FINAL NOTES FOR KSU PSYCHOPHARM SEMINAR

 

LITHIUM:

 

The element, a light, positively charged metal ion, was discovered in 1817. For more than 150 years it has been used for different maladies. Alexander Ure began work in the early 1840s followed by Sir Alfred Garrod in the 1860s. This work introduced the oral use of lithia salts as treatment for gout or “uric acid diathesis.”

 

Gout is a painful inflamation of the joints and an excess of uric acid in the blood. Uric acid in salt form forms in the joints in gout and is the major constituent of kidney stones.

 

Gout was thought to induce mood disorders encompassing mania and depression as these sometimes accompany gout.

 

In the 1880s the American John Aulde and the Dane Carl Lange brought attention to lithium as a prophylactic for depression. Subsequently it was added in small doses to mineral water at the turn of the century but cases of lithium toxicity later put a stop to this practice. It was re-discovered by John Cade, an Australian state hospital superintendent, in the late 40s.

 

Cade thought that there was a toxin that caused schizophrenia and other mental/emotional disorders and could be detected in the urine.

 

To test this he injected the urine of schizophrenic, manic, and normal humans into guinea pigs. They all died but he thought the manic urine more toxic. He then injected common elements in urine into guinea pigs to see the effect. The most deadly proved to be urea but the urea levels in his clients seemed normal.

 

Cade wondered whether some other chemical modified the toxicity of urea in the body. One possibility was uric acid but it was hard to dissolve for injection. He mixed it with various metals to form a salt and found lithium effective in this regard.

This preparation seemed to calm the guinea pigs and block the lethal effects of urea.

 

Cade then added lithium and it calmed the guinea pigs too and he decided to set up a trial on humans. The obscurity of the journal and Cade left his impressive results unnoticed for a number of years.

 

The time gap of 20 years was basically because lithium as a metal ion could not be patented and drug companies were reluctant to spend all the trial money necessary on a drug they could not patent. In addition, the U.S. was slow to work with lithium given the deaths associated with lithium in mineral water. The addition of serum level monitoring made the treatment safe.

 

In the 1970s Michael Sheard gave aggressive rodents lithium since lithium had been shown to raise serotonin levels. The experiement worked and he then treated prison inmates with Lithium in a placebo controlled study. While lithium had no impact on nonviolent behaviors like lying and stealing, it appeared to fully suppress serious assault in the inmates observed and documented by guards. ONLY IMPULSIVE aggression was affected. More importantly, aggression returned upon discontinuation.

 

 

MECHANISM OF ACTION: REPEAT MANTRA: The pharmacology of lithium is incredibly complex. It affects different parts of the brain differently at different times. The effects extend to multiple neurotransmitters and second messenger systems.

The best studied effects of lithium are on serotonin. After short-term use, it appears to increase the synthesis of serotonin by increasing tryptophan reuptake in synapses

 

After 2-3 weeks, it appears to enhance the release of 5-HT from neurons in the parietal cortex and the hippocampus (USE MODEL). Long term administration seems to cause down-regulation in 5-HT1 and 5-HT2 receptors.

 

Lithium appears to increase the rate of synthesis of NE in some parts of the brain. It decreases the excretion of NE metabolites in manic patients and increases the excretion of NE metabolites in depressed patients..

 

Lithium appears to block postsynaptic DA receptors supersensitivity which partly explains the controlling effects on mania and psychosis.

 

There appears to be evidence that lithium affects the G-proteins in second messenger systems. It appears to inhibit some enzymes in particular 2nd messenger systems.

 

CLINICAL USES:

·        control acute, overt psychopathology like mania or psychotic agitation

·        to modify milder, ongoing symptoms like chronic depression or irritability

·        prophylactic maintenance to avert future affective or psychotic episodes

·        to enhance the effect of antidepressants in patients with major depressive episodes.

 

 Bipolar I disorder: Lithium is an effective prophylactic for manic episodes however only about half of lithium-treated patients have complete suppression of all episodes, even with excellent medication compliance. Non-compliance is usually secondary to the recurrence. Many clients are blamed for noncompliance unjustifiably.

 

Rapid-cycling and mixed state bipolar patients generally do less well than patients with less frequent of purely manic episodes.

How long will the client have to take lithium? There are two issues in this question. The first is related to relapse. About half of patients stabilized successfully on lithium then switched to placebo relapse within six months. There are stories of patients relapsing in a few days but these are not from controlled studies and rare.

 

Most clinicians assume that patients stabilized on lithium will continue indefinitely. There is some evidence for slowly titrated withdrawal in patients who have made therapeutically based life changes and seem to be able to manage their illness.

 

 

Lithium is also used as a prophylactic for unipolar depression. It is also used for patients with mood lability, impulsive or episodic violence and anger. In some cases it has been used for alcoholism, menstrual related mood disorder, BPD and chronic schizophrenia that didn’t respond to typical treatments.

 

Bipolar II is usually treated with MAO inhibitors and Bipolar with rapid cycling is treated with tegretol.

 

COMMON SIDE EFFECTS

Neuormuscular and CNS: tremor –usually noticed in the fingers. Dosage reduction can usually make the tremor mild or inconspicous. Some patients complain of slowed mentation and forgetfulness. Memory problems are one of the leading causes of non-compliance and the third most common side-effect.

 

GI: Chronic nausea and diarrhea can occur as signs of lithium toxicity. Episodic nausea can usually be relieved by taking the meds with food.

