Fwd: [SSRI-Research] Peter Breggin MD: Tricyclic Antidepressants: Some General Principles

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[sSRI-Research] Peter Breggin MD: Tricyclic Antidepressants: Some

General Principles

 

Dr. Peter Breggin

Tricyclic Antidepressants: Some General Principles

 

The antidepressants represent a varied group of agents, and their effects on the

brain and mind are little understood. We can, however, make some generalizations

about one group of antidepressants, the tricyclics, which are the best studied

among them. With generic names in parentheses, they include Tofranil or janimine

(imipramine), Elavil or Endep (amitriptyline), Adapin or Sinequan (doxepin),

Surmontil (trimipramine), Norpramin or Pertofrane (desipramine), Aventyl or

Pamelor (nortriptyline), and Vivactil (protriptyline). Another, Anafranil

(clomipramine), is advocated for obsessive-compulsive problems and will be

discussed in chapter 11.

 

Closely related to the tricyclics is Asendin (amoxapine), which turns into a

neuroleptic in the body and presents all of the hazards of that class of drugs,

including tardive dyskinesia and tardive dementia (see chapter 4). Triavil and

Etrafon combine a tricyclic and a neuroleptic, entailing the various dangers of

both drugs, including tardive dyskinesia and tardive dementia from the

neuroleptics, compounded by the unpredictable complexity of their interactions.

 

Limbitrol is a combination of the tricyclic Elavil and the minor tranquilizer

Librium, a sedative or anti anxiety drug that is highly addictive (see chapter

11).(2)

 

Several generalizations can be made about tricyclic antidepressants. First,

evidence for their usefulness is very slim indeed. Research studies generate

extremely variable results and indicate that they are hardly much better than

placebo.

 

Second, they have a dulling effect on the mind. In effective doses they can

produce lethargy and disinterest, that feeling of being " zonked. " They also tend

to produce generalized mental dysfunction and, as we shall see, sometimes

relieve depression by rendering the brain and mind unable to generate higher

psychospiritual responses. But often they are given in smaller doses, which may

have a lesser impact or a placebo effect.

 

As a third general principle, many of the tricyclics have a sedative effect that

aids sleep, for a time, much as does any sedative.

 

Fourth, they can cause severe withdrawal symptoms and can therefore become very

difficult to stop taking. The tricyclics are extremely lethal in overdose and

have numerous side effects.

 

Antidepressant Side Effects

 

The tricyclic antidepressants originally were tested as neuroleptics because

chemically they are very similar to Thorazine (chlorpromazine). They are, in

many ways, neuroleptics in disguise. Their side effects stem mainly from

suppression of the cholinergic nerves of the autonomic nervous system and the

brain, and when the individual tries to stop taking them, the cholinergic system

rebounds with great force, making it hard to get off them.

 

Nearly all of the antidepressants commonly produce the following side effects:

various autonomic nervous system signs, such as blurred vision, dry mouth, and

suppressed function of gut, bladder, and sexual organs, as well as low blood

pressure on standing, weight gain, sleep disturbances, seizures, and impaired

cardiac function. They can bring about anxiety, produce or exacerbate psychotic

symptoms, and cause delirium.

 

They frequently produce sedation, lethargy, and a blunting of emotional

responsiveness, although this often goes unacknowledged by psychiatrists.

 

The antidepressants can cause death when only a few doses are taken at once. In

combination with other depressants of the central nervous system - such as

alcohol, neuroleptics, lithium, sleeping pills, painkillers, and minor

tranquilizers - the antidepressants become increasingly dangerous. They suppress

central nervous system function, thereby impairing respiration, and they cause

cardiac arrhythmias, leading to heart failure. Caution must be taken in regard

to their use by the elderly.

 

A number of years ago antidepressants replaced sedatives as the prescription

medications most frequently involved in successful suicide attempts. Obviously,

there is a built-in danger to giving such lethal drugs to depressed patients who

have a high and unpredictable suicidal potential.

