Sertraline (Zoloft)

Sertraline Introduction and History of Anti Depressants

Prior to the 1950’s the treatment of depression consisted of only three options (Gitlin 1996). One was the use of stimulants similar to amphetamines. Although ECT was clearly effective in treating depression, it was dangerous and frightening to the average patient. The alternative and often used treatment for depression was simply to wait until the symptoms remitted. In 1952 physicians discovered that patients being treated for tuberculosis with a new drug called isoniazid displayed a distinctively elevated mood that was contrary to their condition (Winson, 1985). Shortly thereafter, depressed patients were treated with iproniazid a drug that is related to isoniazid with less dangerous side effects.

In 1957 a researcher named R. Kuhn was attempting to develop new antipsychotic drug (Johnson, 1993; Gitlin, 1996). While working with a drug called imiprimine, he noted that although ineffective in treating psychotic symptoms, it did improve the mood of some schizophrenics. Subsequently, imiprimine was found to change the functional activity of biogenic amines in the rat brain. This lead to the focus in research on noradrenaline and 5-hdroxytryptomine (5-HT) as a possible bases for action of antidepressants.(Ayd and Blackwell as cited in Leonard, 1994). By the 1960’s a number of other drugs were being discovered that could affect depression in humans. Again in rat studies, several mechanisms of action were discovered (often after the drugs themselves were discovered and tested). MAO inhibitors (monoamine oxidase inhibitors) act to prevent interneuronal degradation, reducing the rate of degradation of amines. Tricyclics reduce the rate of reuptake in the presynaptic cleft by impeding the reuptake. Reserpine acts by decreasing the storage of amines in pre-synaptic vesicles (Leonard, 1994).

In recent years, there has been a number of new drugs discovered. In the last 20 years, antidepressants have been developed that show very selective actions on the noradrenergic, serotonergic and dopaminergic systems (Leonard, 1994), although there is no evidence to suggest that these new antidepressants are more effective than the classical antidepressants first discovered back in the 60’s. There is clear evidence that many of the newer drugs have less cardiotoxic side effect and are often better tolerated by patients (Leonard, 1994).

In 1987, the release of fluoxitine introduced the new era of antidepressant drugs. These drugs, called selective serotonine reuptake inhibitors have come to dominate the antidepressant market because of the ease of use, safety and reduction of side effects (Gitlin, 1996). The SSRI’s are also called second generation, atypical or heterocyclic antidepressants (Buelow & Herbert, 1995). Sertraline (Zoloft), an SSRI similar to fluoxitine (Prozac), was the second SSRI and was approved for marketing in December of 1991 in the United States (Buelow & Herbert, 1995).

The purpose of this paper is to describe some of the psychopharmacological properties and uses of Sertraline, other treatments for depression, as well as the interaction of sertraline and psychotherapy

 



 

Pharmacodynamics

The mechanism of action of sertraline is postulated to be related to the drugs inhibiting effect on the reuptake of serotonine (5-HT) (physician insert, 1996). Further, clinical studies in man have shown that sertraline blocks the uptake of serotonine into human platelets. Sertraline is a very selective inhibitor of serotonine reuptake , having only weak effects on other monamines such as norepinephrine and dopamine and is four to five times more potent than fluoxetine in blocking serotonine reuptake (Julien 1996).

In the use of all antidepressants, there is usually a 2 to 6 week delay before the onset of beneficial effects. The action of anti-depressants on neurons takes effect immediately, but the antidepressant effect takes days of weeks to affect a patients mental state (Winson, 1985). As the serotonine levels plasma levels increase to the “therapeutic level” quite rapidly with the use of sertraline, the therapeutic response of the drug cannot be easily explained by the Pharmacokinetic profile and therefore the concentrations of serotonine in the brain (Leonard, 1994). The specific neuronal circuits in which these drugs act to produce their clinical effect is not known. It has also been noted that the effects of ECT have a two to three week delay. This disparity between the immediate effects of antidepressants and the onset of clinical effects has caused some researchers to look to changes in receptor function to explain antidepressant action.

Leonard hypothesizes that antidepressants may change neuronal signal transduction processes distal to the receptor. Another possible explanation for the delay of therapeutic effects is that the common mode of action of all antidepressants is the modification of actual nerve cells and the possible elimination of inappropriate synaptic contacts that are responsible for the psychological effects of depression. Winson (1985) suggests that antidepressants act on the limbic system to produce their affects (the limbic system is associated with memory and emotion) but this is not known for sure.

