Fibromyalgia - New Treatments

Fibromyalgia (FM or FMS) is a condition that causes chronic musculoskeletal pain. Besides widespread pain it is characterized by tender points, painful areas located in certain parts of the body. There are often other symptoms as well, such as fatigue, headaches, cognitive problems, sleep disturbances, anxiety and depression.

People with fibromyalgia frequently have other comorbid illnesses, such as chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), migraines, restless legs syndrome (RLS) and irritable bowel syndrome (IBS). Fibromyalgia commonly occurs together with autoimmune diseases, especially rheumatoid arthritis and lupus (SLE), but it is not thought to be an autoimmune illness. The exact mechanism that causes the illness is not fully understood yet.

Lyrica And Cymbalta

The FDA has approved two medications for fibromyalgia: pregabalin (Lyrica) in June 2007 and duloxetine (Cymbalta) in June 2008. Pregabalin is an anticonvulsant (epilepsy drug), though it is used more often for pain disorders. Duloxetine is an SNRI antidepressant (serotonin and norepinephrine reuptake inhibitor), also used for diabetic neuropathy and stress incontinence.

Despite being in entirely different classes of drug, both Lyrica and Cymbalta can help pain, sleeping problems, fatigue, cognitive impairment, depression and anxiety caused by fibromyalgia, though they don't help everyone and even if you do benefit, you might not get improvement in all of the listed symptoms.

Other Similar Drugs

The drug companies behind these drugs would of course like us to believe they are the magic bullets, but luckily there are many other medications that can help fibromyalgia. The manufacturers of most other drugs just haven't invested in the expensive trials needed to gain FDA approval -- often because the patent is going to expire soon and after that their benefits will drastically drop.

For example, gabapentin (Neurontin) is an anticonvulsant very similar to Lyrica, which used to be widely prescribed for fibromyalgia, but now Lyrica has surpassed it. The drugs have almost identical modes of action. There is no clear evidence showing that either one is more effective. Some people can tolerate pregabalin but not gabapentin, and vice versa. Neurontin comes with a bit cheaper price tag.

Duloxetine is not the only SNRI antidepressant either. Venlafaxine (Effexor) is also an SNRI, though in low doses it does not have that much effect on norepinephrine. Milnacipran (Ixel) is a promising SNRI antidepressant which is not yet available in the United States, but is sold in most of Europe. It has shown good results in preliminary fibromyalgia trials. It is also very inexpensive and thought to be one of the best tolerated antidepressants.

Anticonvulsants And Antidepressants

Generally almost all anticonvulsants, including older names like carbamazepine and lamotrigine and newer players like topiramate, zonisamide and levetiracetam can help the symptoms of fibromyalgia. There are big differences in modes of action among drugs in this class, so even if one does not work or produces intolerable side effects, another one might be worth a try. They tend to be especially helpful for pain, mood problems and migraine prevention, often also for sleep.

The same goes for antidepressants, too. The reason they are used in fibromyalgia is not that fibromyalgia is a psychiatric disorder, but they are also used in many other painful conditions like migraines, chronic headaches, neuropathic pain and IBS. It is thought that fibromyalgia may be associated with a deficit of serotonine and norepinephrine.

The SSRI antidepressants like Fluoxetine (Prozac) are generally not so effective for pain. Many other antidepressants, however, also affect norepinephrine. These include tricyclic antidepressants such as amitriptyline (Elavil) and imipramine which have been used to treat fibromyalgia since the 1980s. They are used in very small doses, usually much smaller ones than would be used for depression. They are especially effective for sleep, but often cause too many side effects.

NMDA Antagonists

A third promising class of drugs is NMDA receptor antagonists. The NMDA receptor is thought to be overactive in fibromyalgia and downregulating it could relieve all symptoms of the condition. NMDA antagonists include the cough suppressant dextromethorphan, amantadine which is used for influenza and Parkinson's disease, the Alzheimer's drug memantine and riluzole, a new drug used for amyotrophic lateral sclerosis (ALS).

