All you need to know about Prozac

If one is taking a short-acting SSRI medication and was told to discontinue it or decrease dosage, but he\she would like to avoid or to minimize the effects of medication withdrawal.

At first, that person should ask his\her physician if a special dose produced by some pharmaceutical companies and offered them as in the form of sample to doctors exists for the specific goal of discontinue.

If such a dose is not available, the main idea is that patient should try to decrease dosage gradually, in a smooth flowing manner. It is usually recommended to use half of the increments that health care provider would normally suggest for the process of discontinue in most people.

Pills

Patient should always carefully read leaflet of his\her drug to make sure that pills can be splitted. He\she can halve pills with help of pill splitter (it can be purchased for some dollars at the nearest pharmacy). This makes very easy to get half-arrow dosage of the original titration recommendation and take each step down for a week.

Capsules

Patient obviously can’t open them and take the contents raw…but dosage can still tapered off. Some empty gel caps should be purchased (just a couple bucks for a hundred). He\she should take a single daily dosage, open capsules and redistribute the medication into the empty gel caps to spread the total daily dosage into smaller increments. Each capsule should be rubbed before storage with a dry cloth to get any of the medication off of the outside of the capsule. A daily dosage amount should be gradually reduced, using each amount for a week.

That method showed a right spirit when discontinuing Paxil, one of the most notorious drugs for causing SSRI Discontinuation Syndrome. Doctor may acknowledge patient with the discontinuation problem and to give him\her helpful suggestions for reducing the discomfort. So, and the side effects were much more tolerable due to abovementioned method.

The main condition of minimizing of withdrawal symptoms is that the brain’s production of acetylcholine is not interrupted. Using food supplements containing choline, lecithin, and B complex is the easiest way to do it. Prerequisite levels of the neurotransmitter acetylcholine in the brain can be maintained with the B vitamins. Shortage of that neurotransmitter induces abstinence symptoms. Choline supplements or lecithin supplements (which are 13 percent choline) are also recommended because they are able to amplify the level of choline used by brain to produce acetylcholine during decreasing of dosage or discontinuing of antidepressant therapy.

Physician can suggest making dietary changes until the drug is not fully discontinued. A wide variety of foods contains lecithin and choline, but many of them are high also in cholesterol and fats. One of the best dietary sources of lecithin and choline is egg yolks. Beef steak, liver, organ meat, spinach, soybeans, cauliflower, wheat germ, peanuts, and brewer’s yeast also contain significant amount of dietary choline.

A lot of medicines (monoamine oxidase inhibitors, tricyclic antidepressants, antiparkinsonian agents, traditional antipsychotics, and clozapine.) acting on the central nervous system can lead to appearance of withdrawal syndrome symptoms. Condition known as rebound (an agitated state of emotion that occurs at the end of the dosage cycle, and lasts for 15-20 minutes, then disappears) was observed in some people. It happens when patient takes medications of short acting. Doctor can prescribe dietary modifications to solve that problem.

That phenomenon was voted as valid by psychiatric professional community. Notwithstanding that the symptoms can be different and have both physical and psychological origin, doctors are able now to detect patterns of SSRI abstinence syndrome.

Pharmacokinetic Differences Between Different SSRIs

nonlinear: half-life elimination is longer at higher plasma concentrations, due to autoinhibition of metabolism; Linear: half-life elimination does not depend on plasma concentration

Patient has been taking antidepressant therapy during 5 weeks or more. His\her physician decided to change dose or discontinue medicine intake. Default, 10mg increments of dose are usually recommended.

After that one can experience severe symptoms. Headache, diarrhea, nausea, vomiting, cold fit, dizziness and fatigue, insomnia, agitation, impaired concentration, vivid dreams, depersonalization, irritability and suicidal thoughts are the most be widespread symptoms of withdrawal syndrome. Abovementioned symptoms can vary in wide range in intensity (from a total absence of to very severe) and time duration (from one to seven weeks) in different people.

It is induced with decreasing dosage or discontinuing of antidepressant medications. This phenomenon is known as SSRI discontinuation syndrome. It can become real Gehenna for the human creature.

One of its reasons is very short half-life of some SSRI medications. Very short half-life leads to absence of active metabolites that can help the drug to stay in the body for a long term. Such medications go in, last a few hours, and are excreted.