Schwartz (personal communication, May 4, 1997) proposes that increased levels of serotonine activate the subcortical areas of the brain and increase REM sleep activity. The implication is that this increased activity allows more complete and effective processing of day residue, allowing a patients unconscious to work out problems and conflicts more actively, thereby reducing depressive symptoms.

 



 

Pharmacokinetics

In man, with daily dosages from 50 to 200 mg, average peak plasma level occurred after 4.5-8.4 hours post dosing (physician insert, 1996). Long (1995) indicates that a mean peak plasma concentration of sertraline is 0.19 mcg/mL and occurs after 6 to 8 hours. Steady state plasma levels are achieved within five to seven days (Julien, 1996). Dosages of sertraline taken with food appears to increase the bioavailabilty of the drug by 40% (Long, 1995).

About 98% of sertraline is plasma protein bound and according to Long (1995) the interactions of sertraline and other highly protein bound drugs has not been sufficiently evaluated. He suggests caution when co-administered with drugs such as warfarin (an anticoagulant) or digitoxin as the shift in plasma concentrations could result in adverse reactions, although he does not describe what these reactions might be. The physician insert (1996) notes that protein binding characteristics of sertraline have little or no effect on the other highly protein bound drugs.

Sertraline and other SSRI’s also block the hepatic metabolism of some medications, thereby increasing their levels in the blood stream (Gitlin, 1996). When used in combination with tricyclics such as imiprimine, caution should be used to avoid toxic blood levels (deVane cited in Gitlin, 1996), although sertraline is expected to have less significant impact in this regard than other SSRI’s. Generally, Gitlin suggests caution in using all SSRI’s in combination with other medications. In placebo-controlled trials, co-administration of sertraline with lithium in normal subjects did not alter the Pharmacokinetic properties of sertraline (Long, 1995), although trials were not conducted with lithium treated patients. For this reason Long suggests that lithium levels be closely monitored in patients who are taking lithium and sertraline concomitantly. He suggests that co-administration of sertraline and lithium could cause serotonine-associated side effects.

Sertraline has been associated with asymptomatic elevations of several hepatic transaminases to a value as much as three times of normal in subjects taking sertraline as compared to placebo groups. These elevations occurred within one to nine weeks of initial dosages and returned to normal after discontinuation of the drug (Long, 1995). Long also reports small increases in serum cholesterol by 3%, triglycerides by approximately 5% and small increases in serum uric acid by approximately 7%. These mean increases apparently have no significant clinical importance.

 



 

Pharmacotherapy

Generally, the use of all antidepressants is similar, with variations in dosages based on the specific drug used, side effect profiles and individual patients. The efficacy of sertraline in the treatment of depression was established in clinical trials when compared to placebo controls for those patients who meet the DSM-III criteria for Major Depression (physician insert, 1996). Sertraline has also been found to be effective in he treatment of Obsessive Compulsive Disorder (Gitlin, 1996; physician insert, 1996).

The use of specific antidepressant drugs (or any psychotropic medication) according to Schwartz (personal communication, May 5, 1997) is based on several specific factors: The first is the experience of the clinician. Over time, most psychopharmacologists become knowledgeable of specific drugs through continued use and clinical observation of their patients. Through this experience, a clinician becomes quite knowledgeable about indications and contraindication of these medications and types of patients best treated. Schwartz argues that the side effect profile and specific patient sensitivities or allergies are a significant factor for consideration in choosing an antidepressant. Sertraline has been shown to be quite safe and have fewer side effects than many of the other antidepressants and many other SSRI’s. Additionally, a psychopharmacologist must consider any medical conditions of the patient, such as heart disease and thyroid problems, that may contraindicate the use of antidepressants.

Because of severe side effects, many antidepressants need to be started at lower than therapeutic dosages, then increased over time. The SSRI’s in general, do not require a gradual increase in dosages as do many other psychotropic medications. Many patients are able to begin with the dosage that is their final and optimal dosage, although Gitlin, (1996) suggests a dosage of 25 mg to start, to be raised in a few days if the patient tolerates the initial dosage. Patients who have a history of drug sensitivities, panic disorder or severe anxiety should be started on even lower dosages. (Gitlin, 1996). Long (1995) recommends a dosage starting at 50 mg to be gradually increased if needed. As sertraline is mildly stimulating for most patients, Gitlin recommends taking the dosage in the morning hours to prevent sleep difficulties. The dosage may range from 50 to 200 mg based of response and amelioration of symptoms.

