Antipsychotic Drugs

Antipsychotic Drugs
(Tx of Schizophrenia & more)

Schizophrenia (Sz)
0.81% in the U.S.A. dx. w/ Sz per NIMH.
Sz is a neurodevelopmental disorder > problems with attention & information processing.
The relationship between Sz & neurochemical findings is NOT clear.

Schizophrenia (Sz)
Positive symptoms:
delusions, hallucinations, bizarre behavior, disturbed thinking, incoherence.

Negative symptoms:
blunted affect, apathy, social withdrawal.

Traditional Antipsychotic Drugs
Classical = Traditional = Neuroleptic = Major Tranquilizer = Antischizophrenic.
Block dopamine receptors. The extent of binding to dopamine receptors predicts efficacy, dose, & liklihood of > side effects.
Therapeutic effects are inseparable from side (toxic) effects on the extrapyramidal motor system.
Treats positive symptoms of sz, but may worsen negative symptoms.
Makes the Sz more manageable.

Traditional Antipsychotic Drugs
Extrapyramidal side (toxic) effects:
parkinsonian symptoms (muscle rididity), slow movements, restlessness.
tardive dyskenisia,
NMS (neuroleptic malignant syndrome).

Traditional Antipsychotic Drugs
Phenothiazines
Most widely used and least $ drugs for tx of psychosis.
Also used for: nausea, vomiting, as sedation, premature ejaculation, itch relief, alcoholic hallucinosis, anti-psychedelic, psychosis of acute mania.

Traditional Antipsychotic Drugs
Phenothiazine Pharmacokinetics:
Oral administration most common > Erratic & unpredictable GI tract absorption.
Metabolized slowly by the liver.
IM injections can increase effectiveness.
Level in brain low, compared with levels in other body tissues (lungs, liver, adrenals, spleen).
Dosage decision made on trial and error basis.

Traditional Antipsychotic Drugs
Phenothiazine Pharmacological Effects:
Block dopamine receptors -- as well as: acetylcholine (dry mouth, dilated pupils, blurred vision , constipation, urinary retention, & tachycardia), serotonin, histamine (sedation, anti-nausea), & norepinepherine (hypotension, sedation) receptors.
Decrease: paranoia, fear, hostility, agitation; reduces the intensity of Sz hallucinations and delusions. (limbic system effects).
Decrease: behavioral arousal, vomiting (brain stem effects).

Traditional Antipsychotic Drugs
Phenothiazine Pharmacological Effects: 
Motor disturbances (basal ganglia):
acute extrapyramidal effects: 
akasthesia - subjective anxiety, restlessness, repetitive seemingly purposeless actions; 
dystonia - involuntary muscle spasms, sustained abnormal posturing of limbs, trunk, face, & tongue; 
parkinsonism - resting tremor, limb rigidity, slowing movement, decreased initiation
tardive (late) dyskinesia - involuntary hyperkinetic movements (sometimes severely disabling). It can appear months after initiation of treatment and is often irreversible
less common toxic effects: skin pigmentation changes, permanently impaired vision, liver dysfunction, blood disorders, NMS.

Traditional Antipsychotic Drugs
Phenothiazine Pharmacological Effects: 
(hypothalamus-pituitary):
Decrease: hunger/appetite, temperature regulation ability.
Males: breast enlargement, blocked ejaculation.
Females: lactation, decreased libido, abnormal menstration, infertility.
High-potency phenothiazines (Prolixin, Stelazine, Trilafon) cause less sedation, less anticholinergic effect; more extrapyramidal effect.
Not drugs of abuse; no tolerance, no dependance.
Does not cure mental illness, long term use is associated with serious side effects.
Phenothiazines

Alternative to Traditional Antipsychotic Meds.
Haldol (haloperidol), 1967.
Similar to the phenothiazines (blocks dopamine receptors). However, fewer serious side effects, less sedating, but has potential for great adverse parkinsonian effects.
Provided an alternative for psychotic patients who did not respond to phenothiazines.

Atypical Antipsychotics
Clozaril (clozapine) 1989.
Used with tx resistant Sz, sometimes with success!
Treats negative symptoms including disorganization. Less extrapyramidal effect, less cognitive inhibition.
Oral absorption.
Expensive.
Blood levels (rarely, but potentially fatal).
Side (toxic) effects: sedation, weight gain, constipation, agranulocytosis (a rare, drug-induced blood disorder that is characterized by a severe reduction in the number of white blood cells), urinary incontinence, hypotention, esophagitiss, seizures, excessive drooling. Withdrawal symptoms (psychosis, hostility, paranoia, nausea, restlessness, agitation, confusion, sweating).