SSRIs are divided on two categories depending on their half-life: long acting and short acting. Prozac is a longer-acting SSRI while Paxil, Effexor, Zoloft and Luvox are short-acting. Decreasing dosage or discontinuing SSRIs with shorter half-life cause so-called anticholinergic rebound. That rebound is defined by an interruption in production of the key neurotransmitter acetylcholine which is used more when a person is under greater stress. The duration time of those symptoms varies in range from 1 to 7 weeks.

Symptoms of SSRI Discontinuation Syndrome

• Neurologic symptoms include:

  • Dizziness;
  • Vertigo;
  • Light headedness;
  • Difficulty walking

• Somatic (bodily) complaints include:

  • Nausea/vomiting;
  • Fatigue;
  • Headaches;
  • Insomnia

• Less common difficulties:

  • Shock-like sensations;
  • Parasthesia (skin crawling, burning or prickling);
  • Visual disturbances;
  • Diarrhea;
  • Muscle pain;
  • Cold fit

• Non-specific mental symptoms:

  • Shock-like sensations;
  • Agitation;
  • Impaired concentration;
  • Vivid dreams;
  • Depersonalization – sense of unreality and loss of self;
  • Irritability;
  • Suicidal thoughts

It was found out due to some double-blind controlled studies that 35-78% of patients who, after five weeks or more of treatment with the medication, abruptly had discontinued certain antidepressants or used 10mg increments or more, experienced one or more of the withdrawal symptoms. When antidepressant therapy had been renewed abstinency’s symptoms severity were ranged from mild-moderate in most patients, to extremely distressing in a small amount and have been lasting from one to seven weeks

A lot of isozymes of the cytochrome P450 system which realize Prozac metabolism are inhibited with medicine. Both Prozac and its active metabolite, norfluoxetine, greatly inhibit CYP2D6 (that enzyme plays the most important role for their metabolism) and mildly inhibit CYP1A2, CYP2B6, CYP2C9/2C19, and CYP3A4. They also inhibit the activity of P-glycoprotein, a type of membrane transport protein that plays an important role in drug transport and metabolism. Great possibility for interactions with many commonly used drugs is caused with those extensive pathways for metabolism of Prozac.

A rare but life-threatening adverse drug reaction known as serotonin syndrome can happen if Prozac is taken together with triptans, tramadol or other serotonergic agents

Suicidality in antidepressant trials

A black box warning predicating about increased risk of suicide in persons younger than 25 is required by FDA for all antidepressant medicications. Dualfold growth of the suicidal ideation and behavior in children and adolescents was observed by two independent groups of the FDA experts. 1.5-fold augmentation of suicidality was reported in the age group of 18–24 years old.

It was observed that suicide addiction in patients olden than 24 had been declined in a minor way while it had decreased in a great measure in group in the age of 65 and older. Donald Klein criticized that analysis. He suggested that suicidality (that is defined as suicidal ideation and behavior) should not be undoubtedly a good surrogate marker for completed suicide. He also supposed that antidepressant medications increasing suicidality might avert actual event of suicide. That supposal runs counter to current beliefs in which suicidal ideation has been in one-to-one correspondence with attempt of suicide in retrospective studies and with suicide in prospective studies.

Suicidality and Prozac

It is hard enough to study suicidal ideation and behavior in clinical trials due to their infrequency. The results of 295 trials of 11 antidepressants for psychiatric indications should be united by FDA experts in order to obtain statistically significant data and analyze them. Probability value of suicidality in children using Prozac amplifies in half as large again (those data are not statistically significant in view of paucity of cases). While it was reported about reduction of probability value of suicidality in adult patients taking Prozac around at one third (those data are statistically significant).

The UK Medicines and Healthcare products Regulatory Agency (MHRA) pursue similiar investigation. The experts of UK MHRA reported about1.5-fold augmentation of probability value of suicide-related events in the children and adolescents on Prozac therapy as opposed to placebo group. Those data also didn’t reach statistical significance. They assert that the rate of self-harm for adults taking Prozac is similar to placebo group while suicidal ideation decreased twice (statistically significantly data)

Severe abstinence symptoms could happen in patients who suddenly discontinued Prozac therapy. It is supposed that adverse effects of the Prozac discontinuation are mild enough. There are two recommended strategies to manage with discontinuation syndrome:

1. To reduce gradually dose of Prozac;
2. To replace Prozac with the other SSRI agent, in situations when gradual changes off the Prozac dose is ineffective.