 

Weight Gain & Endocrine: Some patients gain weight progressively on lithium and it is the second most common reason patients stop taking it. Weight gain is greater in patients who are overweight to begin with. Some patients show decreased thyroid levels and rarely goiter. About 5% develop hypothyroidism and 30% have elevated Thyroid-stimulating hormone levels.

 

Renal: can cause polyuria (passing an excessive quantity of urine) or polydipsia (excessive thirst) in 1 out of 5 patients. Harm can occur if the client is stabilized on lithium and a diuretic is added. This can double the lithium level and the patient will likely develop lithium toxicity. This can also occur with anti-inflammatory drugs like ibuprofin, naproxen, and indomethacin. It is worth checking the kidneys of patients on lithium every 6-12 months.

 

Cardiovascular: can produce benign effects on the EKG

 

Dermatological: rashes have been described, aggravation of psoriasis, alopecia can occur but hair usually regrows with or without the lithium.

 

DOSAGE: initial regimen of 300mg 2-4 times a day for healthy adolescent or adult patients. Plasma levels should be drawn every 3-4 days to ensure early detection of toxic levels.

 

Use in Pregnancy: Lithium is the only psychoactive, non-anti-convulsant drug thought to be associated with a specific birth defect, Ebstein’s anomaly – a serious cardiac abnormality 20 times more common in children born to mothers on lithium

 

Special caution with elderly clients.

 

DANGER: It requires a high dose to reach therapeutic effectx and the dose is close to a toxic dose. Lithium toxicity is a risk and includes symptoms of diahhrea, vomiting, tremors, and muscular weakness, kidney problems, coma, respiratory depression and death.

 

PHARMACOKINETICS: Administered orally in salt form, readily absorbed from the GI tract, passage through blood brain barrier is slow but once plasma levels stabilize, cerebrospinal fluid levels also stabilize at about 1/2 the plasma levels.

 

If the presenting phase is clearly manic, often the client will require both lithium and an anti-psychotic or high potency benzodiazapines. With lithium the client may take 10 days to show therapeutic effects. Once the mood is stable, the anti-psychotic or benzodiazapines may be phased out.

 

Treatment cannot occur until the following lab tests are done: Sodium/Na, calcium/Ca, Phosphorus/P, EKG, Creatinine, Urinalysis, Cthyroid battery, complete CBC.

 

Blood levels need to be taken regularly to monitor plasma levels.

 

CARBAMAZAPINE: (Tegretol) was originally synthesized in 1957 and introduced into the European market in 1960 as an anticonvulsant.

It is structurally similar to the TCAs. The majority of studies show tegretol to be equally effective to lithium in the tx of mania.  The N in each of the 19 studies since 1978 was small, in some cases other medications were used in combination with Tegretol and the designs were variable in terms of controlling for diagnosis.

 

There are now 15b controlled studies of Tegretol in the tx of acute mania and 7 on its maintenance use in bipolar disorder. About 50% of patients will show clear clinical benefit. Some do better on the drug alone and others in combination with lithium. There is some evidence that Tegretol works better than lithium in rapid cyclers.

 

If Tegretol is given with other drugs like Prozac or calcium channel blockers, this will increase the plasma levels because these drugs tend to inhibit liver enzymes.

 

Side effects can include lethargy, sedation, acne, nausea, tremor, ataxia, and visual disturbances. In addition Tegretol can interfere with thyroid functioning and cardiac conduction.

 

CBC and liver function should be monitored every 2 to 3 weeks for the first few months. In addition patients need a physical, CBC,

liver function tests, thyroid function tests, and renal indices prior to being treated with tegretol.

 

Contraindicated with MAOIs

 

Drugs that may increase Tegretol levels include:

·        cimetidine (Tagamet) histamine2 receptor antagonist now OTC (over the counter)

·        erythormycin (antibiotic)

·        diltiazem (FDA Drug Class: Antianginals; Antiarrhythmics; Antihypertensives; Calcium Channel Blockers; Coronary Vasodilators)

·        fluvoxamine

·        fluoxetine

·        doxycycline (tetracycline antibiotic)

·        ketoconazole (for fungal infections used in AIDS patients, can be heptotoxic)

·        prednisolone (corticosteroid)

·        Valporate

·        Warfarin (anticoagulant)

 

 

 

VALPROATE:  (Depkote, Depakene) This is an anti-convulsant chemically unrelated to other psychiatric meds. Numerous uncontrolled and controlled studies support the efficacy of Valproic Acid in treating mania. Seems to have the most favorable side effect profile.

 

May be useful in mixed state and rapid cycling clients. Has good efficacy relative to lithium

 

Common side effects: Major worry is severe, sometimes fatal heptotoxicity. Fatal cases have all been in neonates taking multiple anticonvulsants, particularly barbituates. Children younger than 2 are at greater risk. Conservative estimates note that liver function tests should be done monthly. On the other hand there is evidence that in adults this is unnecessary.

 

Middle of the road estimates are liver tests every 6-12 months.

 

Thrombocytopenia and platelet dysfunction have been reported in patients on valproate. Warning patients  to report easy bruising or bleeding is indicated.

 

Sedation most common side effect. GI upset is second most common.  Tremor, ataxia, alopecia, and weight gain can also occur. Coma and death can result from OD. Hemodialysis and naloxone can reverse the effects.

 

Terotogenic effects: In the first trimester, neural tube defects (spina bifida) can occur.

