SSRI WITHDRAWAL PROCEDURE

Getting Off Antidepressants May Be Made Easier

by Subhuti Dharmananda, Ph.D., Director, Institute for Traditional Medicine, Portland, Oregon

The use of antidepressants has been steadily increasing since they were first developed 50 years ago, with no end in sight (see graph, below). These drugs are not only used for what might be considered a neurologically depressed mental state: about half the prescriptions are for eating disorders, post-traumatic stress syndrome, anxiety disorders, obsessive-compulsive syndromes, chronic pain, and a variety of other conditions. The first major class of drugs put into clinical use for these applications were the tricyclic antidepressants (TCAs); the main drugs are amitriptyline (Elavil), imipramine (Tofranil), and nortriptyline (Pamelor). These were followed by monoamine oxidase inhibitors (MAOIs), of which phenelzine (Nardil) and tranylcypromine (Parnate) are still used for treatment resistant depression. One of the recent additions to the antidepressants is the class of selective serotonin reuptake inhibitors (SSRIs). The commercial names of some SSRIs are well-known, such as: Prozac (fluoxetine), Paxil (paroxetine), Lexapro (escitalopram), and Zoloft (sertraline). The first SSRI, Prozac, was introduced in 1985, so there is now 20 years experience with this group of drugs. A newer class of antidepressants are serotonin-norepinephrine reuptake inhibitors (SNRIs), represented by Effexor (venlafaxine), introduced in 1993 (see Appendix for additional history of the drugs).

          

Demonstration of SSRI action. Serotonin (shown as small spheres, D) is produced in vesicles (A) within the nerve cell (presynaptic neuron, terminal end shown, G). These vesicles migrate to the cell surface (downward arrows), merge with it, and release serotonin into the synaptic cleft (space between neurons). Some of the serotonin travels across the cleft and enters receptors (E) of the postsynaptic neuron (H), which then opens channels for flow of ions, causing transmission of a nerve impulse. Some of the serotonin flows back into the nerve cell and is recycled (shown by upward arrows and F); this is reuptake of serotonin. The SSRI drug molecules (labeled P) fit the channels (B) that allow reuptake, and block them (C). Because of the drug action, more of the serotonin remains in the space outside the nerves where it can interact with receptors to influence the state of the nerve.

Selective serotonin reuptake inhibitors are so-named because they have a significant effect on serotonin systems compared to those of other neurotransmitters. Drugs developed earlier (see Appendix 1 for brief history of development of antidepressant drug therapy), the TCAs and MAOIs, have a mixed and less intense effect on serotonin systems, acting also on another neurotransmitter, norepinephrine (NE), and with other chemicals throughout the body. SSRIs have had remarkable success in treating depression, and, as a result of their specificity, they have reduced side effects compared to TCA's or MAOI's. Effexor, a highly effective SNRI, acts as an SSRI at low dosage and then affects norepinephrine as well at higher dosages. Both the serotonin and norepinephrine systems have important roles in treatment of depression. The drugs have the ultimate effect of leaving more of the affected neurotransmitters in contact with the nerve endings and their receptors by preventing their "reuptake" into nerve cells (see illustration, previous page).

Withdrawing from use of SSRIs (and from SNRIs) is a frequently mentioned concern. Despite their effectiveness and relative low level of side effects, many people are uncomfortable with the idea of using drugs at all and seek to get off their daily antidepressant regimen as soon as possible. Some people get side effects, particularly sexual dysfunction and fatigue, and hope to be able to eventually be freed of those adverse effects by withdrawing from use of the drug after a period of successful treatment. Depressed feelings often arise from stressful situations (brain defects might make it easier to become depressed), and people who find themselves in improved circumstances may be able to stop using drug therapy to control depression. Imbalanced brain function can be exacerbated or induced by poor health habits, and some people may change their lifestyle (e.g., increase exercise) and improve their nutritional status, hoping to reduce the need for use of drugs. In such circumstances, the SSRI or SNRI may be withdrawn. Yet, there are other cases, some with genetic basis, where continued medication is required, despite a desire to cease its use.

