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Selective Serotonin Reuptake Inhibitors

Diseases and Disorders Western Medicine

Paxil® brand name of the generic drug Paroxetine was the most prescribed pharmaceutical drug in 2005. It is part of the drug class of antidepressants and more specifically, selective serotonin reuptake inhibitors (SSRIs). The following is an excerpt of the section on SSRIs in a book by Bob Flaws and Greg Sperber, Integrative Pharmacology, Combining Modern Pharmacology with Chinese Medicine, published in October of 2007.

Depression is a collection of mood disorders that include symptoms of depressed, irritable, and/or anxious mood. Other signs and symptoms may include slumped posture, poor eye contact, monosyllabic or absent speech, guilt, self-denigration, lessened ability to concentrate, indecisiveness, diminished interest in usual activities, social withdrawal, hopelessness, helplessness, recurrent thoughts of death and suicide, anhedonia, loss of libido, and changes of appetite, either reduced or increased. 

Mood disorders which may employ the following therapeutic agents include: major depressive disorder, dysthymic disorder, depressive disorder not otherwise specified, bipolar I and II disorders, cyclothymic disorder, bipolar disorder not otherwise specified, mood disorder due to a general medical condition, substance-induced mood disorder, and mood disorder not otherwise specified. 

All effective anti-depressants potentiate, either directly or indirectly, the effects of serotonin (5-HT), dopamine (DA), and/or norepinephrine (NE). This fact has led to the monoamine theory of depression that states deficiency of monoamines such as 5-HT and NE in certain areas of the brain cause depression.

Selective Serotonin Reuptake Inhibitors

Citalopram (sye TAL oh pram) (Celexa®), Escitalopram (es sye TAL oh pram) (Lexapro®), Fluoxetine (floo OKS e teen) (Prozac®, Prozac® WeeklyTM, Sarafem®, Symbyax™19), Fluvoxamine (floo VOKS a meen) (Luvox), Nefazodone (nef AY zoe done) (Serzone), Paroxetine (pa ROKS e teen) (Paxil®, Paxil CR®, Pexeva®), Sertraline (SER tra leen) (Zoloft®), Trazodone (TRAZ oh done) (Desyrel®).

Serotonin/norepinephrine reuptake inhibitors: Duloxetine (doo LOX e teen) (Cymbalta®), Venlafaxine (VEN la faks een) (Effexor®, Effexor® XR)


This class of drugs is used to treat depression. In addition, these drugs are used in many other disorders including GAD, panic disorder, PMDD, PTSD, and social anxiety disorder, obsessive-compulsive disorder, and pain.

Mechanisms of Action

This class of agents specifically prevents the reuptake of serotonin from the synaptic cleft into the presynaptic neuron, allowing more serotonin to remain longer in the synaptic cleft. Because of this specificity, SSRIs tend to have a better adverse effect profile than other antidepressants. A sub-class of this class of agents is the serotonin and norepinephrine reuptake inhibitors (SNRIs). These agents also prevent the reuptake of norepinephrine in addition to serotonin. Their effects are similar to SSRIs while their adverse effect profiles differ slightly.

Reuptake inhibition does not completely explain their effectiveness as antidepressants. They also can take 3-8 weeks of use before being fully effective indicating there are secondary effects to reuptake inhibition. One leading theory is that other adaptations occur in the brain in the presence of these agents. These changes are not completely understood, but they may include increased postsynaptic receptor formation. There may be an effect of desensitizing dopamine autoreceptors, which may cause extra dopamine to remain in the synaptic cleft and may contribute to their antidepressant effects. Noradrenergic receptors may also be involved. Many other complex observations and theories of effects have also been theorized, but the bottom line is there are complex interactions and we are still exploring how they result in antidepressant activity.


Most SSRIs need to be tapered off when stopping their use.

Citalopram, for children and adolescents, for OCD (unlabeled use), 10-40 mg/day. For adults, initiate at 20 mg/day, increase to 40 mg/day, 60 mg/day maximum dose. Should be increased in 20 mg/day increments with no less than a week between increases. 

Duloxetine, for adults, initiate at 40-60 mg/day in one or two doses. Maximum dose is 60 mg/day. For diabetic neuropathy dose is 60 mg once daily. In the elderly, initiate at 20 mg 1-2 times/day and increase to 40-60 mg/day.

Escitalopram, for adults, initiate at 10 mg/day, may be increased to 20 mg/day after at least one week. In the elderly, initiate at 5-10 mg/day and may be increased by the same amount after at least one week.