 

Drugs that may increase Valproate levels include:

·        cimetidine (Tagamet) histamine2 receptor antagonist now OTC (over the counter)

·        erythormycin (antibiotic)

·        phenothiazines

·        fluvoxamine

·        fluoxetine

·        aspirin

·        ibuprofen

 

Drugs that decrease Valproate levels include

·        rifampin (anti-tubercular)

·        tegretol

 

STIMULANTS

 

The first known stimulant in the West was Cocaine which was isolated in the mid 18th century and, in 1884, given to Bavarian soldiers to decrease fatigue.

 

We will focus primarily on amphetamines since they are still prescribed for ADHD. As Julien noted these are called sympathomimetic agents because they mimic epinephrine. They also act on  norepinephrine and dopamine receptors.

 

Efforts to synthesized amphetamine began in 1887 with the therapeutic intent of relieving asthma symptoms. In the late 19th century epinephrine (adrenaline) was used to treat asthmatics.

 

Naturally created in the adrenal gland, it stimulates “fight/flight” in times of acute distress. The physical reactions include speeding heart rate, increasing muscular strength and endurance, and dilating the bronchial tree permitting deeper and faster breathing. This latter effect was what they wanted to relieve the respiratory distress.

 

The difficulty with this treatment is that epinephrine cannot be taken by mouth because it is rapidly destroyed in the stomach and intestines.

 

In the early 1920’s K.K. Chen, a pharmacologist working for Eli Lilly began to investigate a rare plant used in Chinese medicine called ma huang. In China it had been used to treat bronchial wheezing. Chen and other Lilly chemists isolated the active compound. It was similar to epinephrine and they named it ephedrine.

 

Because it could be administered orally (unlike epinephrine) it became a favorite drug for treating asthma. Since the plant ma huang was rare, numerous attempts were made at synthesizing ephedrine-like substances. Gordon Alles from Los Angeles synthesized one such substance in the 1930’s.

 

This substance was an improvement in that it was prepared in inhalers and could be taken directly into the lungs. The compound was called amphetamine.

 

Under the brand name of Benzedrine these inhalers became quite a popular over-the-counter drug since aside from relieving asthma they induced euphoria and reduced fatigue.

 

People soon realized they could open the inhaler and ingest the contents leading to an amphetamine rush. This became popular on college campuses especially during exams.

 

Psychological studies at the time required the amphetamine be produced in pill-formulation for studies. Thus the first amphetamine pill.

 

Despite problems in amphetamine use, the AMA took a while to catch on. Once they did the movement toward restriction began.

 

Narcolepsy was one of the first conditions to be treated with amphetamine (1935) and it was also used to treat parkinsonism, and, in combination with anti-convulsant drugs, it was used to treat mild epilepsy.

 

Amphetamine was used for barbituate overdose because of its vasoconstriction and bronchial dilation effects. Amphetamines were also used to treat alcoholism, nicotine addiction, and aggressive behavior.

 

The effects of amphetamine on the latter were what spurred research on aggressive children.

 

In the second World War, substantial amphetamine abuse is recorded by Germans, The British, and American soldiers. The Japanese employed amphetamines extensively and after the war, having huge amphetamine stockpiles, they marketed the drug for “elimination of drowsiness and repletion of spirit.”  Needless to say both were accomplished in addition to a creating a dependence problem. By 1948 it is estimated that 5% of the Japanese population between the ages of 15 and 25 was dependent on amphetamine.

 

 

Abuse of amphetamine continued in the counter-culture of San Francisco in the 1960’s. Here mixing LSD with amphetamine was common to enhance the rush and the alertness during the “trip.” Also mainlining became popular to enhance the rush described as “the total body orgasm.”

 

After WWII chemists attempted to tease out the appetite suppressing qualities of amphetamine from the euphoria producing qualities. One compound, Methylphenidate (Ritalin) was discovered in this process producing alertness but not appetite suppression.

 

Although diet pills were developed that did not produce the energy or euphoria they didn’t sell very well.

Another line of research that was aided by amphetamine development was research on schizophrenia. Chronic or large dose usage of stimulants can induce “stimulant psychosis” that mimics the symptoms of paranoid schizophrenia.

 

It was also found that anti-psychotics quickly alleviate the symptoms of stimulant psychosis. Also, when schizophrenic patients whose symptoms were stabilized were given small amounts of amphetamine, in the majority of cases the symptoms returned as soon as the drug was absorbed.

 

The symptoms that returned were always the same as the ones that led them to be medicated in the first place leading researchers to conclude that the same area of the brain was being affected.

 

One major difference between the symptoms of stimulant psychosis and schizophrenia is that the former includes haptic hallucinations whereas the latter rarely does.

 

Amphetamine itself is a simple molecule and forms the template for over 50 pharmacologically active substances (Grilly illustrations).

 

 Amphetamine is made of two chemical compounds (isomers) L and D amphetamine.

 

 

 

D-amphetamine is much more potent and was marketed as Dexedrine. A minor modification in the amphetamine molecule yields the more potent methamphetamine (Methedrine)(Grilly).

 

Since minor changes in the molecule can greatly effect the pharmacological properties of amphetamine the goal was to control symptoms without creating dependence.

 

Some variations of amphetamine ended up having MAO inhibiting properties 5000 stronger than the MAOI's (Parnate)

 

Other alterations can produce anti-depressants like Bupropion (Wellbutrin, Zyban) (remember early uses for nicotine addiction?).