It was proved in some double-blind controlled studies.

There were some blind trials where discontinue of antidepressant therapy for a short time (4–8 days) with further renewal has been studied. It was found out that the most severe side effects had been caused with interruption of paroxetine. Interruption of Zoloft therapy induced severe adverse effects but milder then paroxetine. Prozac showed the best tolerance in that study. Slow elimination of Prozac from the body can explain that result.

32% of members of Prozac discontinued group complain about new or worsened side effects versus 27%of patients who continued treatment in a longer, 6 week-long, blind discontinuation study. Significantly higher 5-7% rate of dizziness at weeks 4-6 and 4% rate of somnolence at week 2 were reported by the patients who had interrupted therapy. Long Prozac half-life in the body was proved with withdrawal symptoms, lasting for a long time. People reported about dizziness persisting to the end of the study

Company Eli Lilly, Prozac manufacturer, doesn’t recommend those people who take monoamine oxidase inhibitors, pimozide (Orap) or thioridazine (Mellaril) to use Prozac . Patients having liver impairment should tell their health care professional about that fact because the elimination of Prozac and its metabolite norfluoxetine is about twice slower in these patients. It induces about double amplification of Prozac exposure. Significant intestinal bleeding can be result of combination of Ibuprofen with Prozac after a period of use.

Nausea (22% vs 9% for placebo), insomnia (19% vs 10% for placebo), somnolence (12% vs 5% for placebo), anorexia (10% vs 3% for placebo), anxiety (12% vs 6% for placebo), nervousness (13% vs 8% for placebo), asthenia (11% vs 6% for placebo) and tremor (9% vs 2% for placebo)are the common adverse effects caused with Prozac and greatly differing from placebo therapy.

7% of patients taking Prozac in clinical trials reported about rash or urticaria, sometimes serious. Discontinuation of the Prozac therapy leaded to that side effect in 32% of those patients. There are some reports about several cases of complications developed in patients with rash. Vasculitis and lupus-like syndrome were observed in those cases. Those systemic events gave occasion to death.

Akathisia is a common side effect of Prozac . It is often accompanied by purposeless movements of the feet and legs, constant pacing, and marked anxiety. Akathisia usually appears after the beginning of the Prozac therapy or increase of the dose. Reducing of Prozac dose, discontinuation of drug or treatment with propranolol can remove or relieve akathisia symptoms. There are proves that akathisia and suicidal attempts are relative. It was reported that there were patients who had been feeling better after the withdrawal of Prozac , but relapsed severe akathisia symptoms after resumption of Prozac therapy. The development of the akathisia forced those patients to wish to make quietus and that it had brought back about their prior suicide attempts. Physician should describe symptoms of akathisia to patients and staff because of coupling of akathisia with suicide and the distress. More rarely, Prozac can cause side effects related with movement disorders such as acute dystonia and tardive dyskinesia.

Increase of rate of poor adaptation of newborns can be resulted with taking Prozac during pregnancy. Mothers having Prozac therapy shouldn’t breastfeed because Prozac was found in milk. Prozac is classified by the American Association of Pediatrics as a drug for which the effect on the breastfeeding baby is still unknown but may be of great importance.