In general, sertraline and other SSRI’s have less side effects than MAO inhibitors and sertraline has less anticholinergic, antihistaminic and cardiovascular adverse effects than the tricyclic antidepressants (Julien, 1996). As with all psychotropic medications, some side effects are expected. In clinical development programs with 1902 subjects with depression, there were a number of adverse side effects noted. The most common side effects associated with 200 mg dosages included: gastrointestinal complaints, nausea, diarrhea and loose stools, ejaculatory delay in males, insomnia and somnolence, tremor, increased sweating, dry mouth and dizziness (Long, 1995).

Although Gitlin (1996) states that withdrawal syndrome is rare with sertraline because of it’s longer half life, Long (1995) reports adverse withdrawal effects in 15% of 2710 subjects in a pre-marketing clinical trial. The most common withdrawal events include insomnia, male sexual dysfunction, somnolence, dizziness, headache, tremor, anorexia, diarrhea, nausea and fatigue.

Sertraline as with any SSRI, should not be prescribed in conjunction with MAO inhibitors. This can cause a reaction referred to as serotonine syndrome that is potentially fatal (Gitlin, 1996). The symptoms of this are characterized by fever, muscular rigidity, hypotension, convulsions and coma. With a half life of 26 hours, a washout period of at least two weeks is needed before administration of any MAO inhibitors.

At the time of publication, Long (1995) reported three cases of sertraline overdose at approximately three to ten times the normal dosages. These three cases all recovered without the need for specific therapy.

Corn (1994) points out that, although it has been more than 30 years since the accidental discovery of iproniazid, the present antidepressants including the SSRI’s are not more efficacious than their earlier cousin drugs. In most cases they are safer in terms of side effects and overdose.

 



 

Other Treatments for Depression

Besides antidepressants, ECT and stimulants are sometimes used to treat depression. Both of these options are important and can be quite effective in certain clinical situations (Gitlin, 1996).

Simply put, ETC or electroconvulsive therapy, is inducing of grand mal seizures with the use of specifically applied electrical current (in a 20-30 milliamp range) applied bilaterally to the temperofrontal region of the skull (Reber, 1995). The patient is sedated using a short acting barbiturate and a muscle relaxant to minimize the intensity of the muscular convulsions.

A physician may choose to use ECT for a number of reasons. Lickey & Gordon (1993) report that depression with psychotic features is the most common reason to use ECT. Many of the patients that fail to respond to antidepressant treatment, improve with the use of ECT. Gitlin (1996) indicates that there are a number of mood related disorders that may be appropriate of use of ECT. Delusional depression, major depression and mania are considered the most responsive and treatable disorders.

Stimulants are used in some cases as a treatment for uncomplicated major depressive disorder, although never as a first order treatment. Gitlin reports that stimulants are used, “as single agents for those depressed patients who either did not respond to or could not tolerate the effects of anti depressants” and “as adjunctive agents, added to an ineffective or partially effective antidepressant”. Patients with apathetic depressive syndromes are also commonly treated with stimulants (Rosenberg, Ahmed, and Hurwitz cited in Gitlin, 1996) often with rapid and dramatic response.

 



 

Interaction with Psychotherapy

For years there has been disagreement between those that hold to a biological model of psychopathology and the those that hold to the psychological/psychodynamic view of disorders. The biological psychiatrists, “as a whole are unappologetic in their view that they have found the road to truth… mental illness… is genetic in origin and should be treated with psychoactive medications, eloctroconvulsive treatment and in some cases psychosurgury…. Their unquestioning confidence in their biological paradigms of mental illness is truly staggering” (Kaiser, 1995). Alternatively, it has been many of the proponents of psychodynamic theory that are clearly anit-biological, believing that all mental suffering has a psychogenic cause that can be treated with psychological or psychoanalytic technique alone. Some practitioners believe that the use of medication is a threat to the psychotherapeutic process. Although it is not within the scope of this paper to explore these issues with the political, economic as well as paradigmatic complexities, there are several issues as to the interaction of antidepressants and psychotherapy that will be discussed.