 

Other compounds such as DOM (dimethoxymethylamphetamine) can produce psychedelic effects similar to mescaline while a chemical relative of methamphetamine (MDMA-methylenedioxy-N-methylamphetamine)) has a strong empathogenic effect. MDMA's schedule I designation has been contested by psychiatrists although presently it is back on schedule I. Other designer drugs of this type are expected to be developed.

 

The molecules in both amphetamine and cocaine are similar to dopamine and norepinephrine. These are the neurotransmitters affected by the drugs.

MECHANISM OF ACTION:

The drug molecules actually enter the synaptic vesicles. There they push norepinephrine and dopamine out into the cleft like a psuedo-exocytosis.

 

From this point, amphetamine inhibits the reuptake mechanism for both norepinephrine and dopamine.

 

Amphetamine also reverses the action of the transporter molecule so that instead of taking DA into the cell, the molecule takes it out of the cell and dumps it in the cleft.

 

The dopamine activity stimulates receptors in the limbic system. The euphoria reported by users is probably tied to the limbic system stimulation.

In addition to the limbic system stimulation, there is a particular noradrenergic structure that bears discussion.

 

Norepinephrine neurons are plentiful in the limbic system and have their origin in a small nucleus in the brain stem called the locus coeruleus. (note the mention of this in the previous lecture-use model) This simply means “blue disc” as it is bluish in appearance.

 

This is a remarkable brain structure because it is only estimated to contain 3000 neurons yet has axons extending to almost half the neurons in the brain. The ramifications are vast since 3000 neurons may influence billions of others.  This is unmatched in any other pathway.

 

The first staining to highlight this situation was done in the 1960’s by two Swedish researchers Kjell Fuxe and Annica Dahlstrom. Their research led to the conclusion that the firing of these cells cause norepinephrine release all over the cortex. This norepinephrine response is thought to be an important part of feeling states.

 

The effects of amphetamine in this brain structure may account for many of the reinforcing properties.

 

INDICATIONS: Amphetamines are used to treat ADHD, obesity, and narcolepsy. We will only focus on ADHD.

 

ADHD is called a heterogeneous disorder with unknown etiology. Like schizophrenia, we imagine that it is many different disorders with common characteristics.

 

We know that there seem to be environmental and genetic contributors and, like most psychiatric disorders, it is overdetermined. It has been called “minimal brain dysfunction” (a garbage category) and “hyperkinetic reaction of childhood.” (DSM-III)

 

Estimates vary about how many cases persist into adulthood (10%-60%). In culturally diverse samples (from Puerto Rico to New Zealand) children with ADHD usually present with one or more comorbid disorders including, mood, anxiety, learning, conduct, and occasionally bipolar disorders. The comorbid disorders may be our clue to the heterogeneous nature of ADHD.

 

The presence of conduct disorder is particularly important because it implies poor prognosis and, in adolescents, an increased chance of substance abuse.

 

Although there are 191 open and  controlled studies with more than 5000 children, teens and adults, the vast majority of the studies (89%) are limited to latency-age Caucasian boys.

 

 

Of the 155 open and controlled studies researching Ritalin, Dexedrine and Cylert, 82% are studying Ritalin.

More than 90% of ADHD cases are treated with Ritalin.

 

Currently drug therapy for ADHD includes Methylphenidate, Pemoline (Cylert), D-amphetamine (dexedrine), and an amphetamine derivative (Adderall). Ritalin and Dexadrine are schedule II drugs, Cylert and Adderall are schedule III drugs.

 

Adderall (d-amphetamine) and Pemoline (Cylert) have a longer term effect but Cylert has more risk of liver damage. There are slow-release versions of Ritalin and Dexedrine.

 

Adderall has been marketed by Richwood Pharmaceuticals as a treatment alternative for ADHD. It was actually developed about 20 years ago as a diet pill but due to its chemical formulation, dissolves slowly and may be administered once daily. There are few peer-reviewed, well-controlled studies of the drug.

 

Ritalin and Dexedrine (but not Cylert) are spontaneously administered by lab animals thus Cylert is thought to be less reinforcing. As schedule III drugs, Adderall and Cylert can be refilled and phoned in to pharmacies.

Between 1990 and 1993, the number of outpatient visits for ADHD went from  1.6 to 4.2 million a year. The amount of Ritalin produced went from about 1700 kilograms to 5100 kilograms annually.

 

The drugs act rapidly (within 30 minutes) and persist 3-4 hours with Pemoline being a bit longer. Elimination half-life for Ritalin is 2.5 hours, for Pemoline 12 hours. Stimulants reduce activity and lengthen sustained attention but the effects on behavior are greater than on attention.

 

Ritalin reduces symptoms in more than 70% (placebo 4%-30%) of school-aged children making it one the most effectively treated childhood psychiatric disorders.

 

It should be noted that attention and concentration improve for non-ADHD children and adults when given doses of Ritalin.

 

Most stimulant trials (84%) are conducted short term (2 months) and we know little about the consequences of long-term stimulant use.

 

A low incidence of liver damage keeps Cylert from being more used. The damage is reversible if detected early enough.

 

AGE: As of 1996 there were five controlled studies for children under age 6 with robust effects reported for behavior in structured situations and improvements in mother-child interactions. We need more research though since there are about 400,000 scripts written annually for this age group.