 

Withdrawal from Tricyclic Antidepressants

 

Recently one of my patients, a man in his twenties, was trying to taper off

small doses of Elavil prescribed by another physician. Over a period of several

weeks we cut back on the medication, until it was stopped. Within a day or two

of complete withdrawal he began to feel ill. It seemed exactly like the flu. He

felt lethargic and his muscles ached. He lacked appetite, felt sick to his

stomach, and vomited in the morning. Despite his tiredness, he had trouble

falling asleep and staying asleep. He felt increasing anxiety as well. A

complete physical evaluation by an internist produced no evidence of an

infection, and I was forced to conclude he had a typical flu-like drug

withdrawal syndrome. He gradually recovered over a few weeks, vomiting for the

last time about a month after ending the medication.

 

In an article with an extensive bibliography entitled " Antidepressant Withdrawal

Symptoms " in the 1987 International Clinical Psychopharmacology, DiSalva and his

colleagues estimate that 55 percent of adults will undergo withdrawal symptoms

when stopping these medications. In addition to the flu-like symptoms,

withdrawal symptoms from antidepressants often make the person seem irrational

and even crazy, with high levels of anxiety and disturbing dreams that awaken

the individual in a state of panic or dread. Often there is jitteriness or

irritability. There are reports of patients becoming high or manic on

withdrawal. Patients also can become depressed, perhaps in response to the

fatigue and lethargy associated with withdrawal.

 

In the May 1981 American Journal of Psychiatry, William Law III and his

colleagues report on their review of the charts of twenty-two children who had

been removed from high doses of a tricyclic antidepressant, Tofranil

(imipramine). Each of the children suffered from two or more of the following

categories of withdrawal symptoms: (1) gastrointestinal complaints, including

epigastric pain, abdominal pain, nausea, vomiting; (2) drowsiness and fatigue;

(3) decreased appetite; (4) tearfulness; (5) apathy and withdrawal; (6)

headaches; and (7) agitation. Tapering didn't seem to help.

 

The mental health professionals working with these children often incorrectly

attributed their withdrawal symptoms to " mental illness, " to specific stresses,

such as " changing visits from family, visiting home, dealing with 'loaded

issues,' " allergies, or viral illnesses. Unfortunately, antidepressants were

reinstituted for some of these children, who were mistakenly diagnosed as

relapsing during the withdrawal period.

 

Anyone being started on an antidepressant should be informed in advance that

withdrawal symptoms are very common and that they can be both confusing and

distressing. For the same reasons discussed in regard to the neuroleptics, the

antidepressants should be considered addictive.

 

As in withdrawing from the neuroleptics (chapter 4), patients trying to stop

taking antidepressants may need emotional support and patience. The patient and

the doctor, and members of the patient's inner circle of friends and family, may

have to put up with troublesome symptoms and behavior during the withdrawal

period.

 

Permanent Mental and Neurological Damage?

 

There is an ominous aspect to these withdrawal symptoms, most of which are

produced by rebound hyper-reactivity of the suppressed cholinergic nerves.

Cholinergic nerves of the autonomic nervous system activate the so-called

vegetative or digestive processes of the body,(3) and when they rebound,

flu-like symptoms develop. However, the cholinergic nerves in the brain play a

major role in mental processes, and when they rebound, they cause mental

disturbances, such as anxiety, depression, or mania.

 

We have seen how a similar rebound hyperactivity of a different neurotransmitter

produces permanent mental and neurological disorders after long-term exposure to

the neuroleptics (chapter 4). The questions must be asked, Are we producing

permanent symptoms of mental dysfunction, including anxiety, depression, or

mania, by giving patients antidepressants? How often do we induce a vicious

circle in which patients attempt to come off the medications and then experience

withdrawal symptoms that are mistaken for a recurrence of depression or other

mental dysfunction - leading to further treatment with the offending medication?

 

Innumerable animal studies have documented that chronic exposure to

antidepressants produces hyperreactivity of the neurotransmitter systems of the

brain. It also can produce chronic subsensitivity or reduced reactivity. These

findings sound a serious - but almost wholly ignored - warning about the danger

of permanent negative effects on the human mind as a result of antidepressant

treatment. If the lessons of neurophysiology hold true, the brain frequently

does not fully revert to normal functioning after prolonged exposure to toxic

medications.