Other drugs that also downregulate the NMDA receptor include e.g. calcium channel blockers, many anticonvulsants, some opioids (methadone and dextropropoxyphene) and the muscle relaxants dantrolene and orphenadrine. Magnesium and the amino acid taurine may also have this effect.

Hormonal Treatments

Fibromyalgia has also been associated with endocrinological (hormonal) deficiencies, especially of growth hormone, thyroid hormone and vitamin D, which is nowadays considered a steroid hormone. Others, such as estrogen, testosterone and cortisol have also been suggested as culprits.

Growth hormone has been shown to be deficient in a subset of people with fibromyalgia and supplementation helps many people. Unfortunately the treatment has to be given as an injection and is very expensive. Luckily some oral drugs can also boost growth hormone secretion, such as the anti-anxiety drug buspirone, the blood pressure drug clonidine and the muscle relaxant baclofen. Melatonin may also have this effect.

Some doctors believe that thyroid supplementation can even completely relieve fibromyalgia symptoms in some cases where laboratory results are supposedly normal. On the other hand many patients have reported excellent results, even complete pain relief with large doses of vitamin D.

Promising Drug Candidates

Many drugs are currently in clinical trials for fibromyalgia. Sodium oxybate (Xyrem) is a sleep aid which can also help depression and pain. It is currently approved for narcolepsy, but is used off-label for severe insomnia. Several trials have demonstrated good efficacy in fibromyalgia, but insurance companies are likely to frown at the price.

Flupirtine (Katadolon) is used in many European countries for e.g. low back pain. It has some NMDA blocking properties and has shown good efficacy in preliminary trials. If clinical trials are successful, the company is planning to market it for fibromyalgia with the brand name Effirma.

Lacosamide (Vimpat) is an anticonvulsant with a novel mode of action. It is not yet on the market, but may be approved in the United States and Europe before the end of 2008. A recent phase IIa trial concluded it was effective and well-tolerated in fibromyalgia.

Low dose naltrexone (LDN) is a treatment that increases the secretion of endorphins, our natural painkillers. Fibromyalgia may be associated with an endorphin deficiency, which could also contribute to fatigue, depression and other symptoms. A clinical trial trying LDN for fibromyalgia is currently running in United States.

Maija Haavisto is a journalist, medical writer and the author of the most comprehensive book published about treatments for chronic fatigue syndrome/myalgic encephalomyelitis, fibromyalgia and related conditions. "Reviving the Broken Marionette: Treatments for CFS/ME and Fibromyalgia" features more than 250 different medications that can be used to treat these debilitating illnesses.

Fibromyalgia - New Treatments

Fibromyalgia (FM or FMS) is a condition that causes chronic musculoskeletal pain. Besides widespread pain it is characterized by tender points, painful areas located in certain parts of the body. There are often other symptoms as well, such as fatigue, headaches, cognitive problems, sleep disturbances, anxiety and depression.

People with fibromyalgia frequently have other comorbid illnesses, such as chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), migraines, restless legs syndrome (RLS) and irritable bowel syndrome (IBS). Fibromyalgia commonly occurs together with autoimmune diseases, especially rheumatoid arthritis and lupus (SLE), but it is not thought to be an autoimmune illness. The exact mechanism that causes the illness is not fully understood yet.

Lyrica And Cymbalta

The FDA has approved two medications for fibromyalgia: pregabalin (Lyrica) in June 2007 and duloxetine (Cymbalta) in June 2008. Pregabalin is an anticonvulsant (epilepsy drug), though it is used more often for pain disorders. Duloxetine is an SNRI antidepressant (serotonin and norepinephrine reuptake inhibitor), also used for diabetic neuropathy and stress incontinence.

Despite being in entirely different classes of drug, both Lyrica and Cymbalta can help pain, sleeping problems, fatigue, cognitive impairment, depression and anxiety caused by fibromyalgia, though they don't help everyone and even if you do benefit, you might not get improvement in all of the listed symptoms.

Other Similar Drugs

The drug companies behind these drugs would of course like us to believe they are the magic bullets, but luckily there are many other medications that can help fibromyalgia. The manufacturers of most other drugs just haven't invested in the expensive trials needed to gain FDA approval -- often because the patent is going to expire soon and after that their benefits will drastically drop.