 

Little research has been conducted on the effectiveness of stimulants on teenagers. It is widely believed that amphetamines will be abused and/or produce aggression in teens and adults so many children are taken off of them at adolescence. This belief has no scientific support.

 

In the first study to document the effect of stimulant medication on junior high boys with ADHD, William Pellham and Steven Evans did an 8 week double blind study. Students taking Ritalin showed dramatic improvement in grades, from D- to B- averages. There was also a 50% reduction in ratings of disruptive behavior.

 

The study is in the 1991 Journal of Abnormal Child Psychology, vol. 19 #5. Because the results were so dramatic a larger study is being planned.

 

GENDER:

The gender ratio of children with ADHD is 10 boys to1 girl. It is thought that girls are under-diagnosed due to less aggressive behavior. The ratio drops to 2:1 in epidemiological and adult samples. There are concerns about the undertreatment of the disorder in females. In addition, there is little research on the safety and efficacy of stimulant use with female clients. 96% of the current studies are with males.

 

ABUSE:

There is concern that stimulants to treat hyperactive children increase the likelihood of any drug abuse or dependence in adulthood. If the gateway theory of drug use is true, then this is a major concern for children on Ritalin (site recent article in Science). Thus far this has not been supported.

 

Evidence is accumulating linking ADHD and drug abuse/dependence in later life. The evidence is such that ADHD is linked as a pre-disposing factor that may be genetically transmitted.

 

Personal characteristics like emotional lability, hyperactivity, and social impulsivity are good predictors of later substance abuse.

 

HOWEVER, One controlled follow-up study of 75 children found no evidence that stimulant abuse is higher for adolescents treated for ADHD as children.

 

In recent years behavior therapy has proved a useful adjunct to drug therapy and helps keep the drug doses lower.

 

 

SIDE EFFECTS: there are 5 main stimulant-related side effects insomnia, reduced appetite, stomachace, headache, and dizziness. Most of these are based on short term trials and may be under-reported.

 

Serious, late-appearing side effects have not been reported despite 30 years of extensive use. The main concerns are increased potential for future substance use (not supported), stimulant related growth delays, and heptotoxicity.

 

Regarding the growth delays, follow-ups in adult life reveal no significant losses. The growth curves of ADHD children, stimulant treated or not, have demonstrated slower advances than controls.

 

There have been some hepatic tumors in children treated long-term with Pemoline (4 per 100,000). Because of this Pemoline is only for non-responders to other stimulants and must be closely monitored. 

Vocal or motor tics appear in 1% of children taking Ritalin. These may appear after several months. When children have pre-existing tic disorders, there is no worsening of the disorders.

 

It should be noted that there is a perception by some clinicians that some children show a loss of responsiveness to stimulants over months to tx.

 

Some may need dosage adjustment but, within the therapeutic range, this is not necessarily a tolerance effect. In many cases the child’s growth necessitates higher dosages for increased body weight. In other cases the reason is non-compliance on the part of the child, parents, or both.

 

ALTERNATIVES: There are alternatives to Ritalin and stimulant tx of ADHD but most alternatives have risks and side effects of their own.

 

TCAs are showing some promise due to their action on the noradrenergic system. Well-controlled studies of Desipramine (Norpramin) have made it the second line tx for ADHD.

The biggest barrier is that four children died on Desipramine in 1988. It is hard to link the deaths to DMI per se although it does cause cardiac arrythmias (was Seldane involved?) but obviously the incident has made therapists cautious.

 

Bupropion (Wellbutrin, Zyban) which is a noradrenergic agent, chemically similar to amphetamine, has been effecting results in controlled studies. Many subjects do as well as stimulant medicated subjects.

 

BuSpar has weak dopaminergic activity and in one 10 subject study to date has been shown to decrease aggressivity and ameliorate the symptoms of ADHD.

 

A newer type antidepressant venlafaxine (Effexor) was successful in reducing the symptoms of ADHD due to its acting on both norepinephrine and serotonin receptors. (slight effect on DA).

 

There appears to be no efficacy for the SSRIs in Tx of ADHD.

 

 

Interestingly, about 60% of people with ADD are smokers compared to 30% in the population at large. Researchers at Duke University are looking at treating children with nicotine patches for ADHD.

 

Recent studies have also shown that Clonodine was effective in reducing hyperactivity in 7 out of 10 children so diagnosed. The problem is that clonodin actually inhibits norepinephrine adding to the confusion of trying to map out the disorder. (Clonodine is used to treat high blood pressure, Tourettes, and mania).

 

There has been a five-fold increase in CLON prescriptions between 1990 and 1995 for ADHD. CLON has a favorable side-effect profile inducing sedation at night. CLON is used with stimulants in ADHD + Conduct Disorder but this carries a high rate of heart rate and blood pressure abnormalities. There were 4 deaths among that group.

 

CLINICAL IMPLICATIONS: ADHD - Before drug intervention, a complete physical and neurological examination should be conducted to establish that the child is not suffering from hypoxia (insufficient blood supply to the brain), low calcium, low blood sugar, , or hyperthyroidism all of which can result in hyperactive symptoms.

 

Also it is important to really determine whether the child is hyperactive since no norms for childhood activity exist.

If amphetamines are used, different children will respond to different drugs and we're not sure why. The amphetamines can cause insomnia and interfere with appetite causing delays in growth. The following drugs are the drugs of choice:

 

Dosages of Ritalin need to be individualized. The dose to some degree depends on the symptoms you want to treat. Dosage may range from 10 to 60 mg. daily. Because of its short half life, Ritalin will need to be taken throughout the day. Effects wear off in about 3 hours.