 

Tardive Dyskinesia and Tardive Dementia from Antidepressants

 

Many clinicians continue to believe that only the neuroleptics, and not the

antidepressants, cause tardive dyskinesia, with its permanent, untreatable tics

and spasms of the voluntary muscles. However, some studies suggest that the

tricyclic antidepressants also produce tardive dyskinesia, but much less

frequently. These findings are not surprising in light of the similarity between

the chemical structures of the tricyclics and the phenothiazine neuroleptics.

One report found a relatively high incidence of 6 percent.

 

Since the tricyclic antidepressants closely resemble neuroleptics, and since all

antidepressants powerfully affect the brain and mind, I am very concerned about

the largely unexplored danger of permanent cognitive dysfunction and brain

atrophy similar to that found during prolonged neuroleptic treatment. Patients

diagnosed with " affective disorders " (depression, manic-depression, and

schizoaffective disorder) are showing up with atrophy on brain scan, suggesting

that antidepressants may play a role in causing brain damage. However, the

studies done thus far do not rule out electroshock, neuroleptics, and other

drugs as possible culprits. Many patients with diagnoses of affective disorders

have received a broad spectrum of brain-disabling treatments. Of course, the

biopsychiatrists who perform the studies assume that the brain pathology is due

to mental illness.

 

Depression Caused by the Antidepressants?

 

There are reports that administration of the antidepressants can cause

depression, especially early in the treatment. Namir Damluji and James Ferguson

discuss " Paradoxical Worsening of Depressive Symptomatology Caused by

Antidepressants " in the October 1988 Journal of Clinical Psychopharmacology.

They describe four cases of major depression that were exacerbated to the point

of suicidal behavior. Improvement followed immediately on stopping the

medication.

 

Any drug that disrupts mental function can make people feel more helpless and

despairing. Drugs that cause mental confusion, sluggishness, and physical

fatigue are especially prone to precipitate or worsen depression. Harvey

Greenberg and H. Robert Blank report a series of cases who felt dazed, fatigued,

and confused in the June 15, 1973, issue of the New York State Journal of

Medicine; but little attention is paid to these problems in the literature or

clinical practice.

 

Meanwhile, some psychiatrists persist in telling patients and the public that

these drugs have no " psychoactive " or mental effects at all.(4) When uninformed

patients then feel numbed or " zonked " from the medication, they are very likely

to think their condition is worsening, thereby encouraging suicidal feelings.

Dr. Caligari's Psychiatric Drugs puts it bluntly:

 

What psychiatrists call " depression " - lethargy, apathy, nervousness,

hopelessness, helplessness and unhappiness - is a serious problem often

unrecognized as drug-related (drug-induced). Because of their depressant and

debilitating effects, psychiatric drugs can make people feel so bad they want to

kill themselves. (P. 18)

 

Antidepressants and Suicide

 

In helping seriously depressed people, reducing the suicide rate is one of the

first concerns. Do antidepressants have a beneficial impact on suicide? Despite

the relative ease of conducting objective studies of suicide rates - the

criterion of death is an indisputable one - there is no published evidence that

the antidepressants are helpful in reducing suicide. In the PDR, the

manufacturers of the various antidepressants warn practitioners not to rely on

the medications to prevent suicide.

 

One study, " Mortality in Depressed Patients Treated with Electroconvulsive

Therapy and Antidepressants, " by David Avery and George Winokur in the September

1976 Archives of General Psychiatry, shows an increased suicide rate among

patients receiving antidepressant therapy.

 

Since antidepressants are now the drugs most commonly implicated in successful

suicides, it would seem far more appropriate to designate them as " suicide

drugs " rather than antisuicide drugs. Yet psychiatrists persist in giving them

to depressed patients who are suicidal.

 

Do They Work?

 

The antidepressants have many drawbacks, but do they work? Is there convincing

evidence for efficacy to balance against the costs and risks of taking these

toxic agents?

 

It is difficult to evaluate the effectiveness of drugs for depression.

Spontaneous improvement of depression (that is, with no psychiatric treatment

whatsoever) takes place in at least one-quarter of patients within the first

month or so of becoming depressed and in one-half or more over a few months.