The problem of side effects from using the drugs is substantial. A study-interview (1) involving 672 patients who had discontinued or switched SSRIs was carried out to elicit reasons for the change, documenting the status at 3 and 6 months after starting treatment. It was noted that 43% of patients discontinued or switched their SSRI because of an adverse effect within the first 3 months of starting, while another 27% did so for this reason in the second 3 months. The adverse effect most frequently reported as the reason for early discontinuation or switching was drowsiness/fatigue (10.2%), followed by anxiety, headache, and nausea (each at just over 5%). In a review of clinical studies involving SSRIs, it was found that 27% of patients withdrew from the studies due to either adverse events or lack of efficacy (2).

Changes in serotonin transport function and in neuroreceptor loading that occur over the course of antidepressant use create a dependence on the drug that takes some time to be eliminated even when the drug is no longer needed to stabilize depression. Adverse effects that can arise from reducing the drug dose have been given a name: SSRI Withdrawal Syndrome or SSRI Discontinuation Syndrome. To avoid this syndrome, very gradual withdrawal-as little as 5% dosage decline per week-has been recommended; rarely are the drugs withdrawn at a rate of more than 20% per week. Unfortunately, many patients are hesitant to spend this much time withdrawing from the drug, and many physicians do not recommend such gradual dosage decline, believing that the majority of the patients will do well with relatively rapid withdrawal, so SSRI Withdrawal Syndrome can readily occur; some patients may experience the symptoms even with very gradual tapering of dosage. A sample tapering schedule has been recommended for commonly used drugs (3); other tapering schedules may be prescribed to patients:

The duration of withdrawal depends on the starting dose and the characteristics of the drug (such as its half life in the body). In the schedule presented here, reductions in dosage are made at two week intervals, usually involving 2-4 months of withdrawal duration.

In the following section, this article provides some suggestions regarding Chinese herbal assistance in alleviating or avoiding withdrawal symptoms, especially if one of the more rapid withdrawal schedules is attempted. It is important to note, however, that all patients taking SSRIs or SNRIs should consult with the prescribing physician, or with a psychiatrist, prior to considering any withdrawal from the drug. And, practitioners who offer Chinese therapies (such as acupuncture and herbs) must remain aware that those who suffer severe depression, which has been controlled by drugs, may suffer from their original neurological symptoms during and after withdrawal. Concern should be expressed and appropriate observation taken to consider potential complications of suicidal ideation, which can be intense and unforeseen during SSRI withdrawal. Eating disorders or behavioral problems associated with reduction or elimination of the drug could lead to harm as well. In most cases, antidepressant drugs are intended for a limited duration of use (e.g., one year) to be supplemented by psychological counseling to help alleviate the ideation and behavioral problems; nonetheless, long-term therapy can be vital to the neurological health of some patients.

SSRI Withdrawal Syndrome and Interpretation by TCM

A listing of symptoms that have been repeatedly observed in patients withdrawing from SSRIs is arranged in the left column of the following table by general type, and paired with a potential TCM interpretation of the symptoms in the right column (offered by the current author).

Summing up the notes about TCM interpretation, the withdrawal syndrome may revolve around the problems of qi and blood deficiency, which may be accompanied by qi stagnation and dampness accumulation (in rare cases, also by internal wind). These deficiency syndromes of Chinese medicine are attributed to the spleen (for qi) and liver (for blood); a Western interpretation of the same pattern might be a relative deficiency in serotonin availability or an imbalance of neurotransmitters that occurs when the drugs are removed.

Essentially, one component of what is referred to as qi and blood in the Chinese system may be: 1) the availability of serotonin to receptors that is needed for healthy neurological functions; and 2) functional supports for neuroreceptor systems or transporters that also contribute to central nervous system activities. For example, abnormal cortisol levels (and other signs of adrenal system imbalances) are noted in anxiety, stress, and depression. Cortisol levels and cortisol regulating hormones (such as adrenocorticotrophic hormone, ACTH), as measured by metabolite excretion in the urine, have been associated with various TCM-defined deficiency states by some Chinese researchers. Rehmannia and other tonic herbs have been shown in laboratory animal studies to affect the cortisol levels. The concepts of qi and blood were not originally depicted by any reference to chemical constituents, and so this interpretation would involve adding a new viewpoint. Chinese researchers have, during the past several decades, attempted to attach biochemical markers to yin and yang, qi and blood, the internal organs, and certain syndromes, with some limited success.