Atypical Antipsychotics
Risperdal (risperidone), 1993
Improved control of psychotic symptoms, with minimal extrapyramidal effects.
Well absorbed orally.
Reduces positive symptoms; less extrapyramidal effect.
Side (toxic) effects: decreased memory, sleep disorders, agitation, anxiety, headache, nausea, weight gain. Extrapyramidal effects are seen at high doses and in patients with new onset of Sz.

Atypical Antipsychotics
Zyprexa (olanzapine), 1996
Absorbed orally.
Improves positive & negative symptoms (per manufacturer). Reduces agitation and aggression.
Extrapyramidal effects are rare (per manufacturer).
Used to treat Bipolar Disorder, Pervasive Developmental Disorder
Side (toxic) effects: weight gain, sedation, orthostatic hypotention, dizziness.

Atypical Antipsychotics
Seroquel (quetiapine) 1998.
Reduces positive symptoms, sometimes reduces negative symptoms.
Low extrapyramidal side effects.
Used to treat drug-induced psychosis in Parkinson’s Disease, Bipolar Disorder, Schizoaffective Disorder.

Psychopharmacology of Bipolar Disorder (J16)

Psychopharmacology 
of Bipolar Disorder

Bipolar Disorder
Characterized by recurrent episodes of mania & depression.
Occurs in est. 1% to 4% of people.
Bipolar I = severe;
Bipolar II = less severe.
Many famous persons with Bipolar.
>55% of bipolar pts have hx of substance abuse (ETOH 82% of that).

Lithium (Li)
Historically, the most recommended drug for tx. of bipolar disorder.
Effectively treats 60% - 80% of acute hypomanic and manic episodes.
Less effective than predicted by clinical trials; patients noncompliant.
Natural course of bipolar is worse with Li non-compliance than with untreated disease.

Lithium (Li)
Efficacy is in question.
Research suggests that Li is a good adjunct to antidepressant medication in people with treatment resistant depression.
Li & antiepileptic drug (combination tx) is common.

Lithium (Li)
Pharmacokinetics
Oral administration > rapid and complete absorption.
Not metabolized. Excreted unchanged mostly via kidneys.
Long half-life. Steady state is reached in about 2 weeks.
Narrow theraputic range. Too low = no effect. Too high = toxic. Blood levels need close monitored (not always the case).
Closely resembles table salt. Lower salt intake or increased loss (aerobic activity) > toxicity.

Lithium (Li)
Pharmacodynamics
No psychotropic effect in normal people @ clinical dose.
Specific action on mania without other brain effects.
No one really knows the mechanism of acction.

Lithium (Li)
Narrow therapeutic range; blood levels need close monitoring.
Not taken when pregnant.
No antidote.
Course of disease probably worse if Li stopped, compared with never taken .

Lithium (Li)
Toxicity (Side Effects):
GI tract (nausea, vomiting, diarrhea, abdominal pain), 
kidneys (>urine output, thirst), thyroid (enlarged), 
cardiovascular system, 
skin (rash), 
nervous system(slight tremor, lethargy, confusion, slurred speech, ataxia, muscle weakness, nystagmus).
Long term: weight gain (30%>obese), poor memory,

Lithium (Li)
Lifelong commitment.
Noncompliance 
(because of toxic effects).
50% stop Li a.m.a.
> morbidity 
>manic episodes >suicide

Anticonvulsants
Tegretol (carbamazipine)

Much better than Li for rapid cycling bipolar.
Toxic effects: GI upset, sedation, ataxia, visual disturbances, rashes, mild reduced cognition.
Contraindicated during pregnancy.
Adverse blood reactions can occur; blood needs to be monitored.
Drug interactions are common & tolerance develops.

Anticonvulsants
Depakote (valproic acid)
The most widely used antimanic drug.
Very effective in tx of acute mania, mixed states, schizo-affective disorder, & rapid-cycling bipolar disorder.
Used in combination with Li for some; used in pregnant women. Also used for Borderline PD, and behavioral disorders, and anxiety.
Toxic effects: GI upset, sedation, hand tremor, hair loss, liver changes, cognitive decline.

Anticonvulsants
Neurontin (gabapentin)
“off label”: bipolar, anxiety, behavioral dyscontrol, substance dependency, borderline PD, peripheral neuropathy.
pharmacokinetics: not bound to plasma proteins, not metabolized, excreted unchanged thru kidneys, few drug interactions.
Used to augment Li (and other drugs).
Toxic (side) effects: sleepiness, dizziness, ataxia, nystagmus, double vision.