For example, gabapentin (Neurontin) is an anticonvulsant very similar to Lyrica, which used to be widely prescribed for fibromyalgia, but now Lyrica has surpassed it. The drugs have almost identical modes of action. There is no clear evidence showing that either one is more effective. Some people can tolerate pregabalin but not gabapentin, and vice versa. Neurontin comes with a bit cheaper price tag.

Duloxetine is not the only SNRI antidepressant either. Venlafaxine (Effexor) is also an SNRI, though in low doses it does not have that much effect on norepinephrine. Milnacipran (Ixel) is a promising SNRI antidepressant which is not yet available in the United States, but is sold in most of Europe. It has shown good results in preliminary fibromyalgia trials. It is also very inexpensive and thought to be one of the best tolerated antidepressants.

Anticonvulsants And Antidepressants

Generally almost all anticonvulsants, including older names like carbamazepine and lamotrigine and newer players like topiramate, zonisamide and levetiracetam can help the symptoms of fibromyalgia. There are big differences in modes of action among drugs in this class, so even if one does not work or produces intolerable side effects, another one might be worth a try. They tend to be especially helpful for pain, mood problems and migraine prevention, often also for sleep.

The same goes for antidepressants, too. The reason they are used in fibromyalgia is not that fibromyalgia is a psychiatric disorder, but they are also used in many other painful conditions like migraines, chronic headaches, neuropathic pain and IBS. It is thought that fibromyalgia may be associated with a deficit of serotonine and norepinephrine.

The SSRI antidepressants like fluoxetine (Prozac) are generally not so effective for pain. Many other antidepressants, however, also affect norepinephrine. These include tricyclic antidepressants such as amitriptyline (Elavil) and imipramine which have been used to treat fibromyalgia since the 1980s. They are used in very small doses, usually much smaller ones than would be used for depression. They are especially effective for sleep, but often cause too many side effects.

NMDA Antagonists

A third promising class of drugs is NMDA receptor antagonists. The NMDA receptor is thought to be overactive in fibromyalgia and downregulating it could relieve all symptoms of the condition. NMDA antagonists include the cough suppressant dextromethorphan, amantadine which is used for influenza and Parkinson's disease, the Alzheimer's drug memantine and riluzole, a new drug used for amyotrophic lateral sclerosis (ALS).

Other drugs that also downregulate the NMDA receptor include e.g. calcium channel blockers, many anticonvulsants, some opioids (methadone and dextropropoxyphene) and the muscle relaxants dantrolene and orphenadrine. Magnesium and the amino acid taurine may also have this effect.

Hormonal Treatments

Fibromyalgia has also been associated with endocrinological (hormonal) deficiencies, especially of growth hormone, thyroid hormone and vitamin D, which is nowadays considered a steroid hormone. Others, such as estrogen, testosterone and cortisol have also been suggested as culprits.

Growth hormone has been shown to be deficient in a subset of people with fibromyalgia and supplementation helps many people. Unfortunately the treatment has to be given as an injection and is very expensive. Luckily some oral drugs can also boost growth hormone secretion, such as the anti-anxiety drug buspirone, the blood pressure drug clonidine and the muscle relaxant baclofen. Melatonin may also have this effect.

Some doctors believe that thyroid supplementation can even completely relieve fibromyalgia symptoms in some cases where laboratory results are supposedly normal. On the other hand many patients have reported excellent results, even complete pain relief with large doses of vitamin D.

Promising Drug Candidates

Many drugs are currently in clinical trials for fibromyalgia. Sodium oxybate (Xyrem) is a sleep aid which can also help depression and pain. It is currently approved for narcolepsy, but is used off-label for severe insomnia. Several trials have demonstrated good efficacy in fibromyalgia, but insurance companies are likely to frown at the price.

Flupirtine (Katadolon) is used in many European countries for e.g. low back pain. It has some NMDA blocking properties and has shown good efficacy in preliminary trials. If clinical trials are successful, the company is planning to market it for fibromyalgia with the brand name Effirma.