Key herbs that might be considered for SSRI withdrawal syndrome based on the symptom analysis include:

Atractylodes (white atractylodes): tonifies qi, resolves damp
Peony (white peony): nourishes blood, vitalizes blood circulation
Tang-kuei: nourishes blood, vitalizes blood circulation
Zizyphus: nourishes liver and heart blood and clams shen
Saussurea: circulates qi, calms shen
Ginseng: tonifies qi, calms shen
Astragalus: tonifies qi, raises yang qi
Polygala: resolves phlegm, calms shen
Fu-shen or Hoelen: resolves damp, calms shen
Pinellia: resolves damp, lowers stomach qi
Citrus: resolves damp, circulates qi

A formula with such ingredients can be constructed from the traditional formula Gui Pi Tang (a qi and blood tonic with sedative effects), which includes atractylodes, zizyphus, saussurea, ginseng, fu-shen (or the less-sedative portion called hoelen), astragalus, tang-kuei, and polygala. According to Giovanni Maciocia, who is widely respected for his knowledge of TCM, this formula is itself used for treating depression (4). He noted that: "The formula Gui Pi Tang tonifies spleen-qi and heart-blood and calms the mind: it is ideally suited to treat post-natal depression and insomnia. This formula is also recommended by Wu Qian in his Golden Mirror of Medicine for post-natal depression from worry, pensiveness, and sadness." The ingredients may be provided as a decoction (Gui Pi Tang), dried decoction, or in tablet form (Gui Pi Wan), such as this preparation by Pine Mountain (5):

To make this tablet, the ingredients are ground to powder, except jujube and ginger, which are dried extracts. For those with a more significant level of "damp" syndrome (especially with digestive disturbance), one might add to Gui Pi Tang one of the following:

Er Chen Wan aka Citrus and Pinellia Combination (has citrus, pinellia, hoelen)
Si Jun Zi Tang aka Major Four Herbs Formula (has ginseng, atractylodes, hoelen)
Wu Ling San aka Hoelen Five Herb Formula (has atractylodes and hoelen)
Xiang Sha Liu Jun Zi Tang aka Saussurea and Cardamom Combination (has ginseng, saussurea, hoelen, atractylodes, citrus, and pinellia)
Xiao Yao San aka Tang-kuei and Bupleurum Formula (has hoelen, atractylodes, tang-kuei, and peony)

Hoelen Five Herb Formula was used in a small study of gastro-intestinal reactions from taking SSRIs (rather than the withdrawal syndrome), with apparently favorable results (6). Of 20 patients treated by this formula, nausea and dyspepsia disappeared in 9 patients, decreased in 4 patients, and decreased slightly in 2 patients (the other 5 patients displayed no change). No adverse events were noted.

While there have not been studies providing clinical evidence for efficacy of Gui Pi Tang, or any of the herbs mentioned, to alleviate SSRI discontinuation symptoms, it is a characteristic of modern Chinese medicine practices to select herbs on the basis of symptom patterns, with the expectation of attaining some level of effect. The symptoms are understood to be a manifestation of an underlying imbalance, whether described in ancient terms (e.g., qi and blood deficiency) or modern terms (e.g., neurotransmitter release and reuptake), which generates symptoms via common mechanisms that can be affected by the herbs. We assume that starting an herbal formula along with gradual drug dose reductions would give time for the herbs to have the desired effects.

According to the doctrine of traditional Chinese medicine, a patient who is feeling depressed or in a neurologically compromised state of depression should be provided with a therapeutic regimen for any identifiable Chinese medicine syndrome, regardless of using or not using antidepressant drugs. It is expected that certain syndromes contribute to depression, such as liver qi stagnation, spleen qi deficiency, liver-spleen disharmony (a combination of liver qi stagnation and spleen qi deficiency), and disturbance of spirit. These underlying disorders should be addressed, whenever possible, prior to discontinuing antidepressant medication. Otherwise, a patient and a practitioner may become confused between the SSRI discontinuation symptoms and pre-existing imbalances, making it difficult to determine whether the drug therapy might need to be resumed or replaced by another drug of similar nature or whether the symptoms will subside without unnecessary alarm.