Psychotherapy
A combination of drug therapy & psychotherapy is the most effective treatment for bipolar illness.

Article: Managing Compliance

MANAGING COMPLIANCE Psychiatric Times, by Dr. Richard Balon.

Compliance with treatment, or treatment adherence, is a very important clinical issue. In prescribing medication, compliance usually means "the extent to which the patient takes the medication as prescribed". Many mental disorders require more than just a brief medication intervention. For some patients, several months or years of medication or even lifelong medication is necessary. For instance, the recommended treatment time for the first episode of depression is six to twelve months, but almost half of patients stop taking their antidepressant within three months for various reasons. Noncompliance can have serious consequences, such as relapse or recurrence of the illness. Therefore enhancing medication compliance (or preventing noncompliance) is an important treatment goal for patients and clinicians. The first step in this process is the recognition and prevention of factors that could lead to noncompliance.

I found this article interesting because it addresses the role of toxic effects on noncompliance and hopefully will offer others in the class insight into how significant a factor it is in developing treatment strategies.

See http://www.psychiatrictimes.com/p020543.html


Thanks to Richard G.

Article: FDA Hears Antidepressant-Kid Suicide Debate

FDA Hears Antidepressant-Kid Suicide Debate


By Daniel DeNoon
WebMD Medical News Reviewed By Brunilda Nazario, MD
on Monday, February 02, 2004

Do antidepressants make some children suicidal? If so, do the drugs' benefits outweigh their risks? It is not easy to answer this question as much of the data remains in the hands of the pharmaceutical companies that sponsored the studies. Also, when the drug companies were asked to comb through their data for any sign that antidepressants increased suicidal thoughts or behaviors, the results were disappointing. The different companies interpreted the FDA request in different ways, making the resulting information difficult to interpret.

At the heart of the problem is the nature of depression and its treatment. Depression can be deadly. Suicide is much more common in depressed people than in others. Children react differently to antidepressants than adults. And there's reason to think that antidepressants may, in some people, lead to changes in brain chemistry that make suicidal behavior more likely. On the other hand, untreated depression can lead to suicide, too. Advocates of antidepressants warn that the FDA should not take one of the few treatments for depression out of the hands of doctors.

SEE: http://www.webmd.com/content/article/81/96955.htm

Thanks to Helen F.

Antiepileptics

Antiepileptics

Seizure
Seizures are manifestations of electrical disturbances in the brain.
Epilepsy = CNS disorder characterized by brief, chronic seizures with rapid onset. Often associated with focal (localized) brain lesions.

Antiseizure Meds.
Limit repetitive firing of neurons -- by blocking channels that sodium ions flow through & preventing repetitive discharge, which is implicated in seizure activity. (Traditional.)
OR
Enhance GABA-mediated synaptic inhibition by reducing the metabolism of GABA.
(Newer. Also tx. of bipolar.)

Traditional Antiepileptic Drugs.
Barbiturates:
phenobarbitol (generic barb). 1st widely used antiepileptic.
Mebral (mephobarbital). Used occasionally.
Gemonil (metharbital). Used occasionally.

Hydantoins 
Zarontin (ethosuximide)
Mysoline (primidone)
Tegretol (carbamazepine)
Dilantin (phenytoin). Widely used. 

Antiseizure Meds.
Benzodiazepines. Possess antiepileptic properties.
Klonopin, Tranxene
ETOH. Possess antiepileptic properties.

Antiseizure Meds.
GABAergic
Depakine (valproic acid), 1978
Felbatol (felbamate). Rarely used because of toxic effects, including aplastic anemia (serious, failure of bone marrow to produce cells) and liver failure. At first thought to be free of serious side effects.
Neurontin (gabapentin). 1995.Widely used for psych & pain.
Lamictal (lamotrigine). 1995. Used as anti-depressant, anti-manic.
Topamax (topiramate). Also use for anti-manic.
Gabitril (tiagabine). 1998. Also used for anti-manic.