Lacosamide (Vimpat) is an anticonvulsant with a novel mode of action. It is not yet on the market, but may be approved in the United States and Europe before the end of 2008. A recent phase IIa trial concluded it was effective and well-tolerated in fibromyalgia.

Low dose naltrexone (LDN) is a treatment that increases the secretion of endorphins, our natural painkillers. Fibromyalgia may be associated with an endorphin deficiency, which could also contribute to fatigue, depression and other symptoms. A clinical trial trying LDN for fibromyalgia is currently running in United States.

Maija Haavisto is a journalist, medical writer and the author of the most comprehensive book published about treatments for chronic fatigue syndrome/myalgic encephalomyelitis, fibromyalgia and related conditions. "Reviving the Broken Marionette: Treatments for CFS/ME and Fibromyalgia" features more than 250 different medications that can be used to treat these debilitating illnesses.

Abuse Of Antidepressants And How To Avoid

There is a reason why there are strict laws against medicines being sold only with a prescription-not only are they harmful taken without a doctor's consultation, but also usually do not take effect in the manner desired by the consumer. Incorrect or excessive dosage is potentially dangerous.

Antidepressants are medicines used for depression treatment.Antidepressants help by raising the extent ofexcitatory neurotransmitters, such as serotonin, that stimulate chemicals in the brain to stabilize mood disorders.Such medicines are helpful as they are usually safe, non-addictive and provide substantial relief as therapeutic medicines towards mental disorders. They are also commonly safe from abuse.

Some antidepressants which have shown evidence of abuse, especially those that are tricyclic and heterocyclic, i.e. antidepressants which are monoamine oxidase inhibitors (MAOIs).

Banned in 1970s, these MAOIs are now proven safe and are now used for different mental disorders including eating disorders, panic attacks and anxiety.

The first selective serotonin reuptake inhibitor (SSRI) to be approved by the U.S. Food and Drug A(FDA) was Prozac (Fluoxetine) in 1987.

Some SSRIs like Fluoxetine are not as effective as the MAOIs or tricyclics and have been found to be more tolerable and safe from abuse. Medications like Effexor (Venlafaxine), an SSNRI or "selective serotonin and norepinephrine reuptake inhibitor", and Wellbutrin (Bupropion), a dopamine reuptake blocking compound are other alternatives in treating anxiety and mood disorders, but have had their share of controversies.

Antidepressants have received a mixed response from medical experts, as it is considered as addictive by some and non-addictive by others.

Refusal of antidepressants to depression patients has sometimes proved fatal, as in the case of suicides.

Abuse of antidepressants has led to addiction, as in cases of methadone-treated addicts by increasing the effects of methadone. These misconceptions have led to people as well as doctors presuming that antidepressants are substances of abuse.

Ceasing to use antidepressants may at times lead to withdrawal symptoms that cannot be considered as abuse and dependence of antidepressants.

The new antidepressants:

* are more effective than tricyclic antidepressants and monoamine oxidase inhibitors
* cost less than the older depression medication.
* reduce chances of depression relapse.
* help in treating other mental disorders like panic attacks, anxiety, post-traumatic stress disorder
* chronic fatigue apart from cases of schizophrenia

When to start and discontinue use of antidepressants
Early detection of a mood episode differs from person to person and is different for mood elevations and depressions.

Though the disorder can be treated over a period, early intervention is always better.

Medical advancement coupled with treatment like psychotherapy, EMDR treatment are a boon to the society in which the number of people suffering from mental disorders like bipolar disorder increases dramatically.

Right antidepressants are individually prescribed, based on his/her medical history, as well as physical acceptance along with its effectiveness.

Antidepressants cannot and must not be discontinued immediately and without approval from the doctor who is treating the patient, as the extent of side effects towards the antidepressants is at its peak during the initial stages of administration and mellow down with the continuation of usage antidepressants.

The medication is weaned off slowly. Immediate discontinuation can lead to marked physical and mental disturbances. The patients are forewarned by the doctor to not practice self-therapy, such as in the cases of bipolar disorder.