References

1. Bull SA, et al., Discontinuing or switching selective serotonin-reuptake inhibitors, Annals of Pharmacotherapy 2002; 36(4): 578-584.
2. C Barbui et al., Selective serotonin reuptake inhibitors versus tricyclic and heterocyclic antidepressants: comparison of drug adherence., In: The Cochrane Library, Issue 4, 2000. Oxford: Update Software.
3. Skaehill PA and Welch EB, SSRI withdrawal syndrome, 1997 American Society of Consultant Pharmacists, Inc., http://www.ascp.com/public/pubs/tcp/1997/oct/ssri.html..
4. Maciocia G, Post-natal depression, http://www.giovanni-maciocia.com/articles/postnatal.html.
5. Dharmananda S, A Bag of Pearls, 2004 Institute for Traditional Medicine, Portland, OR.
6. Yamada K, Yagi G, and Kanba S, Effectiveness of Gorei-san for treatment of SSRI-induced nausea and dyspepsia: preliminary observations, Clinical Neuropharmacology 2003; 26(3): 112-114.
7. Lieberman JA, History of the use of antidepressants in primary care, Primary Care Companion, Journal of Clinical Psychiatry 2003; 5 (supplement 7).

APPENDIX: Brief Note on the Discovery of Antidepressants

The description below was taken primarily from one section of a lengthy report by Dr. Joseph Lieberman (7).

In 1952, while being studied as a possible treatment for tuberculosis, the antibacterial agent iproniazid was discovered to have psychoactive properties. It was noted that even terminally ill patients who were given this drug became cheerful, more optimistic, and more physically active. Soon after its development, it was shown that iproniazid and similar chemical compounds slowed the breakdown of the monoamines norepinephrine (NE), serotonin (5-HT), and dopamine (DA) via inhibition of the mitochondrial enzyme monoamine oxidase-hence this class became known as monoamine oxidase inhibitors (MAOIs). Despite this reported effect, MAOIs were not used clinically for treatment of depressed patients until almost a decade later.

Development of distinctly different antidepressant agents also occurred during this time. Molecular modifications of phenothiazines led to synthesis of imipramine, the first clinically useful tricyclic antidepressant (TCA). These agents were found to block the removal or "reuptake" of NE and 5-HT from the synapse, thus increasing the levels of these transmitters available for binding with receptors. While MAOIs and TCAs presented major advances in treatment of depressed patients, their use was hindered by significant safety issues, unpleasant side effects (e.g., sedation), as well as potentially dangerous drug and substance interactions. Further modifications of the phenothiazine molecule yielded comparatively safer and better-tolerated TCAs, including amitriptyline. Among the problems with these drugs were their effects on other neurotransmitters, such as dopamine, histamine, and acetylcholine, which could lead to neurological changes other than alleviation of depression.

From the 1960s on, great strides were being made in understanding the basic functional elements of the nervous system. With technical advances allowing greater knowledge of neurology and relying on growing clinical experience with psychoactive drugs, clinicians and researchers were better equipped to formulate hypotheses about the causes of mental illnesses and to elucidate the mechanisms by which drugs exerted their behavioral effects. The theory that depression is based largely on decreased levels of certain neurotransmitters, such as NE, DA, and 5-HT, was evaluated. Refinements of this proposal led to the notion that depression was primarily due to NE deficits; others claimed that decreased brain levels of 5-HT play a key in the pathogenesis of depression. Fueled by the serotonin hypothesis of depression, a search for structural analogs of diphenhydramine (shown to be inactive against NE but active against 5-HT) with antidepressant properties led to the development of fluoxetine, the first selective serotonin reuptake inhibitor (SSRI), known by the brand name Prozac.

The search for alternative and better antidepressants continues. During the 1990s, a number of antidepressants with dual NE and 5-HT action-like those seen with the TCAs-but with minimal histamine or acetylcholine effects, have been developed. These compounds include the serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine (Effexor) and duloxetine (Cymbalta); in addition there is the antidepressant mirtazapine (Remeron) that affects serotonin and norepinephrine by means other than affecting reuptake of the neurotransmitters. These "dual-acting" antidepressants are particularly used for patients with severe depression and for those who do not tolerate the SSRIs; however, with the dual action comes the possibility of higher frequency of adverse effects for some users.

Acknowledgement: I would like to thank Craig G. Johnson, M.D. (psychiatrist) for numerous helpful suggestions in the preparation of this manuscript.

September 2004