Neurofeedback (NF)
EEG Biofeedback
1972. Case presentation. 23 y.o. woman with 7 yr hx generalized tonic-clonic seizure (w/occ. incontinence) of unknown origin. Meds not helpful, but taking Dilantin 200 mg and Mebarol 200 mg. NF 2x/wk for 3 months; enhance SMR (11-15 Hz) > seizures stopped. Tx. continued (briefly) and she became seizure free without meds.
Neurofeedback (NF)

EEG Biofeedback
Adequate control of epilepsy with medication at best (pts. w/ localized partial seizures -- the most common type) est. as low as 30%.
In 18 published studies (N=174), with different NF protocols: 82% showed significant (>30%) seizure reduction, with an average seizure reduction >50%. Many subjects showed reduction in severity as well. About 5% had complete control for up to 1 year, even when meds were reduced or discontinued. Most patients only responded with SMR reward (not other NF). In studies that looked at pre & post EEG changes, 66% showed significant EEG changes.

Psychostimulants

Psychostimulants


Amphetamines
Amphetamines = sympathomimetic agents: 
mimic the actions of adrenaline.
Effects: (alerting response: fight or flight) Stimulate CNS: vasoconstriction, hypertension, tachycardia. tremor, restlessness, >motor activity, agitation, insomnia.
Abuse: violent behavior, paranoia, psychosis. Permanent (long term neurotoxicity): sleep dysfunction, sexual dysfunction, depression, movement disorders.
Psychostimulants: Amphetamines
1935-1946 - used to treat many things: schizophrenia, morphine addiction, smoking, heart block, head injury, radiation sickness, hypotension, sea-sickness, hiccups, caffeine dependence.
WWII - used to enhance performance of soldiers and ameliorate fatigue.
late 1940s - Large scale (oral) abuse evident with students and truck drivers. Used (ineffectively) for diet.
1960s - injectable abuse. Current abuse -- methamphetamine (including smoking and free-base).

Amphetamines
Current Medical uses:
Narcolepsy treatment.
ADHD treatment.


Non- Amphetamines
Ritalin (methylphenidate);
Ritalin-SR: sustained release;
Concerta: sustained release, newer form.

The mechanism of action for calming ADHD is unclear.
Theory: 1) increases dopamine, 2) increases serotonin, 3) balances dopamine & serotonin.

Non- Amphetamines
Cylert (pemoline).
Mechanism of action. Theory: potentiates dopamine.
Psychostimulants: Non- Amphetamines
Meridia (sibutramine). Antagonist; increases serotonin, norepinephrine, dopamine.
Was used for weight loss.

Non- Amphetamines
Modafinil.
Mechanism of action is unclear; probably unique.
Used to treat narcolepsy.


Treatment of ADHD
Psychostimulants can help with the core symptoms: inattention, impulsivity, hyperactivity, BUT NOT with the wide range of clinical problems in ADHD.
Psychostimulants do NOT help with: 35%-45% of “inattentive” type; 
10%-30% of “combined” type.

Neurofeedback: Treatment of ADHD
Neurofeedback (NF).
Lubar & Shouse, 1976 & 1979. Operant conditioning. Supported the hypotheses that > 12-15 Hz (SMR) or 16-20 Hz (beta) while < 4-8 Hz (theta) -- over sensorimotor or central frontal region -- improves attention & reduces impulsivity and hyperactivity. These findings are supported with numerous case studies.

Neurofeedback: Treatment of ADHD
Controlled Studies:
Linden, et al, 1996. N=18, age 5-15 w/ADHD. No meds. Randomized study: NF (40 sessions over 6 months) vs. waiting group. NF group > IQ and reduced ADHD sx. on a behavior rating scale.
Rossiter & LaVaque (1995). N=46, age 8-21 w/ADHD. Participants chose Ritalin or NF (20 sessions over 3 months). Both groups improved on TOVA (attention), and behavioral rating scales w/o significant difference.

Neurofeedback: Treatment of ADHD
Monastra et al, 2002. N=100, age 6-19. One year comprehensive program all received Ritalin, family therapy, & academic support. 51 received NF. All showed significant improvement in attention (TOVA) and behavior (ADDES) while using Ritalin. Only NF group sustained gains when Ritalin dc’d. QEEG showed significant reduction in cortical slowing in only the NF group. Parenting style effected behavior at home, but not in school.

The Truth About Drug Companies

The Truth About Drug Companies
by Marcia Angell, M.D.

Problems:
Big Pharma produces too many me-too drugs, and too few innovative ones.
The FDA is too much in the thrall of the industry it regulates.
Drug co. have too much control over clinical research on their own products.
Patents & other exclusive marketing rights are undesirably long & too elastic.

Problems:
Drug co. have too much influence over medical education about their own products.
Important information about research & development, marketing, & pricing is kept secret.
Prices are too hight and too variable.