Fluoxetine, for children, for depression, 8-18 years, 10-20 mg/day, lower-weight children can be started at 10 mg/day, may increase to 20 mg/day after 1 week if needed; for OCD, 7-18 years, initiate at 10 mg/day, in adolescents and higher-weight children, dose may be increased to 20 mg/day after 2 weeks, usual range is 10-60 mg/day; for selective mutism (unlabeled use), 5-18 years, initiate at 5-10 mg/day; increase as needed up to a usual maximum dose of 60 mg/day. For adults, initiate at 20 mg/day mane, can be increased every several weeks by 20 mg/day up to a maximum of 80 mg/day. Doses over 20 mg can be given once or twice daily. Usual dosage range is between 20-40 mg/day. Patients on 20 mg/day of Prozac®, may be changed to 90 mg/week of Prozac® WeeklyTM, starting 7 days after the last 20 mg dose. Usual dose for OCD is 40-80 mg/day, for premenstrual dysphoric disorder 20 mg/day continuously or 20 mg/day starting 14 days before menses and through first full day, for bulimia nervosa 60-80 mg/day, for panic disorder, start at 10 mg/day, after one week, increase to 20 mg/day, and dose may be increased every several weeks.

Fluvoxamine, for children 8-17 years, initiate at 25 mg nocte, adjust in 25 mg increments at 4- to 7-day intervals, as tolerated, to maximum therapeutic benefit range of 50-200 mg/day; maximum doses are: for children: 8-11 years, 200 mg/day, for adolescents, 300 mg/day, lower doses may be effective in female versus male patients. For adults, initiate at 50 mg nocte and increase in 50 mg increments at 4 to 7 day intervals until a usual dosage range of 100-300 mg/day is reached. When total dosage exceeds 50 mg/day, agent should be given in two divided doses.

Nefazodone, for children and adolescents (unlabeled use), for depression, 300-400 mg/day (mean: 3.4 mg/kg). For adults, initiate at 200 mg/day in two divided doses, should be increased to 300-600 mg/day in two divided doses. In the elderly, initiate at 50 mg bid, increase to 100 mg bid, usual maintenance dose is 200-400 mg/day.

Paroxetine, for children, for depression (unlabeled use; not recommended by FDA), initiate at 10 mg/day and adjust upward on an individual basis to 20 mg/day; for OCD (unlabeled use), initiate at 10 mg/day and increase as necessary to 60 mg/day; for self-injurious behavior (unlabeled use), 20 mg/day; for social phobia (unlabeled use), 2.5-15 mg/day. For adults, for Paxil® and Pexeva, initiate at 20 mg mane, if needed, increase by 10 mg/day increments with at least one week intervals. Maximum dose is 50 mg/day. Paxil CR, should be initiated at 25 mg once daily and may be increased by 12.5 mg/day at least one week intervals until a maximum dose of 62.5 mg/day is achieved. Can be used in conditions other than depression, such as GAD, OCD, panic disorder, PMDD, PTSD, and social anxiety disorder, at similar but variable doses. In the elderly, halve the initial dose.

Sertraline, for children and adolescents, for OCD, for 6-12 years, initiate at 25 mg once daily, for 13-17 years, initiate at 50 mg once daily, may increase daily dose, at intervals of not less than 1 week, to a maximum of 200 mg/day, if sleepiness is noted, give at bedtime. For adults, initiate at 50 mg/day, may be increased at intervals not less than one week to a maximum of 200 mg/day. Should be given at bedtime if sleepiness is noted; for panic disorder, PTSD, and social anxiety disorder, should be initiated at 25 mg once daily and increased to 50 mg after one week. In the elderly, initiate at 25 mg/day and increase by 25 mg/day every 2-3 days.

Trazodone, for children 6-12 years, for depression (unlabeled use), initiate at 1.5-2 mg/kg/day in divided doses, increase gradually every 3-4 days as needed up to a maximum of 6 mg/kg/day in 3 divided doses. For adolescents, for depression (unlabeled use), initiate at 25-50 mg/day, increase to 100-150 mg/day in divided doses. For adults, initiate at 50 mg tid, may be increased by 50 mg/day every 3-7 days with a maximum of 600 mg/day. In the elderly, initiate at 25-50 mg nocte with 25-50 mg/day increases occurring weekly until a usual dose of 75-150 mg/day is achieved.

Venlafaxine, for children and adolescents, for ADHD (unlabeled use), initiate at 12.5 mg/day, for children less than 40 kg, increase by 12.5 mg/week to maximum of 50 mg/day in 2 divided doses, for children 40 kg or heavier, increase by 25 mg/week to maximum of 75 mg/day in 3 divided doses. For adults, Effexor®, 75 mg/day administered in 2 or 3 divided doses, taken with food, may be increased in 75 mg/day increments at minimal 4 day increments, maximum dose is 225-375 mg/day. Effexor® XR, 75 mg once daily with food, dose may be increased every 4 days by 75 mg/day increments, as tolerated, up to a maximum of 225 mg/day.

Adverse effects

Nausea and vomiting and headaches are common side effects of SSRIs. Loss of libido, delayed ejaculation, and anorgasmia are common side effects that are generally under-reported. Overdosage does not result in arrhythmias as in TCAs, but can cause seizures. In general, SSRIs are well tolerated and have better side effect profiles than other antidepressants.

Duloxetine has been shown to increase the risk of additional liver damage in those patients with preexisting liver disease and should not be used in this patient population.