Even people with severe depression have a high rate of recovery 'without

psychiatric treatment. Since it takes most antidepressants a month or more to

have their presumed beneficial effect, it easily overlaps with spontaneous

recovery. In addition, placebo has a potent effect on depressed patients; most

experts indicate that 40 percent or more will improve during the first month or

two of taking a " sugar pill. "

 

The slightly higher rates of improvement for antidepressants over inert

placebos, such as a sugar pill, may itself be a special kind of placebo effect.

I call this the enhanced placebo effect. Consciously or not, when taking an

inert placebo the patient realizes that his mind and body are not being impinged

upon strongly by the medication. In sharp contrast, the antidepressants have

many obvious physical side effects, so the patient receiving them is likely to

believe that he or she is taking a powerful medicine. The concept of the

enhanced placebo reflects the wisdom that led hucksters to make patent medicines

taste awful.

 

Ironically, enthusiasm for the use of antidepressants has been skyrocketing

among practicing psychiatrists at the same time that research has cast more and

more doubt on their efficacy. In The Limits of Biological Treatments for

Psychological Distress (1989), Seymour Fisher and Roger Greenberg conclude that

years of research have failed to provide justification for their use. Here are

some highlights from their thoroughly documented review:

 

a.. Even the most positive reviews by drug advocates indicate that 30

percent to 40 percent of studies show no difference between the drugs and

placebos. Since it is relatively harmless,(5) placebo may be the best treatment.

 

b.. When the standard of " substantial improvement " is used in antidepressant

studies, the reported rates of improvement average out to a very meager 25

percent.

c.. Active placebos that cause side effects are rarely used in controlled

studies and would probably perform as well as antidepressants.

d.. Powerful investigator bias is often at work, since some teams repeatedly

find considerable efficacy while others find very little or none. Placebo

efficacy, for example, varies from zero to 91 percent in one series of studies

(p. 21).

e.. There are no standard criteria for determining " improvement " and

psychiatric standards are often behavioral, such as " sleeps better " or " gaining

weight, " rather than psychological, such as " feels better about life " or

" actively building a better future. "

f.. Controlled studies of the newer, more highly promoted antidepressants

provide still less evidence of efficacy: " An overview of all 16 studies

indicates that the majority (62%) show no difference in the percentage of

patients benefiting from an active drug as opposed to a placebo " (P. 19).

g.. Controlled studies comparing drugs and psychotherapy tend to favor

psychotherapy: " Psychotherapy had its main effect on mood, apathy, suicidal

ideation, work, and interest, whereas medication mainly influenced sleep and

appetite " (p. 13). They conclude, " Although drugs may help patients with their

sleep disturbances, research shows they are often less efficient than

psychotherapy in helping patients with depression and apathy and frequently

ineffective in aiding patients in their social adjustment, interpersonal

relationships, or work performance " (p. 16).

Psychotherapy Versus Antidepressants at NIMH

 

NIMH coordinated a large-scale, highly publicized study at several medical

centers, comparing cognitive behavior therapy, interpersonal psychotherapy,

antidepressants, and placebo over a sixteen-week period. A recent publication,

by senior author Irene Elkin in the November 1989 Archives of General

Psychiatry, confirms how difficult it is to find any differences under these

conditions between brief psychotherapy, drug therapy, and placebo. When the

treatments - including placebo - were compared for the entire sample of 250

patients, no difference was found among them.

 

For more severely impaired patients there was a relatively greater benefit from

interpersonal psychotherapy and the antidepressant. In these cases the drug

performed slightly better than psychotherapy, according to the investigators;

but the data show no meaningful difference. To find the drugs slightly superior

required fancy statistical footwork based on a limited number of criteria. This

did not prevent biopsychiatrists from making much ado about nothing in the

press.

 

Most experienced psychotherapists would probably do far better than those

working within the strictures of the NIMH comparative study. First, sixteen

weeks for psychotherapy is very short and the time limit is very arbitrary.

Depressed patients want to know that their therapist will be much more available

than that. Second, the therapy methods used were stilted and routinized to

conform to distinctions between cognitive behavioral and relationship models.

Most therapists would never limit themselves to one orthodoxy, and they rarely

list either one of the NIMH techniques among their repertoire. For example,

hardly anyone in the membership directory of the American Academy of

Psychotherapists includes either one among the many and varied approaches.

Considering such handicaps, psychotherapy performed surprisingly well.