Solutions:
U.S. patent law should be enforced in its original form. For example, Prozac should not have been granted a new patent to treat premenstrual tension.
*** The FDA should require comparison of new drugs with old drugs for the same condition; not comparison with placebos.
The FDA needs to be strengthened as an independent agency. It is now dependent on the pharmaceutical industry. The FDA is on big pharma’s payroll via the Prescription Drug User Fee Act (expires 2007) -- authorized drug companies to pay “user fees” to the FDA for each drug reviewed. The FDA needs more govt. funding. FDA advisory committees should exclude experts with financial ties to drug companies.

Solutions:
Create an institute (via NIA) to oversee clinical testing of drugs. Big pharma should no longer be permitted to control the clinical testing of their own drugs.
Curb monopoly marketing rights. The period of exclusivity for brand-name drugs is too long and too easily stretched -- leading to inflated costs.
Get big pharma out of medical education. Big pharma does a poor job of providing medical education; they do an excellent job of selling drugs. Eliminate industry sponsored teaching materials. Professional organizatins should be self-supporting.

Solutions:
Direct-to-consumer advertising should be prohibited in the U.S., as it is in other advanced countries.
The pharmaceutical industry should be regarded as a public utility; its books should be open.
Establish reasonable and uniform pricing. Now, the most vulnerable people pay the highest prices. Unfortunately, the Medicare reform bill of 2003 forbids Medicare to use its purchasing power to bargain for lower prices.

Internet-based psychiatric treatments.

from:

Net-based psychiatric treatments sometimes beneficial
10/26/2006 12:17:13 PM, by Eric Bangeman

A yet-to-be-published study is making some startling claims about psychological treatment. According to researchers at The Australian National University in Canberra, spending time on therapeutic and educational web sites can be just as effective as regular visits to the psychotherapist.

Researchers studied a group of patients who were referred to two web sites: The MoodGYM and education site BluePages. The MoodGYM is therapeutic in nature, a cognitive behavior therapy site dedicated to preventing depression by helping users to "identify and overcome problem emotions," showing them how to "develop good coping skills for the future" in order to enjoy good mental health. BluePages is a depression education site, providing information about the symptoms of and treatments for depression.


After 12 months, users of both web sites reported improvement. Interestingly enough, the educational site BluePages proved to be more effective than the behavior-therapy site. BluePages users "were less likely to use actions that did not have an evidence basis," researcher Helen Christensen said. "We don't know exactly why the Internet interventions are so effective in the longer term, but it may be that there is a reduction in use of ineffective and potentially damaging treatments."

"In some ways the results are not that surprising," psychotherapist Kerry DeVries told Ars Technica. "Cognitive behavioral strategies—sometimes in conjunction with medication—are the most effective means of treating depression." DeVries also believes willingness to use the web sites shows the kind of initiative needed to successfully treat depression. "A person who is visiting an educational site like BluePages is taking the necessary steps with her own self-care. That's a key component of successful treatment for depression."

The researchers believe that the results indicate that Internet-based strategies—educational and therapeutic—can be as effective as in-office treatment. If that is indeed the case, educational and treatment-focused sites could become useful tools in treating people in remote or rural areas for whom access to professional help is problematic. Some therapists make use of remote treatments already, mostly over the phone, but using the Internet as a means of delivering psychiatric care is a relatively new phenomenon. While it can't replace individual psychotherapy or medication in all instances, the study does show that sites dedicated to education and treatment can be a valuable tool in the therapist's arsenal.

The Hamilton Rating Scale for Depression (HAM-D)

From:

HAMILTON Patient Name: ____________________________
RATING SCALE Rater Name: ____________________________
FOR DEPRESSION Date: ____________________________

Activity Score

Depressed mood _______
Sad, hopeless, helpless, worthless
0 = Absent
1 = Gloomy attitude, pessimism, hopelessness
2 = Occasional weeping
3 = Frequent weeping
4 = Patient reports highlight these feelings states in his/her spontaneous verbal and
non-verbal communication.

Feelings of guilt _______
0 = Absent
1 = Self-reproach, feels he/she has let people down
2 = Ideas of guilt or rumination over past errors or sinful deeds
3 = Present illness is punishment
4 = Hears accusatory or denunciatory voices and/or experiences threatening visual
hallucinations. Delusions of guilt.