 

Ritalin - 10-60mg daily

Dexedrine      - 5-40 mg daily

Cylert - 37.5 - 112.5 mg daily

 

CAFFIENE: most widely used The typical adult in the US consumes about 400 mg of caffiene a day with coffee and tea consumption accounting for about 90% of that. behaviorally active drug in the world.

 

A 5 ounce cup of coffee has between 60-180 mgs of caffiene in it.

 

Cigarette smokers metabolize caffiene at an accelerated rate. Upon smoking cessation, caffeiene plasma levels increase more than 200% which could contribute to the jitteriness of nicotine withdrawal.

 

Some findings indicate that the most pleasant aspect of caffiene for heavy coffee drinkers is its ability to ward off caffiene withdrawal.

 

MECHANISM OF ACTION: the central mechanism of action is the inhibition of central adenosine receptors. Adenosine is a potent enzyme that inhibits synaptic transmission in the brain areas related to arousal and vigilance.

At the same time caffiene seems to enhance Dopamine and norepinephrine activity.

 

EDE 778: Herbaceuticals (phytotherapy >Gk. meaning plant theray)

 

It is estimated that 40% of Americans have tried “alternative therapies” with herbal therapies being the most common alternative therapy (Gray, 1999). It is estimated that 40-60% of those using herbal remedies do so without telling their physician (Guthrie, 1999). The majority are middle/upper-middle class Caucasians paying out-of-pocket.

 

In Germany, herb use is more common with depression being treated with Hypericum perforatum (St. John’s Wort) 4x as often as with fluoxetine (Gray 1999).

 

Reasons people use herbal remedies:

·                    Mistrust of allopathic medicine (>Gk allo = other, pathes = suffering from)

·                    Belief that “natural products are less toxic than synthetic drugs – real misconception when you look at the number of active compounds in plants and the number that can kill you (potentially toxic herbs include Belladona, Sassafras, Ephedra, and Licorice)

·                    Anecdotal testimony (hard to refute because of the lack of research)

·                    They don’t require a prescription

 

DIFFERENCES BETWEEN HERBS AND DRUGS:

 

Drug                                                                                         Herb

Dose established                                                      only guidelines

Efficacy proof                                                   efficacy proof not required

Usually monosubstance                         complex compound

FDA approval required                         No FDA approval

Patentable                                                                    not patentable

Potency standards                                            potency varies

 

 

PROBLEMS

Contaminants found

 

CHINESE PATENT MEDICINES:

Mercury

Arsenic

Aspirin

Phenobarbital

Phenacetin

 

INDIAN MEDICINES
carbamazepine

Chlordiaepoxide (Librium)

 

(Silfman, et. al., 1998)

 

PROBLEMS REVIEWING EFFICACY:

 

Various problems hinder the study of herbs:

·                    isolation of naturally occurring compounds (most research focuses on drug/receptor interaction)

·                    inaccurate identification of plant species – example there are 250 varieties of the herb valerian and they vary in the concentrate of active compounds.

·                    Variations in composition: chemical composition of plants varies with genetic factors, climate, growing season, soil quality, rainfall, and post-harvest storage conditions. Any of these can affect the composition.

·                    Preparation methods: dried, as tea, as extract. Various solvents may be used including alcohol, oils, or water. The amount of active ingredient varies with the prep. Method.

·                    Lack of standardization: in addition to the problems already mentioned, adulteration and substitution often occur when the plant material is expensive. Tyler (1994) found that many preparations of ginseng have no ginseng in them.

·                    Chemical complexity: (repeat mantra) Plants contain thousands of chemicals. For example at least 40 chemical compounds contribute to the aroma of coffee.  This means each herbal preparation may have a variety of pharmacological effects.

·                    Inadequate study designs: because herbal remedies are not marketed as drugs they are exempted from the regulatory process.  The fact that you can’t patent a naturally occurring element precludes making a lot of money on the element. German pharmaceutical companies have not invested  the same resources into conducting clinical trials of herbs as they have for allopathic meds.

·                    Difficulties accessing data: most of us don’t speak German and that is where much of the data is – German journals. There are two recent translations of German authored books on phytotherapy.

 

 

 

One phenomenon is the marketing of combination herbal products that are often marketed as calming or anti-tension products. One example is TRANQUILON. Each tablet contains

 

·                    300 mg SJW

·                    90 mg passion flower

·                    70 mg hops

·                    30 mg skullcap

·                    40 mg Black cohosh

·                    30 mg wood betony

·                    30 mg chamomile

·                    15 mg lady’s slipper

·                    10 mg cayenne

·                    5 mg chlorophyll

·                    40 mg elemental calcium

·                    10 mg elemental magnesium

 

The ad claims the Tranquilon formula contains the unique  SJW, ten natural complementary herbs, and calcium, working together for the synergistic effect 2-3 tablets a day.

 

Obviously we don’t know if there is a synergistic effect or not.

 

Better Known Herbal Remdies for Psychiatric Problems

 

St. John’s Wort (depression)

Kava Kava (anxiety)

Valerian Root

Passion Flower

Hops

Melatonin (sleep disruption)

Ginkgo (memory loss/dementia)

 

St. John’s Wort (“Wort” means plant or vegetable derived from OE “wyrt.” It is usually only used in combination e.g. figwort)

 

This is an aromatic perennial with yellow flowers that are abundant in June – the time of year the birthday of John the Baptist is celebrated. The plant is native to Europe and grows wild in Asia, North America, and South America.

