological toxic effects and malignant hyperpyrexia can occur, sometimes with fatal results.

Antihistamines - Amphetamines may counteract the sedative effect of antihistamines.

Antihypertensives - Amphetamines may antagonize the hypotensive effects of antihypertensives.

Chlorpromazine - Chlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning.

Ethosuximide - Amphetamines may delay intestinal absorption of ethosuximide.

Haloperidol - Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of amphetamines.

Lithium carbonate - The anorectic and stimulatory effects of amphetamines may be inhibited by lithium carbonate.

Meperidine - Amphetamines pone the analgesic effect of meperidine.

Methenamine therapy - Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy.

Norepinephrine - Amphetamines enhance the adrenergic effect of norepinephrine.

Phenobarbital - Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action.

Phenytoin - Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action.

Propoxyphene - In cases of propoxyphene overdose, amphetamine CNS stimulation is potentiated and fatal convulsions can occur.

Veratrum alkaloids - Amphetamines inhibit the hypotensive effect of veratrum alkaloids.

Precautions:

Caution is to be exercised in prescribing amphetamines for patients with even mild hypertension.

The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage.

Amphetamines may impair the ability of the patient to engage in potentially hazardous activities s.c. as operating machinery or vehicles; the patient should therefore be cautioned accordingly.

Adverse Reactions:

Cardiovascular: Palpitations, tachycardia, elevation of blood pressure There have been isolated reports of cardiomyopathy associated with chronic amphetamine use.

Central Nervous System: Psychotic episodes at recommended doses (rare), overstimulation, restlessness. dizziness, insomnia, euphoria. dyskinesia, dysphoria, tremor, headache, exacerbation of motor and phonictics and Tourette's syndrome.

Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects when amphetamines are used for other than the anorectic effect.

Allergic: Urticaria.

Endocrine: Impotence. Changes in libido.

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Methylphenidate HCL (Ritalin) and sustained-release preparations (Ritalin-SR, Concerta, Metadate CD):

Ritalin is said to affect as much as a 70% improvement in those affected with ADHD. Ritalin is supposed to induce hyperperfusion [increase blood supply] to the frontal lobes of the brain. Of all the ADHD medications, Ritalin is the most inconsistently absorbed. Some adults and children absorb as much as 80-90% of the medication, whereas others only absorb 30-40% of a medication dose.

Methylphenidate is derived from the same family as cocaine and increases blood flow to the basal ganglia and decreases flow to frontal and motoric regions. The basal ganglia are involved in the control of movement. Parkinson's disease, for example, is caused by a degeneration of certain neurons located in the mid-brain that send axons to parts of the basal ganglia. Cerebral studies in persons with ADHD have shown cerebral hypoperfusion in the frontal lobe and decreased blood flow to the caudate nucleus. The amygdala, considered by some anatomists to be part of the basal ganglia, is located within the temporal lobe near its rostral tip. The side effects of Methylphenidate include facial tics and a delay in the onset of action.

Some important facts to remember about Ritalin & Methylphenidate:

1. Its onset of action is rapid: 20-30 minutes.
2. It has the shortest duration of action of 2-4 hours. Many children only benefit for 3 hours from medication.
3. There may be a significant "rebound" when the medication wears off, constituted by over-agitation and/or anxiety.

Summary Drug Monograph:

Clinical Pharmacology:

The mode of action of Methylphenidate hydrochloride (Ritalin) in man is not completely understood, but methylphenidate presumably activates the brain stem arousal system and cortex to produce its stimulant effect.

There is neither specific evidence which clearly establishes the mechanism whereby methylphenidate produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system.
Methylphenidate hydrochloride in extended-release tablets is more slowly but as extensively absorbed as in the regular tablets. Bioavailability of the MD Pharmaceutical Inc. methylphenidate hydrochloride extended-release tablet was compared to a sustained release reference product and an immediate-release product. The extent of absorption for the three products was similar, and the rate of absorption of the two sustained-release products was not statistically different.

Dosage and Aministration:
Children (6 years and over):

Methylphenidate hydrochloride should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended.

If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

Tablets: Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg weekly.

Extended-Release Tablets: Methylphenidale hydrochloride extended-release tablets have a duration of action of approximately 8 hours. Therefore, the extended-release tablets may be used in place of the immediate-release tablets when the 8-hour dosage of methylphenidate hydrochloride extended-release tablets corresponds to the titrated 8-hour dosage of the immediate-release tablets. Methylphenidate hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed.
If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug.

Methylphenidate should be periodically discontinued to assess the child's condition. Improvement may be sustained when the drug is either temporarily or permanently discontinued. Drug treatment should not and need not be indefinite and usually may be discontinued after puberty.

Warnings:
Methylphenidate should not be used in children under six years, since safety and efficacy in this age group have not been established.

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Sufficient data on safety and efficacy of long-term use of methylphenidate hydrochloride in children are not yet available. Although a causal relationship has not been established, suppression of growth ( i.e., weight gain, and/or height) has been reported with the long-term use of stimulants in children. Therefore, patients requiring long-term therapy should be carefully monitored. Methylphenidate should not be used for severe depression of either exogenous or endogenous origin. Clinical experience suggests that in psychotic children, administration of methylphenidate may exacerbate symptoms of behavior disturbance and thought disorder.

Methylphenidals should not be used for the prevention or treatment of normal fatigue states. There is some clinical evidence that methylphenidate may lower the convulsive threshold in patients with prior history of seizures, with prior EEG abnormalities in absence of seizures, a.d. very rarely, in absence of history of seizures and no prior EEG evidence of seizures. Safe concomitant use of anticonvulsants and methylphenidate has not been established. In the presence of seizures, the drug should be discontinued. Use cautiously in patients with hypertension. Blood pressure should be monitored at appropriate intervals in all patients taking methylphenidate, especially those with hypertension.

Symptoms of visual disturbances have been encountered in rare cases. Difficulties with accommodation and blurring of vision have been reported.

Drug Interactions:
Methylphenidate may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents and MAO inhibitors. Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, phenytoin, primidone), phenylbutazone, and tricyclic anti-depressants (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with methylphenidate.

Precautions:

Patients with an element of agitation may react adversely; discontinue therapy if necessary. Periodic C.C. differential, and platelet counts are advised during prolonged therapy.

Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe methylphenidate should depend on the physician's assessment of the chronicity and severity of the child's symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics.

When these symptoms are associated with acute stress reactions, treatment with methylphenidate is usually not indicated.

Long-term effects of methylphenidate in children have not been well established.

Adverse Reactions:
Nervousness and insomnia are the most common adverse reactions but are usually controlled by reducing dosage and omitting the drug in the afternoon or evening.

Other reactions indude hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy. There have been rare reports of Tourette's syndrome.

Toxic psychosis has been reported. Although a definite causal relationship has not been established, the following have been reported in patients taking this drug: instances of abnormal liver function, ranging from transaminase elevation to hepatic coma; isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood; a few instances of scalp hair loss.

In children, loss of appetite, abdominal pain, weight loss during prolonged therapy,insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed above may also occur.

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Detailed information on stimulant medications for ADHD, including uses, dosages and side-effects.

Psychostimulants are controlled substances that calm persons with ADHD rather than stimulate them. While we know that ADHD affected persons have neurochemical correlates these have not been accurately determined. However, it has been asserted that the dopamine and norepinephrine circuits are affected in ADHD.

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