Sorry Rover, No Drug Detox for Misbehaving Dogs on Antidepressants

Apparently the FDA, Big Pharma and the veterinarians of America think it's okay for our dogs to experience the same horrendous withdrawal symptoms and side-effects that people have experienced on fluoxetine. But I think it's obvious that Reconcile is Ely Lilly's attempt to 'reconcile' the loss of billions of dollars since the patent on Prozac expired back in 2001, prompting a flood of generic fluoxetine drugs onto the market. Over 23 million prescriptions of generic fluoxetine were filled in the US last year alone - money that didn't go into Lilly's pockets.

Prozac is one of the dangerous selective serotonin reuptake inhibitor (SSRI) class of mood-altering drugs involved in countless court cases and class action suits that have cost Big Pharma billions of dollars in fines and settlements. They concern addictive prescription drugs that require drug detox, rehab, and others with fatal side effects. We know that business and the bottom line counts for more than sending thousands of people into drug detox or rehab, or early graves.

Lilly's new doggy-Prozac is aimed at a slice of Big Pharma's newest expanding market - our pets and their psychiatric disorders. Reconcile is supposed to treat a doggie ailment called "separation anxiety" - in other words, if your dog goes wacko when he's left alone, stuff a Reconcile in its mouth. Give me a break! The animal needs an owner willing to establish who's boss, not a drug pusher.

Fluoxetine isn't conventionally addictive and doesn't require drug rehab like OxyContin and other prescription painkillers, although a drug detox would be appropriate, but suddenly discontinuing Prozac can produce awful physical and mental withdrawal symptoms - patients describe 'brain zaps' and 'fever jolts' and other nasty symptoms that can last weeks or even months. Here Rover, come get your meds!

But that's the least of its problems. Prozac has been implicated in dozens of suicides and acts of deadly aggression against others, including school shootings. Remember Joseph Wesbecker of Kentucky, who took some Prozac and went to work and opened fire with an assault rifle killing 8 people, injuring 12 others, and then turning the gun on himself? Are we going to see pet owners claiming that Reconcile caused Rover go nuts and kill a bunch of other dogs at the park, and then turn and bite himself to death?

But seriously, the tests conducted by Lilly's new Elanco Animal Health Division on hundreds of dogs show that fluoxetine has a similarly horrendous list of side-effects on our canine friends as it does on people. Is this what we want our pets to go through because we're too lazy or incompetent to be a dog owner?

But if, after weighing all the alternatives, you still think putting your dog on drugs is the solution, then you probably shouldn't have a pet. Most dog experts will tell you, it's usually a human's bad habit that is causing the dog's problem. Just ask The Dog Whisperer, or watch his television show.

The dog drug Reconcile is nothing more than an extension of the money-making drugging of America. And a drugged dog has no drug detox program or drug rehab program to go to for help - he only has you. Help him, don't drug him.

Review Of SSRIs - Selective Serotonin Reuptake Inhibitors

The most significant class of antidepressants marketed in recent years is the selective serotonin reuptake inhibitors (SSRIs). The six SSRIs available in the United States are citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). The primary uses for the SSRIs include unipolar and bipolar major depression and all of the anxiety disorders. However, controlled trials also support the use of SSRIs in the treatment of other psychiatric disorders including dysthymia, premenstrual dysphoria, bulimia nervosa, obesity, borderline personality disorder, alcoholism, rheumatic pain, and migraine headache.

Among the SSRIs, there are more similarities than differences. Although all SSRI drugs have the same the mechanism of action, each SSRI has a slightly different pharmacological and pharmacokinetic characteristics. This leads to differences among the SSRIs in their half-lives, clinical activity, side effects, and drug interactions. There are differences between SSRIs that could be clinically significant.

The first drug in the SSRI class was Prozac (Fluoxetine), which hit the United States market in 1987. Prozac was FDA approved on December 29, 1987. It is manufactured by Eli Lilly and Company.

Zoloft (Sertraline hydrochloride) was the second SSRI to come to market in the United States, and it was approved by the FDA on December 30, 1991. Zoloft is manufactured by Pfizer Inc.

Paxil (Paroxetine hydrochloride) was the third SSRI to come to market in the United States and was approved by the FDA on December 29, 1992. Paxil is manufactured by GlaxoSmithKline.

