Neuron Culture

One theory about antidepressants is that they relieve depression by encouraging neurogenesis — the creation of new neurons. Neuroskeptic reviews a study that argues against this idea.

the neurogenesis hypothesis has problems of its own. A new paper claims to add to what seems like a growing list of counter-examples: Ageing abolishes the effects of fluoxetine on neurogenesis.

The researchers, Couillard-Despres et. al. from the University of Regensburg in Germany, found that fluoxetine (Prozac) enhances hippocampal neurogenesis in mice – as expected – but found in addition that this only holds true in young mice. In middle-aged and older mice, there was no such effect. That’s a new finding, and a very important one.

I’ve seen SSRIs work on enough people to believe they DO work. But as the various proposed mechanisms are cast increasingly into doubt, and sober evaluations of their efficacy increasingly show them barely besting placebo, it’s reasonable to wonder how much of their effect is placebo. Update Jan 21 2009: This post from Bad Science does exactly such wondering. Among other things it cites a 2002 JAMA study that showed that the placebo effect had grown significantly in antidepressant clinical trials — suggesting it had perhaps risen along with public confidence in SSRIs. So will it drop if and as public confidence in SSRI efficacy falls? Many, many interesting questions here…

Read the whole post at Neuroskeptic or the abstract at Molecular Psychiatry. (Paper is behind a pay firewall.)

Update: As Neuroskeptic points out in the comments, this study of older mice is only a first study of its kind, and only a small one, and with its own quirks; as with any single study, one can’t consider it definitive. Yet it points out some possible limitations of the database underlying the neurogenesis theory, for if SSRIs work by encouraging neurogenesis but don’t do so in older patients, why do SSRIs relieve depression (to the extent they do) in older patients as well as young? With luck we’ll see more work on this.


Comments

  1. #1 Neuroskeptic
    January 21, 2009

    Thanks for the link! (…only problem is that the “Read the whole post at Neuroskeptic” link is broken. here it is

    To be fair, this was a pretty small study and not without its own quirks but I think the neurogenesis theory is starting to take hits from several directions now.

  2. #2 Dan
    January 31, 2009

    Pharmacologically Enhancing Psychotropic Pharmaceuticals
    In the 1930s, physicians approached the mental illness of depression a bit differently that we do today. While acknowledging a likely cause of depression in one of their patients is often due to some great misfortune, they seemed to focus on what is called a complex. A complex is disturbances of ideas and impulses that are the cause of consistent habitual patterns of thought, feelings, and behavior. An example of this state of mind of one who is depressed is one who experiences an exaggerated or obsessive concern or fear. And the etiology for this mental disorder was often undefined. People react differently to life stressors in their life, so depression cannot be empirically determined.

    In the 1930s, psychotherapy such as cognitive therapy was recommended for treating the depressed patient, and not pharmacological therapy. Also considered for the depressed patient was positive lifestyle changes that would lessen the pain that the depression was causing them. Try and be grateful, they would tell their patient, as well as thankful and appreciative for whatever good may be in their life, and normally the depressed patient would eventually recover.

    Times have changed since then.

    Presently, serotonin-enhancing drugs are the therapeutic regimens for those who are suspect of having a depressed state, or perhaps the patient simply asks for these types of drugs due to their perception that they are depressed. Furthermore, and remarkably, various other mood disorders one may have can be treated with these drugs, typically called SSRIs.

    What is remarkable is that the mood disorders which will be discussed later are subject to debate and have also been brought to the attention to so many others through disease awareness campaigns by the makers of these SSRI drugs. So mental flaws claimed to be relieved by SSRI drugs may not be the case at all.

    With depression, the most severe cognitive and behavioral malfunctions are expressed in what is called a major depressive disorder, which is also called clinical depression or major depression. Symptoms of this type of depression, which is the most concerning to health care providers in particular due to its severity, include decreased or flat affect, decreased interest in activities once enjoyable, self perceptions of worthiness, guilt, regret, helplessness, and hopeless by the sufferer, to name a few of the diagnostic features that may be present with one who has such a major depressive disorder.
    The disease has a vexing insistence on staying with the victim for a lengthy period of time- often continuing to progress symptomatically in severity and discomfort. This disease is very disabling, and cannot be lifted by one’s will, so all health care professionals likely agree that depression is a potentially serious condition with their patients. Suicidal ideation and attempts are associated with major depression.