Suicide _______
0 = Absent
1 = Feels life is not worth living
2 = Wishes he/she were dead, or any thoughts of possible death to self
3 = Suicide, ideas or half-hearted attempt
4 = Attempts at suicide (any serious attempt rates 4)

Insomnia, early _______
0 = No difficulty falling asleep
1 = Complaints of occasional difficulty in falling asleep i.e. more than half-hour
2 = Complaints of nightly difficulty falling asleep

Insomnia, middle _______
0 = No difficulty
1 = Patient complains of being restless and disturbed during the night
2 = Walking during the night – any getting out of bed rates 2 (except voiding bladder)

Insomnia, late _______
0 = No difficulty
1 = Waking in the early hours of the morning but goes back to sleep
2 = Unable to fall asleep again if he/she gets out of bed


Page 1 Score ______

Provided by the Internet Stroke Center — www.strokecenter.org



Work and activities _______
0 = No difficulty
1 = Thoughts and feelings of incapacity related to activities: work or hobbies
2 = Loss of interest in activity – hobbies or work – either directly reported by patient or
indirectly seen in listlessness, in decisions and vacillation (feels he/she has to push
self to work or activities)
3 = Decrease in actual time spent in activities or decrease in productivity. In hospital,
rate 3 if patient does not spend at leas three hours a day in activities
4 = Stopped working because of present illness. In hospital rate 4 if patient engages
in no activities except supervised ward chores

Retardation _______
Slowness of thought and speech; impaired ability to concentrate; decreased motor activity
0 = Normal speech and thought
1 = Slight retardation at interview
2 = Obvious retardation at interview
3 = Interview difficult
4 = Interview impossible

Agitation _______
0 = None
1 = Fidgetiness
2 = Playing with hands, hair, obvious restlessness
3 = Moving about; can’t sit still
4 = Hand wringing, nail biting, hair pulling, biting of lips, patient is on the run

Anxiety, psychic _______
Demonstrated by:
• subjective tension and irritability, loss of concentration
• worrying about minor matters
• apprehension
• fears expressed without questioning
• feelings of panic
• feeling jumpy
0 = Absent
1 = Mild
2 = Moderate
3 = Severe
4 = Incapacitating



Page 2 Score ______

Provided by the Internet Stroke Center — www.strokecenter.org







Anxiety, somatic _______
Physiological concomitants of anxiety such as:
• gastrointestinal: dry mouth, wind, indigestion, diarrhea, cramps, belching
• cardiovascular: palpations, headaches
• respiratory: hyperventilation, sighing
• urinary frequency
• sweating
• giddiness, blurred vision
• tinnitus
0 = Absent
1 = Mild
2 = Moderate
3 = Severe
4 = Incapacitating

Somatic symptoms: gastrointestinal _______
0 = None
1 = Loss of appetite but eating without encouragement
2 = Difficulty eating without urging. Requests or requires laxatives or medication for GI symptoms

Somatic symptoms: general _______
0 = None
1 = Heaviness in limbs, back or head; backaches, headaches, muscle aches, loss of energy, fatigability
2 = Any clear-cut symptom rates 2

General Symptoms
Symptoms such as: loss of libido, menstrual disturbances _______
0 = Absent
1 = Mild
2 = Severe

Hypochondriasis _______
0 = Not present
1 = Self-absorption (bodily)
2 = Preoccupation with health
3 = Strong conviction of some bodily illness
4 = Hypochondrial delusions

Page 3 Score ______
Provided by the Internet Stroke Center — www.strokecenter.org
Loss of Weight
Rate either ‘A’ or ‘B’:
A When rating by history:
0 = No weight loss
1 = Probable weight loss associated with present illness
2 = Definite (according to patient) weight loss
B Actual weight changes (weekly):
0 = Less than 1 lb (0.5 kg) weigh loss in one week
1 = 1-2 lb (0.5 kg-1.0 kg) weight loss in week
2 = Greater than 2 lb (1 kg) weight loss in week
3 = Not assessed

Insight _______
0 = Acknowledges being depressed and ill
1 = Acknowledges illness but attributes cause to bad food, overwork, virus, need for rest, etc.
2 = Denies being ill at all


Page 4 Score ______
TOTAL Score ______





Reference
Hamilton M. “Development of a rating scale for primary depressive illness.”
Br J Soc Clin Psychol. 1967;6:278-296.




Provided by the Internet Stroke Center — www.strokecenter.org

Drugs to Treat Depresssion (J15)

Psychopharmacology 
of Depression

History of Antidepressants
From:< http://web.grinnell.edu/courses/sst/f01/SST395-01/PublicPages/PerfectDrugs/Chris/history/index2.html>
Prior to the 1950s, psychotherapy was the treatment of choice for depression and anxiety.
All mental disorders, psychiatrists believed, are caused by anxiety -- resulting from internal conflicts. Other common treatments included: fresh air, electric shock, and lobotomy.