Red Flags

The use of antidepressant drugs in patients with major depressive disorder and/or suicidal ideation can precipitate a suicide attempt. While a patient may have suicidal thoughts in the middle of a major depressive episode, they often do not have enough energy to carry through on the thoughts. As an antidepressant starts to work, the patient will gain energy but the antidepressant effects may not have fully engaged. In other words, they now have the energy to attempt suicide, but the medication hasn’t worked well enough yet to change the thoughts of suicide. Careful oversight needs to be employed when using any antidepressant in patients with major depression to prevent suicide.

Recent studies have caused the FDA to issue a warning not to use paroxetine during pregnancy as it may increase the chance of congenital malformations.



SSRIs can interact with the metabolism of β-adrenergic receptor antagonists, caffeine, several antipsychotic agents, most tricyclic antidepressants (TCAs), barbituates, phenytoin, imipramine, benzodiazepines and carbamazepine. Some serotonin reuptake inhibitors may compete for metabolism and cause TCA levels to become toxic when co-administered.

Combined use of ethanol or other sedatives with SSRIs may cause toxic sedation.

Co-administration of monoamine oxidase inhibitors (MAOIs) and SSRIs can cause “serotonin syndrome.” Symptoms of this include: akathisia-like restlessness, muscle fasciculations, myoclonus, hyperreflexia, sweating, penile erection, shivering, tremors, and ultimately seizures and coma. Other medications beside MAOIs may cause this syndrome, including: meperidine, pentazocine, dextrometorphan, fenfluramine, and rarely TCAs.



  • Guan Ye Lian Qiao (St. John’s wort) (C-) – and Yin Guo Ye (Ginkgo leaf) were concurrently used with buspirone and fluoxetine. One case report reported that a hypomanic episode occurred in a patient which ended with cessation of herbs (Spinella & Eaton, 2002) Level 4 evidence.
  • Yin Guo Ye (Gingko leaf) (C-) – and St. John’s Wort were concurrently used with buspirone and fluoxetine. One case report reported that a hypomanic episode occurred in a patient which ended with cessation of herbs (Spinella & Eaton, 2002) Level 4 evidence.

Selective Serotonin Reuptake Inhibitors (SSRIs)

  • Guan Ye Lian Qiao (St. John’s wort) (D) – inhibits serotonin reuptake and may cause “serotonin syndrome” when used concurrently with an SSRI, expert opinion (Chen & Chen, 2004) Level 5 evidence.
  • Guan Ye Lian Qiao (St. John’s wort) (C-) – and Yin Guo Ye (Ginkgo leaf) were concurrently used with buspirone and fluoxetine. One case report reported that a hypomanic episode occurred in a patient which ended with cessation of herbs (Spinella & Eaton, 2002) Level 4 evidence.
  • Rou Cong Rong (Cistanche) (Indeterminate) – may interact with sympathomimetics, monoamine oxidase inhibitors, selective serotonin inhibitors, and tricyclic antidepressants by increasing the activities of neurotransmitters such as norepinephrine, dopamine, and serotonin (Chinese language article cited in Chen & Chen, 2004) Indeterminate level of evidence.
  • Yin Guo Ye (Ginkgo leaf) (C-) – and Guan Ye Lian Qiao (St. John’s wort) were concurrently used with buspirone and fluoxetine. One case report reported that a hypomanic episode occurred in a patient which ended with cessation of herbs (Spinella & Eaton, 2002) Level 4 evidence.

Chinese Medical perspective

This class of drugs treats:

  • Depression
  • Generalized anxiety disorder (GAD), social anxiety disorder, and panic disorders
  • Premenstrual dysphoric disorder (PMDD)
  • Post-traumatic stress disorder (PTSD)
  • Obsessive-compulsive disorder (OCD)

The side effects of these medications include:

  • Nausea and vomiting
  • Headache
  • Decreased libido
  • Delayed or inability to ejaculate and anorgasmia

All of the intended therapeutic uses of this class of antidepressants typically include a combination of liver depression with spleen vacuity complicated on a case-by-case basis with phlegm and depressive heat. We now know that all depression includes some anxiety. Anxiety is a form of fear and is commonly due to nonconstruction and malnourishment of the heart spirit because of a liver-spleen disorder. All premenstrual syndrome (PMS) or PMDD, an especially severe form of PMS) involves a liver-spleen disharmony, while PTSD and OCD both also involve a lot of fear and fright. Given their side effects, it appears that these drugs are attacking and draining and, therefore, can damage and consume the qi. Therefore, they appear to be qi-rectifying medicinals which particularly affect the spleen’s relationship with kidneys. We posit this latter point because of the decreased libido, delayed or inability to ejaculate, and anorgasmia.


Akathisia: The inability to remain seated, includes motor restlessness and a feeling of muscle twitching, may be a side effect of antipsychotic medication

Anhedonia: Inability to feel pleasure or happiness from activities that would normally provide such feelings

Anorgasmia: Inability to have an orgasm

Autoreceptors: A receptor located on a neuron that binds a neurotransmitter from the same neuron which then regulates that neuron

Fasciculations: Involuntary twitchings of muscle fibers

Myoclonus: A single or series of shock-like contractions of muscle groups

Synaptic cleft: The space between the two neurons of a synapse; the space into which the neurotransmitters are released

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