Luvox (Fluvoxamine maleate) was the next SSRI FDA approved on December 05, 1994. However, now its marketing status is "Discontinued".

Celexa (Citalopram hydrobromide) was approved by the FDA on July 17, 1998. Celexa is manufactured by Forest Pharmaceuticals, Inc.

Lexapro (Escitalopram oxalate) is the newest and most selective of the SSRIs approved by the FDA on August 14, 2002. Lexapro is manufactured by Forest Pharmaceuticals, Inc. Lexapro is a cleaner, improved version of Celexa.

Mechanism of action

The brain communicates with itself through the use of special chemicals called neurotransmitters, such as serotonin and norepinephrine. Neurotransmitters carry signals from one nerve cell to another. Low levels of serotonin and norepinephrine have not been proven to cause depression but it widely believed that elevation of these chemicals is associated with improvement in mood in depressed people.

All SSRIs have the same general mechanism of action. SSRIs seem to relieve symptoms of depression by blocking the reabsorption (reuptake) of serotonin by certain nerve cells in the brain. This leaves more serotonin available, which enhances neurotransmission (sending of nerve impulses) and improves mood. In due course, the levels of natural serotonin will rise again, and in some instances the SSRI can be reduced and withdrawn.

Approved indications and uses

SSRIs have been primarily used for the treatment of depression and have been studied for several indications outside of depression.

Celexa (Citalopram) is indicated for the treatment of:

• depression

Lexapro (Escitalopram) is indicated for the treatment of:

• major depressive disorder
• generalized anxiety disorder (GAD)

Paxil (Paroxetine) is indicated for the treatment of:

• major depressive disorder
• obsessive compulsive disorder (OCD)
• panic disorder
• social anxiety disorder
• generalized anxiety disorder
• posttraumatic stress disorder (PTSD)

Prozac (Fluoxetine) is indicated for the treatment of:

• major depressive disorder
• obsessive-compulsive disorder
• moderate to severe bulimia nervosa
• panic disorder
• in January 2003, Prozac was approved by the FDA for the treatment of depression and OCD in children and adolescents who are 7 to 17 years of age.

Zoloft (Sertraline) is indicated for the treatment of:

• major depressive disorder
• obsessive-compulsive disorder
• panic disorder
• posttraumatic stress disorder
• premenstrual dysphoric disorder (PMDD) in adults (newest indication)
• social anxiety disorder

Efficacy

Clinical trials comparing an SSRI with another SSRI indicate that drugs in this class are equally efficacious. Each SSRI produces approximately a 60% overall response rate (ie, at least a 50% reduction in symptoms as a result of treatment).

Adverse reactions & side effects

While SSRIs do not appear to differ in overall tolerability, the reported incidences of specific adverse effects vary. Adverse effects that patients experience are usually mild to moderate and do not require dose reductions or discontinuation. SSRIs possess the following adverse effects:

• Nausea. The most coomon side effect accociated with use of SSRIs is nausea. Paroxetine and sertraline have been associated with slightly more cases of nausea.
• Sexual dysfunction. Depression itself may cause sexual dysfunction and all SSRIs have been associated with sexual dysfunction during therapy in men and women. There may be lesser detrimental effect on sexual function by fluoxetine compared to other agents. Citalopram has been associated with loss of libido. Paroxetine appears to cause the highest rate of sexual dysfunction.
• Anticholinergic effects. Paroxetine causes a higher rate of anticholinergic effects, such as dry mouth, constipation, and cognitive disruption, compared with other SSRIs. These effects may be particularly difficult to tolerate for elderly or concomitantly medically ill patients.
• Weight. The SSRIs vary in their effect on the weight. Sertraline is generally associated with a small degree of weight loss in the acute phase of treatment, whereas paroxetine can cause weight gain after long-term treatment. Fluoxetine has the most potent appetite-suppressing effects in the short term and produces a greater degree of weight loss than paroxetine, sertraline, citalopram, or escitalopram.
• Diarrhea. Sertraline and fluoxetine are more frequently associated with diarrhea, paroxetine has a lower incidence.
• Anxiety, agitation, insomnia. Fluoxetine has been associated with highest rate of anxiety and agitation. Escitalopram and paroxatine are less likely to cause insomnia than fluoxetine and sertraline.
• Dry mouth. Citalopram and paroxetine are more likely to cause dry mouth than escitalopram and fluoxetine.
• Drowsiness, fatigue. Paroxetine has been associated with highest rate of drowsiness, somnolence than other SSRIs.
• Headache. Sertraline and fluoxetine are associated with higher level of headache.