History of Antidepressants
From: http://web.grinnell.edu/courses/sst/f01/SST395-01/PublicPages/PerfectDrugs/Chris/history/index2.html
1949, serendipity, John Cade, an Australian psychiatrist, observed the sedating effects of lithium in guinea pigs. He determined lithium to be safe for human consumption by trying it himself. Then administered it to manic patients, who were subsequently relieved of their manic symptoms.
1960s, widespread use of lithium.

History of Antidepressants
From: http://www.coolnurse.com/lsd.htm
1938, LSD synthesized by Dr. Albert Hofmann of Swiss Sandoz, as a circulatory and respiratory stimulant; no real benefits identified.
1948, Sandoz Laboratories began marketing LSD in USA, trade name “Delysid,” as a psychiatric cure-all --for everything from schizophrenia to criminal behavior, sexual perversions and alcoholism. Sandoz, suggested that psychiatrists take the drug themselves in order to “gain an understanding of the subjective experiences of the schizophrenic.” LSD was prescribed as treatment to over 40,000 patients. Although initial observations on the benefits of LSD were highly optimistic, empirical data developed subsequently proved much less promising.

History of Antidepressants
From: http://web.grinnell.edu/courses/sst/f01/SST395-01/PublicPages/PerfectDrugs/Chris/history/index2.html
1952, Robert Kuhn thus discovered, imipramine for tx of depression.
inspired by the introduction of chlorpromazine for treating schizophrenia, he searched for antidepressant agents among similar compounds, antihistamines -- a class of drugs found in cough syrups.
History of Antidepressants
From: http://web.grinnell.edu/courses/sst/f01/SST395-01/PublicPages/PerfectDrugs/Chris/history/index2.html
1953, pharmaceutical treatment of unipolar depression began; observation (serendipity, again) iproniazid, a tuberculosis drug, had side-effect of boundless energy. Termed "psychic energizer" by Nathan Kline, first investigated its psychological effects, proposed that might prove useful in treating depression.
1957, following initial clinical success in depression trials, >400,000 prescriptions in a year. Many people treated with iproniazid developed jaundice > withdrawn from the market.

History of Antidepressants
From: http://web.grinnell.edu/courses/sst/f01/SST395-01/PublicPages/PerfectDrugs/Chris/history/index2.html
1971, David Wong, at Eli Lilly, began, like other researchers at the time, testing anithistamines for blockage of norepinephrine reuptake. After realizing through his antihistamine studies that similar compounds can have dramatically differing effects on neurotransmitter systems, Wong began testing compounds that failed to block norepinephrine reuptake. One of these nearly forgotton compounds, fluoxetine hydrochloride, he discovered, blocked reuptake of serotonin but not of other neurotransmitters. Over a decade later, after countless animal and clinical studies, fluoxetine hyrdrochloride was released to the world as Prozac. This changed the landscape of psychiatry, expanding the pharmaceutical treatment of depression to epidemic proportions.

Theory: Mechanism of Drug Action
“It is difficult to state with certainty that reuptake inhibition is the essential feature needed for antidepressant efficacy.”
c1965, the biological amine theory of mania & depression: drug induced increases in norepinephrine (a catecholamine) & serotonin > relief from depression; therefore, deficiencies in those neurotransmitters causes major depressive episodes.
BUT, the time course of action is great between the quick increase in those neurotransmitters soon after the drug is taken & the 3-6 weeks before the depression lifts.
Tricyclic Antidepressants (TCA)
• Oral
• amitriptyline (Elavil)
• Syrup (Canada)
• Tablets (U.S. and Canada)
• amoxapine (Asendin)
• Tablets (U.S. and Canada)
• clomipramine (Anafranil)
• Capsules (U.S.)
• Tablets (Canada)
• desipramine (Norpramin)
• Tablets (U.S. and Canada)
• doxepin (Adapin, Sinequan)
• Capsules (U.S. and Canada)
• Oral solution (U.S.)
• imipramine (Tofranil)
• Capsules (U.S.)
• Tablets (U.S. and Canada)
• nortriptyline (Pamelor, Aventyl)
• Capsules (U.S. and Canada)
• Oral solution (U.S.)
• protriptyline
• Tablets (U.S. and Canada)
• trimipramine
• Capsules (U.S. and Canada)
• Tablets (Canada)
• Parenteral
• amitriptyline (Elavil)
• Injection (U.S.)
• imipramine (Tofranil)
• Injection (U.S.)