 

SJW has been used medicinally for over 2000 years. Its use in treating mood disorders was pioneered by a German physician in 1939.

 

Although traditionally prepared as tea, currently it is prepared in ethanol and methanol extracts. The methanol extract with all the research in Germany is labeled LI 160 in the literature.

 

MECHANISM OF ACTION: Early studies assumed the active ingredient was hypericin and that it inhibited MAO. Currently it is thought that the extract blocks reuptake of NE, 5-HT with the subsequent down-regulation of receptors.

 

There have been 15 clinical trials with the methanol extract and 12 with ethanol extracts. Of these, 9 were well controlled, 5 used placebo and showed significant results over placebo.

 

Overall, patients who took the extract showed greater improvement on Hamilton Rating Scale for Depression (HAMD) 61% of people taking SJW responded compared to 24% taking placebo. “Response” was defined as <50% decline in HAMD scores.

 

There have been 4 studies comparing LI 160 to Ludiomil (secondary amine), Tofranil, and Elavil. No significant difference found between SJW and these agents. I need to get these studies to clarify the results. The TCA dosages were low but LI 160 was better tolerated (Wheatley, 1997).

 

LI 160 does not appear to be an inducer or inhibitor of cytochrome P450 enzyme system.

 

Overall, it seems that 900 mg per day of SJW is an effective antidepressant for mild to moderate depression.

 

German commission E has prepared monographs on herbal remedies uses, indications, contraindications, side effects and doses

 

KAVA: An Herbal Anxiolytic www.kavaking.com

 

The kava shrub is native to Polynesia and the Pacific Islands. It has been used there for millennia primarily in liquid form made by grinding the dried rhizome (underground stem) and mixing with water and coconut milk.

 

It was described by European invaders/explorers in the 18th century as having a calming effect. The crude drug can be derived from the rhizome but most now are ethanol-water or acetone extracts.

 

At high doses it can cause intoxication. There are no reports of withdrawal upon discontinution. Some people report dermopathy – yellowish scaly skin eruption and reddedned eyes.

 

Kava is one of the few herbal treatments where the active ingredient is known. Meyer (1967) proved that the effects of Kava were due to kavapyrones. These pyrones act as muscle relaxants, anticonvulsants, and reduce excitability in the limbic system. The do this through inhibition of voltage-dependent sodium channels, increasing the number of GABA-A receptors, blocking NE reuptake, and suppressing release of Glutamate (which metabolizes into Glutamic Acid which serves an excitatory function).

 

Three double-blind, placebo-controlled studies support the use of kava as an anxiolytic (Warnecke, 1991; Kinzler et. al, 1991; Volz & Kieser, 1997). The only problem with these studies is that the patient population was not clearly defined by diagnosis so we don’t know the efficacy of of Kava particularly with panic disorder.

 

VALERIAN ROOT: This is another commonly prescribed herb in Europe. It is a mild sedative/anxiolytic. Usually given 400-450 mg in extract form.

 

The rhizome and roots are harvested, dried and served as tea or used to make an extract. Valerian extract contains over 100 different constituents. It is not known which of these is responsible for its effects.

 

Studies in humans verifies its efficacy  as a mild sedative. The roots have many components but it looks like it may inhibit the metabolism of GABA.

 

In studies, 400-900 mg of valerian extract decreased sleep latency and nocturnal awakenings and improved subjective sleep quality. In some cases the beneficial effects were seen only after 2-4 weeks of therapy (Balderer & Borbely, 1985; Leathwood & Chauffard,  1982; Leathwood et. al., 1982)

 

PASSION FLOWER AND HOPS: Both used as sedative/anxiolytic but there is little scientific data on either.

 

Passion flower is a climbing vine native to North America. It has fallen into disuse in this country but is the most common herbal hypnotic in Great Britain. Components of its extract bind to GABA receptors.

 

Hops are the fruit of the hop plant – a vine native to Europe. Although used primarily for making beer they have been used as a tonic for over 1000 years. Their use as a sleeping aid resulted from the observation that hop pickers tired easily possibly due to the transfer of hop resin from hands to mouth.

 

Studies have not confirmed that hop resin, hop extract, or lipophilic hop concentrates have a sedative effect. There does not appear to be sufficient data to support its use as a sleep aid. 

 

MELATONIN: This is a hormone produced by the pineal (resembling pine cone) gland. It bind to the suprachiasmic nucleus which is the body’s circadian pace maker – internal clock. The SCN normally produces an alerting signal which is thought to be blunted by melatonin. Melatonin is useful in initiating sleep but not real helpful in maintaining sleep because there may be a rebound in the SCN.

 

Various doses are used (1-100mg) and anything over 5mg raises the melatonin in the blood to higher than normal levels. The melatonin in health food stores is labeled to range between 1-5 mg but the actual range is much more variable.

 

Other substances used as sleep aids but lacking data to confirm their effectiveness include Lemon balm, lavender, chamomile, catnip, and sour orange.  

 

GINKGO BILOBA: An Herbal cognitive enhancer.

 

Ginkgo trees are native to East Asia. There were first imported to Europe from Japan during the 18th century and are common ornamental trees throughout Europe and North America.

 

Ginkgo fruit and seeds have been used in China for medicinal purposes for millennia. Ginkgo has been used to treat people with asthma and leaves are used to dress wounds.