Concentration of Prozac can achieve relatively high levels. It becomes maximal in 6-8 hours after medicine intake. Plasma proteins, particularly albumin, highly bind Prozac.
Enzyme CYP2D6 of cytochrome P450 system helps to metabolize Prozac. Reaction of Prozac metabolism happens in the liver. There is wide range of genetic variability in the function of CYP2D6 that’s why the role of that enzyme in the metabolism of Prozac may be clinically essential.
The distinctive feature of Prozac and its active metabolite norfluoxetine from other antidepressant medications is their very slow excretion. Half –life of Prozac elimination can vary from 1-3 days after single dose to 4-6 day of after continuous use. Likewise, the half-life of norfluoxetine becomes longer (16 days) after long termed use. That fact can be explained due to that Prozac and norfluoxetine inhibit their own metabolism with time. That’s why drug and its active metabolite concentration in blood keeps on growing during the first weeks of therapy, and their steady concentration in the blood is achieved only after four weeks after treatment beginning. Moreover, the brain levels of Prozac and its metabolites have been increasing through at least the first five weeks of treatment. A patient receives the full benefits of the current dose for at least a month since its initiation. The average of achieving consistent response is about 29 days. Likewise, complete elimination of Prozac may take several weeks. The brain levels of Prozac run down only by 50% during the first week after the treatment had been discontinued, The blood level of norfluoxetine after 4 weeks the treatment discontinuation is about 80% of the level registered by the end of the first treatment week, and after 7 weeks the treatment had been discontinued it is still possible to detect norfluoxetine in the blood.
Prozac levels in brain increases very slowly during first 5 weeks of therapy. It is distinction feature of Prozac’s pharmacokinetics. That fact aggravates to find out the most optimal dose for continuous treatment. It was proved that one 60-mg dose of Prozac per week has similar effect as 20 mg/day for the continuation treatment of patients responding to 20 mg/day of Prozac. 5 mg/day Prozac was significantly superior to placebo and equivalent to 20 mg/day; while Prozac 80 mg/week had similar results as 60 mg/day Prozac or 150 mg/day amitriptyline. Increasing of dose to 60mg/day in patients who did not respond to 20mg/day therapy is not essentially different from results got in patients continuing the 20 mg/day treatment.
There is speculation based on the results of recent trials. It tries to explain the resistance to the SSRIs Paxil and Celexa. That hypothesis says that the genetic variation of P-glycoprotein (Pgp) transporter can induce resistance to abovementioned medications. Paxil and Celexa are Pgp substrates and Pgp carries them from the brain, while Prozac is not a substrate of that protein. That’s why replacement of Paxil and Celexa with Prozac can bring positive dynamics in patients who don’t respond on those drugs.

Cooperation between Bryan Molloy and Robert Rathbun in 1970 at leaded to utility invention of Prozac.

Antihistamine diphenhydramine showed some antidepressant-like properties. That fact was known at that time. These scientists chose 3-phenoxy-3-phenylpropylamine (a compound structurally similar to diphenhydramine) as terminus a quo. Dozens of its derivatives have been synthesized by Molloy. A selective norepinephrine reuptake inhibitor Nisoxetine became a result of proving the physiological effects of those agents in mice.

Another Eli Lilly scientist, David Wong, trying to discover a derivative inhibiting only serotonin reuptake, suggested that series of laboratory researches dedicated to reuptake of serotonin, norepinephrine and dopamine should be prospected again. In May 1972 Jong-Sir Horng carrying out that test discovered agent which was named later Prozac. It acted as the most potent and effective selective inhibitor of serotonin reuptake of the series.

Lilly scientists claimed Prozac to be the first selective serotonin reuptake inhibitor (SSRI). But they had to issue a correction two years later,where they declared that zimelidine developed by Arvid Carlsson and colleagues had been the first SSRI.

In August 2001 Prozac patent of Eli Lilly expired that induced inflow of generic drugs onto the market. Eli Lilly rebranded Prozac as “Sarafem” for the treatment of premenstrual dysphoric disorder in attempt to reimburse loss caused with reduction of sales of Prozac in Eli Lilly.

FDA has approved Prozac as the treatment of major depression (MDD), obsessive compulsive disorder (OCD), bulimia nervosa and panic disorder. Prozac proved its efficacy for depression in 6-week long double-blind controlled trials where it also relieved anxiety and improved sleep. Prozac was more effective against placebo for the prevention of depression relapse when the patients, who originally responded to Prozac, were treated for a further 38 weeks. It was found out in placebo-controlled trials that Prozac therapy is effective both in geriatric and pediatric depression.

Physicians can prescribe Prozac for treatment OCD both in adults and children. As against to depression treatment higher doses of Prozac have been more effective in treatment of Obsessive–compulsive disorder. Prozac approved itself as perfect drug in treatment of patients suffering from panic disorder. Using Prozac therapy in such patients leads to exceeding reduction of frequency of panic attacks. Quantity of binge-eating and purging episodes of bulimia nervosa can be significantly decreased if Prosac is taken. It was proved that using placebo for the prevention of bulimia nervosa is not nearly as good as long-termed (year-long) Prozac treatment.