Tricyclic Antidepressants (TCA)
Pharmacologic Actions of TCAs (now mostly available as generics, so not researched)
1. Block presynaptic norepinephrine reuptake transporter.
2. Block the presynaptic serotonin reuptake transporter.
3. Block postsynaptiac histamine receptors.
4. Block postsynaptic acetycholine receptors.

Tricyclic Antidepressants (TCA)
Equally effective on HAM-D* as SSRIs (for anxiety too).
*see pdf
As effective as St. Johns Wort.
No recreational value (not euphoric).
Withdrawal is not dangerous
(as it can be with SSRIs).

Tricyclic Antidepressants (TCA)
Exert a wide variety of CNS effect, so have more toxic (side) effects than SSRIs. (esp.with children & elderly).
Potentially fatal if taken in overdose, because of cardiotoxic effects.
Not used much for children; not shown to work & high potential for toxicity w/ cases of sudden death.
Can impair: attention, memory, motor speed, dexterity.
2nd-Generation (Atypical) Antidepressants
bupropion (Wellbutrin)
venlafaxine (Effexor)
mirtazapine (Remeron)
trazadone (Desyrel)
nefazadone (Serzone)
2nd-Generation (Atypical) Antidepressants
c1978-c1985, effort to overcome disadvantages of TCAs:
slow onset
limited efficacy
significant side effects

2nd-Generation (Atypical) Antidepressants
Ludiomil, (rarely) cause seizures, so not used much.
Asendin, has parkinsonian-like side (toxic) effecct.
Desyrel, short onset of action (1 week) with c 1 month for optimal effect. Drowsiness is a side effect, used hs.
Welbutrin or Zyban, antidepressant & anticraving (nicotine & other drugs); side (toxic) effects: psychosis, seizures, panic, >libido, weight loss.
Effexor, > cognitive & psychomotor function, not anticholinergic, takes 1-2 weeks, modest toxic effects, may be superior tx for major depression.

SSRIs (Serotonin-Specific Reuptake Inhibitors)

• fluoxetine (trade name: Prozac, Fontex, Seromex, Seronil, Sarafem)
• sertraline (trade name: Zoloft, Lustral)
• escitalopram oxalate (trade name: Lexapro, Cipralex)
• citalopram (trade name: Celexa, Cipramil, Emocal, Sepram)
• fluvoxamine maleate (trade name: Luvox, Faverin)
• Paroxetine (trade name: Paxil, Seroxat, Aropax)

SSRIs (Serotonin-Specific Reuptake Inhibitors)
The connection between serotonin and depression remains unclear.
All SSRIs appear equally effective.
Indications include: major depression, anxiety disorders, childhood anxiety, ADHD, morbid obesity, alcohol abuse.

SSRIs (Serotonin-Specific Reuptake Inhibitors)
Serotonin Syndrome (from hi dose or drug interaction)
Potentially lethal: confusion, hypomania, agitation, fever, chills, sweating, diarrhea, tachycardia, movement disorders.
Resolves 23-48 hrs after dc.

SSRIs (Serotonin-Specific Reuptake Inhibitors)
Serotonin Withdrawal Syndrome:
c60% people become dependent
onset a few days after dc, 
lasts 3-4 weeks
Dizziness, vertigo, ataxia
Nausea, vomiting, diarrhea
Fatigue, lethargy, chills
Sensory disturbances
Insomnia, vivid dreams
Anxiety, crying spells

SSRIs (Serotonin-Specific Reuptake Inhibitors)
Children & SSRIs
1991-1995, antidepressant use increased greatly in children and even preschoolers. They are only marginally more effective than placebo, and psychological interventions have similar efficacy.
No empirical evidence to support psychotropic drug treatment in very young children.
“It appears that behaviorally disturbed children are now increasingly subjected to quick and inexpensive pharmacological fixes as opposed to informed, multimodal therapy associated with optimal outcomes.”Coyle, Journal of American Medical Association, 2000.
.
SSRIs (Serotonin-Specific Reuptake Inhibitors)
Antidepressants
What antidepressants should you and your health care practitioner monitor closely?

According to the FDA, drugs that require close monitoring are citalopram (Celexa), duloxetine (Cymbalta), venlafaxine (Effexor), escitalopram (Lexapro), fluvoxamine (Luvox), paroxetine (Paxil), fluoxetine (Prozac), mirtazapine (Remeron), nefazodone (Serzone), bupropion (Wellbutrin), and sertaline (Zoloft).