Currently most Ginkgo products are derived from the dried leaves.  The therapeutic extracts are Egb 761 and LI 1370. The active ingredient seems to be flavonoid and the leaves are harvested in May when the flavonoid content is at its highest.

 

Gingko, like other herbs, contains a large number of substances that have been demonstrated to have a wide variety of pharmacological properties.

 

The flavonoids are thought to be antioxidants which could account for ginkgo’s reputed effects in ALZ patients since free-radical damage is thought to play a role in the loss of hippocampal Ach neurone.

The ginkgolides are thought to inhibit platelet activating factor. This effect may play a role in patients with vascular dementias using the same mechanism as aspirin in forestalling additional strokes.

 

More than 40 controlled studies have been conducted to determine Ginkgo efficacy for treating dementia – most in France and Germany. Although these studies appear to demonstrate positive effects, the patient populations were poorly defined, the numbers were small, the randomization poorly done, and the outcome measures were not standard.

 

Many of these shortcomings were corrected in the LeBars study in 1997. This 52 week, randomized, double-blind, placebo-controlled study had an n of 309 patients, 202 of which completed the study. Patients had either ALZ (236) or vascular dementia (73). They were 45-90 years of age and had a mini-mental score between 9 and 26

 

Outcome measures included the ALZ Disease Assessment Scale  - Cognitive subscale (ADAS-Cog), geriatric Evaulation by Relatives Rating Instrument (GERRI) and the Clinical Global Impression of Change (CGIC).

 

On average the ADAS-Cog and the GERRI showed significantly less decline in the Ginkgo extract group than in the placebo. 27% of the exp. Group versus 14% of the placebo group. The improvement was equivalent to a 6 month delay in the progression of the disease. The results were comparable to the effects of 80-120 mg of cognex (tacrine).

 

Based on the study only a minority (25-30%) of ALZ patients would be expected to respond which is similar to levels of response for cognitive enhancers (30-40%).

 

Ginkgo is used heavily in France, Germany and the United States. Its use in the US increased following the publication of a trial used with patients with dementia (LeBars, et. al., 1997).

 

References

 

            Astin, J. A. (1998). Why patients use alternative medicine: Results of a national study. Journal of the American Medical Association, 279, 1548-53.

 

Balderer, G, & Bobely, A. A. (1985). Effect of valerian on human sleep. Psychopharmacology (Berl), 87, 406-409.

 

            Bennett, J. & Brown, C. M. (2000). Use of herbal remedies by patients in a health maintenance organization. Journal of the American Pharmacists Association, 40 353-358.

 

            Eisenberg, D. M., Davis, R. B., Ettner, S. L., et. al. (1998). Trends in alternative medicine use in the United States, 1990-1997. Journal of the American Medical Association, 280, 1569-75.

 

            Gray, G. E. (1999). A psychiatric perspective on herbal remedies. Directions in psychiatry, 19, 349-359.

 

            Gutherie, S. K. (1999). Herbaceuticals in psychiatry. Unpublished lecture given at The Medical College of Ohio, Toledo, OH, September 24.

 

            Kinzler, E., Kroner, J., & Helman, E. (1991). Effect of a special kava extract in patients with anxiety, tension, and excitation states of non-psychotic genesis: Double blind study with placebos over 4 weeks. Arzneimittelforschung, 41 584-588.

 

Klesper, T. B., & Klesper, M. E. (1999). Unsafe and potentially safe herbal therapies. American Journal of Health Systems and Pharmaceuticals, 56 125-38.

 

Leathwood, P. D., & Chauffard, F. (1982) Quantifying the effects of mild sedatives. Journal of Psychiatric Research, 17, 115-122.

 

            Leathwood, P. D., Chauffard, F., Heck, E, & Munoz-Box, R. (1982). Aqueous extract of valerian rood (Caleriana officinalis L.) improves sleep quality in man. Pharmacology and Biochemical Behavior, 17 65-71.,

 

            LeBars, P. L., Katz, M. M., Berman, N., Itil, T. M., Freedman, A. M., & Schatzberg, A. F. (1997). A placebo-controlled , double-blind randomized trial of an extract of Ginkgo biloba for dementia. Journal of the American Medical Association, 278, 1327-1332.

 

            Meyer, H. J. (1967). Pharmacology of kava. Psychopharmacology Bulletin, 4, 10-11.

 

            Slifman, N. R., Obermeyer, W. R., Musser, S. M., orrell, W. A., Chichowicz, S. M., & Love, L. A. (1998). Contamination of botanical dietary supplements by digitalis lanata. The New England Journal of Medicine, 339, 806-811.

 

            Tyler, V. E. (1994). Herbs of choice: The therapeutic use of phytomedicincals. New York: Pharmaceutical Products Press.

 

            Volz, H. P. (1997). Controlled clinical trials of hypericum extracts in depressed patients: An overview. Pharmacopsychiatry, 30 (supp 2), 72-76.

 

Warnecke, G. (1991). Pscyosomatic dysfunctions in the female climacteric: Clinical effectiveness and tolerance of kava extract KS 1490. Fortschr Med., 109, 119-122.

 

Wheatley, D. (1997). LI 160, an extract of St. John’s Wort, versus amitriptyline in mildly to moderately depressed outpatients: A controlled 6-week clinical trial. Pharmacopsychiatry,  30 (suppl 2),  77-80.