In some cases, antidepressants may be associated with worsening symptoms of depression or suicidal thoughts or behavior, particularly early in treatment or when you change your dosage. Be sure to talk to your doctor about any changes in your symptoms. You may need more careful monitoring at the beginning of treatment or upon a change in treatment, or you may need to stop the medication if your symptoms worsen.

Pharmacokinetics

Some of the key differences among SSRIs are due to differences in their pharmacokinetic properties. The only pharmacokinetic parameters shared by all the SSRIs is that they are relatively slowly, but completely, absorbed from the gut. They differ with regard to their protein binding, metabolism, half-lives, whether they have linear or nonlinear pharmacokinetics, whether they have active metabolites.

Half-life

The half-life of a drug is the time required to achieve steady-state plasma concentrations (i.e., to metabolize half the dose and lower blood concentrations by 50%). Half-life can be used to estimate how long it will take to clear a drug from the body after treatment is discontinued.

Fluoxetine is unique because of its long half-life and the long half-life of its active metabolite norfluoxetine. Fluoxetine has a half-life of 4-6 days and its active metabolite, norfluoxetine, has a half-life of 4-16 days. In comparison, citalopram, escitalopram, paroxetine, and sertraline have shorter half-lives in the range of 20-35 hours, and steady-state concentrations (and therapeutic effect) are reached much more rapidly. The long half-life of fluoxetine may blunt the effects of missed doses or treatment discontinuation and makes it easier to discontinue than any of the other SSRIs. On the other hand, fluoxetine requires a much longer washout period than the other SSRIs (several weeks), particularly when switching to monoamine oxidase inhibitors (MAOIs) or TCA.

Antidepressants with relatively short half-lives are desirable for people with multiple comorbidities and complex, multiple-drug regimens because they allow for once-daily dosing. A short half-life enables physicians to switch more rapidly and safely to an alternative antidepressant if treatment fails or if unfavorable drug reactions occur.

Linear and nonlinear pharmacokinetic.

One of the important differences to note among the SSRIs is whether their pharmacokinetic properties are linear or nonlinear.

Citalopram, escitalopram and sertraline show linear and dose-proportional pharmacokinetics. Plasma concentrations of these drugs are proportional to the daily dose administered and, therefore, predictable. In contrast, fluvoxamine, fluoxetine and paroxetine have nonlinear pharmacokinetics. Higher doses may produce much greater increases in plasma drug concentrations than would otherwise be expected. Thus, increasing the dose of paroxetine or fluoxetine can result in disproportionate and unpredictable increases in plasma levels, half-lives, and adverse effects. Titration of fluoxetine and paroxetine doses may therefore be more difficult than with citalopram, escitalopram and sertraline.

Drug Interactions

The interaction between monoamine oxidase inhibitors (MAOIs) and SSRIs is the most important drug interaction limiting SSRI use. This combination may lead to the development of a hyperserotonergic syndrome consisting of excitement, diaphoresis, rigidity, hyperthermia, tachycardia, hypertension, and possibly death. The severity of this interaction necessitates at least 5 week washout when switching a patient from fluoxetine to an MAOI to allow complete elimination of the fluoxetine. At least 14 days should be allowed after stopping citalopram, escitalopram, paroxetine or sertraline before starting an MAOI. This difference in washout time between fluoxetine and citalopram, escitalopram, paroxetine and sertraline when switching from an SSRI to an MAOI is one of the key differences between SSRIs.

Citalopram, escitalopram and sertraline have the lowest potential for drug interactions among the SSRIs. Citalopram should be avoided in patients likely to take overdoses. Sertraline would be preferable for cardiac patients taking beta blockers or type IC antiarrhythmic agents.