Wolf (1988) suggests that the threat of psychopharmacology to psychotherapy is more theoretical than real. He states that the “giving of medications to patients in the psychotherapeutic treatment… [is] quite common and helpful to many patients as well as therapists. Most therapists agree that a certain level of distress in necessary for successful therapy. Although may be some truth to the concern that a medication induced reduction in symptoms may diminish a patient’s motivation for therapy (Gitlin, 1996), Wolf makes the point that many depressed patients are not able to do the work required for psychotherapy unless their symptoms are somewhat relieved by antidepressants. A very depressed patient may expend most of his energy focusing on his lack of functioning and frustrations in the world, rather than more underlying conflicts or interpersonal problems that may contribute to the depressive symptoms. Gitlin makes the point that there is no consistent evidence that psychopharmacology reduces motivation to continue treatment when used in combination with psychotherapy. Therefore, careful use of antidepressants may in fact improve therapeutic response.

It is this writer’s belief that the use of anti-depressants (and perhaps anxiolytics) can improve therapeutic response and even deepen therapeutic activity. If, as Swchartz says (personal communication, May 4, 1997), antidepressants improve the functioning of the subcorticle processes, patients in psychoanalytic psychotherapy or psychoanalysis may be able to access material that would otherwise be more rigidly and intractably defended against. Sertraline has been found useful in reducing the symptoms of Obsessive Compulsive Disorder. These symptoms are seen as defenses against threatening aggressive or sexual material by some psychoanalytic theorists. Historically, these patients are considered difficult therapeutic subjects because their defenses are so effective in keeping the threatening issues at bay. For a patient in psychotherapy, perhaps reducing these symptoms allows more of the underlying material to emerge, permitting this material to be analyzed. Further, if sertraline in fact increases REM sleep and improves a patient’s ability to process unconscious data, perhaps dream life will improve, giving the patient and therapist access to even more conflictual and pertinent issues.

It is also possible that the use of sertraline or other antidepressant medication in conjunction with psychotherapy can improve the relationship between the therapist and patient. A patient who is suffering from depression is often isolated and may have poor self esteem, making the development of interpersonal relationships difficult. Antidepressants generally improve a patient’s ability to relate to others by feeling better about themselves. As the transference relationship is tantamount to many forms of therapy, improving a patient’s ability to relate to others may have a side effect of improving one’s ability to connect with the therapist, thereby introducing new depth to the transference relationship and ultimately improving outcome.

Kernberg (1999) points out that use of medication is justified if the level of patient symptoms is so great that it interferes with the “establishment and preservation” of patient-therapist communication. He recommends several principles that should be followed in medicating patients in psychodynamic treatment. First, medication should be given in sufficient amounts to produce pharmacological rather than placebo effects. Second, medication should be given for a sufficient length of time to establish a new baseline for patient functioning. Third, the medication should be consistently discussed, including it’s unconscious meanings to the relationship to prevent undo distortion of the transference relationship by primitive defensive operations that may be masked by the use of medication. Of course, these principles apply to severely disturbed patients with narcissistic or borderline personality organization, although they generally apply to other patients as well.

In the case of severely disturbed patients, it is expected that improving their overall functioning will allow the time in therapy to be spent on more long standing issues rather than extra-therapy disruption and crisis. This could include emergency calls and perhaps hospitalizations. Improving a patient’s functioning external to therapy, may serve to keep these disruptive influences to a minimum and might help to focus on deeper therapeutic work rather than crisis management.

The use of medication concomitant to therapy is a complex issue that has only been touched on briefly in this paper. In the future, with further research, it is hoped that we as clinicians will gain better understanding of the action of psychotropic medications and their interaction with psychotherapy. As psychiatry and psychology mature and professional learn to better work together, perhaps both professions will learn to value the position and benefit of the other.

 



 

References

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Boyer, W. F. & Freighner, J. P. (1993). Pharmacokinetics of drug interactions. In G. Beulow & S. Herbert (Eds.), Selective Serotonine Re-uptake Inhibitors: The Clinical Use of Citalopram, Fluoxetine, Fluvoxamine, Paroxetine, and Sertraline. (Pp. 81-87). NY: John Wiley & Sons.

Boyer, W. F. & Freighner, J. P. (1993). The serotonine hypothesis: Necessary but not sufficient. In G. Beulow & S. Herbert (Eds.), Selective Serotonine Re-uptake Inhibitors: The Clinical Use of Citalopram, Fluoxetine, Fluvoxamine, Paroxetine, and Sertraline. (Pp. 71-75). NY: John Wiley & Sons.

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