Wednesday, 29 May 2013

Venlafaxine (EFFEXOR) and Desvenlafaxine (PRISTIQ) vs. SSRIs

Venlafaxine (EFFEXOR) is an antidepressant that appears to work by serving as a serotonin-norepinephrine reuptake inhibitor (SNRI; other drugs of this class include duloxetine [CYMBALTA] and milnacipran [SAVELLA]). What this means is that it increases the availability of the neurotransmitters serotonin and norepinephrine in the synapse [the parts of neurons (electrically signalling brain cells) where neurotransmitters are used as chemical messengers between cells]. This in turn leads to increase in signalling mediated by these two neurotransmitters and since they play key roles in mood regulation this tends to lead to improvements in the moods of the depressed. Interestingly clinical studies have demonstrated that on average venlafaxine is a superior antidepressant, when measured by how many patients achieve a remission (or disappearance) of their symptoms whilst on it, to the selective serotonin reuptake inhibitors (SSRIs) that work solely on serotonin such as sertraline [ZOLOFT], fluoxetine [PROZAC] and escitalopram [LEXAPRO]. On average clinical studies have demonstrated that around 45% of patients achieve a remission of their depression while on venlafaxine, whereas 35% of patients achieve a remission while on SSRIs and 25% of patients receiving a placebo achieve a remission. Albeit to be fair these clinical trials primarily involved fluoxetine as the SSRI used with only one using another SSRI, namely, sertraline.

How venlafaxine manages to achieve such high remission rates in clinical trials isn't 100% clear but we do have our theories, or rather theory since I've only seen one such theory. It is that by working both on serotonin and norepinephrine it manages to correct two anomalies found in depressed patients that we believe contribute to depression, that is low serotonin and norepinephrine levels in the synapse. The problem with this theory is that at the standard doses venlafaxine is relatively selective for serotonin, that is the increase in norepinephrine availability in the synapse it is able to induce is comparatively small compared to the increase in the availability of serotonin in the synapse it causes at the same doses and hence you would expect that norepinephrine would contribute negligibly to venlafaxine's antidepressant effects at therapeutic doses.

Interestingly venlafaxine is metabolised (or transformed) in the body to a drug known as desvenlafaxine, that similarly also serves as a SNRI, and it is believed that this is responsible for many of venlafaxine's antidepressant effects. What's particularly interesting is that desvenlafaxine is actually used in medicine as an antidepressant in its own rights and is currently sold under the brand name PRISTIQ. Despite desvenlafaxine hitting the market relatively recently (2008 in the US) so far the available evidence is suggesting that it is less effective an antidepressant than venlafaxine.

This isn't to say that there isn't any reasons why doctors would rather give their patients SSRIs instead of venlafaxine and desvenlafaxine. For one they both can cause dry mouth, which if chronic and uncontrolled can lead to poor dental health and cavities. Secondly they both pose a risk of causing insomnia and since a common complaint in patients with major depressive disorder (MDD) is difficulty falling and staying asleep this can very easily be seen as a potential issue. Thirdly they can both cause a loss of appetite which can be a problem in adolescents since drugs that suppress appetite have been linked to stunted growth in adolescents. On top of that they also have the following common (>5% of patients get these) side effects (according to Micromedex -- the online database JCU gives me access to):

  • Headaches
  • Blurred vision
  • Dizziness
  • Somnolence (a near-sleep state. People often have a very strong desire for sleep, or they sleep for unusually long periods)
  • Tremors
  • Nervousness
  • Sexual dysfunction, especially in males
  • Weight loss
  • High blood pressure
  • Sweating
  • Unusual dreams
  • Weakness/fatigue
  • Elevated blood triglycerides (desvenlafaxine only)
  • Elevated blood cholesterol (desvenlafaxine only)
  • Nausea (very common on venlafaxine 21-58%)
  • Vomiting (only with desvenlafaxine)

Venlafaxine and desvenlafaxine are also amongst the most "touchy" of antidepressants so to speak, namely if patients forget to take one of their doses odds are it won't be long before they know about it due to withdrawal symptoms. See antidepressants that work by increasing serotonin availability in the synapse cause some adaptive changes in the brain after chronic use and if these antidepressants are suddenly and abruptly stopped they can lead to the emergence of a collection of symptoms commonly referred to as SSRI withdrawal syndrome. Since venlafaxine and desvenlafaxine last a relatively short time in the body (and thus you are under their effects for a shorter time after you take them) compared to most other antidepressants they are particularly prone to causing SSRI withdrawal when doses are missed. Consequently when patients need to, for whatever reason, stop taking venlafaxine it is nearly always a good idea for them to gradually reduce their dosages over a period of weeks instead of abruptly stopping them. The only time a doctor is likely to recommend that a patient abruptly stops their treatment is when the side effects are just unacceptably and life-threateningly severe.

The fact that venlafaxine and desvenlafaxine increase norepinephrine availability in the synapse means that they also may be of benefit in Attention Deficit Hyperactivity Disorder (ADHD) because this is an action they share with the ADHD meds atomoxetine (strattera) and methylphenidate (ritalin, concerta). This may also be of benefit in depression seeing how a common symptom of major depressive disorder is a mental "clouding" and in particular concentration problems.

Aside from major depressive disorder venlafaxine has found use in the following conditions (according to Micromedex):

  • Generalised anxiety disorder (GAD. GAD is a disorder characterised by irrational and disproportionate worry over everyday things; it is FDA approved for this indication) 
  • Panic disorder (an anxiety disorder characterised by recurring and severe panic attacks. It is also FDA approved for this indication) 
  • Social phobia (intense and often disabling fear of social situations. It is FDA approved for this indication) 
  • Attention deficit hyperactivity disorder (ADHD; not FDA approved) 
  • Binging - Eating disorder (not FDA approved) 
  • Bipolar disorder, depressed phase (not FDA approved) 
  • Cerebrovascular accident - Depression (depression resulting from a stroke, not FDA approved) 
  • Depression - Perimenopausal disorder (not FDA approved) 
  • Dysthymia (mild chronic depression. Not FDA approved) 
  • Hot sweats, Breast cancer-related (not FDA approved) 
  • Menopausal flushing (not FDA approved) 
  • Obsessive-compulsive disorder (not FDA approved) 
  • Posttraumatic stress disorder (not FDA approved) 
  • Premenstrual dysphoric disorder (Basically a more severe form of the depressive symptoms associated with PMS; not FDA approved) 
  • Recurrent major depressive episodes; Prophylaxis (trying to prevent further major depressive episodes; not FDA approved) 
  • Tension-type headache; Prophylaxis (trying to prevent further further tension headaches; not FDA approved) 

Whereas aside from MDD desvenlafaxine is used (although not FDA approved) only for treating menopausal flushing according to Micromedex.

The standard adult doses of venlafaxine are 75-375 mg per day (usually 225 mg/day is the max adult dosage but sometimes 375mg is set as the upper limit) with higher doses usually preferred for patients with anxiety disorders. The standard adult dose of desvenlafaxine is around 50 mg a day.

Venlafaxine comes in two forms, immediate release and extended release tablets. They are basically what they sound like; immediate release tablets release the drug ASAP whereas extended release tablets release the drug gradually over a period of hours. Extended release tablets have the clear advantage of only having to be administered (or taken) once a day whereas immediate release tablets are usually required to be taken 2-3 times a day.

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