    These SSRI drugs mentioned earlier are known by some health care providers as third generation anti-depressants. Such drugs, drugs that affect the mind, are called psychotropic medications. SSRIs also include a few drugs in this class that include the addition of a norepinephrine uptake inhibitor added to the SSRI in one capsule, and these drugs are referred to as SNRI medications. The combination of two different drugs has made them the top class of prescriptions for psychological misalignment.
    There are several available SSRIs presently, yet it is believed that only two SNRIs are available, which are Cymbalta and Effexor.

    Some consider these classes of meds, the serotonin enhancers in these medications, have been considered the next generation mood enhancers- after the benzodiazepine hype decades ago, which was followed by what were called trycyclic drugs for depression for some time.

    Furthermore, regarding SNRIs, adding the additional agent of norepinepherine is presumed to increase the effectiveness of SSRIs by some, yet not everyone claims relief from these types of drugs.
    Some Definitions:

    Serotonin is a neurotransmitter thought to be associated with mood. The hypothesis was first suggested in the mid 1960s that this neurotransmitter may play a role in moods and emotions in humans. Yet to this day, the serotonin correlation with such behavioral and mental conditions is only theoretical. In fact, the psychiatrist’s bible, which is known as the DSM, states that the definite etiology of depression remains a mystery and remains unknown with complete certainty. So a chemical imbalance in the brain is not proven to be the cause of mood disorders, it is only suspected as a result of limited scientific evidence. In fact, diagnosing mental diseases such as depression is based on subjective assessment only, as interpreted by the prescriber, so one could question the accuracy of such diagnoses.

    Norepinepherine is a stress hormone, which many believe help those who have such mood disorders as depression. Basically, with the theory that by adding this hormone, the SSRI will be more efficacious for a patient prescribed such a med, as suggested earlier.

    And the depressive state of a patient certainly can be aggravated by another mood disorder at the same time with some patients. Anxiety usually exists with one who has a major depressive disorder. An objective diagnosis of such a mental condition is rather impossible to assess objectively. Therefore any diagnosis made for a mental abnormality lacks complete accuracy and assurance.

    Such illnesses can only be assessed conceptually, so the diagnosis or impression concluded by the patient’s health care provider is dependent on subjective criteria expressed by the suspected patient that is not mentally sound. At times, there have been screening programs that have been used for identifying depressed patients have proven to be largely ineffective.

    A social patient history is uncertain and tricky as well, some have said, yet is obtained often from such patients. There is no objective diagnostic testing for any mental malfunction to validate as to whether or not such a disease is present. A health care provider has to assess as to whether certain non-verbal or vocalized features are present with a patient in order to conclude confidently that one may have in fact some degree or level of depression. To assess a suspected depressed patient is further complicated by the fact that the exact cause of major depression is unknown. Research says that there is a strong genetic component to this illness.

    The diagnosis of depression as well as mood disorders that may exist within patients has increased quite a bit over the past few decades. Some have asked themselves, as well as others- actually how many people are really and actually depressed? What is believed is that if one determined to be cognitively impaired from a mental paradigm, then this may be in fact major depression. If this mental disorder is determined by a health care provider, it is possible that pharmacological therapy may be considered reasonable and necessary, as well as psychotherapy either suggested to be performed with or in place of medicinal therapy.

    Studies show that both therapies working together may be of most benefit for the depressive patient, yet it is not a guaranteed protocol for treatment in this way.

    It has been reported that around 10 percent of the U.S. population will at some point be affected by an episode of what may be a major depressive disorder. This is much greater in number than just a few decades ago. Perhaps media sources are to blame, by suggesting to their viewers that they may in fact be depressed. So the diagnosis and medicinal treatment have remarkably increased in a relatively short period of time in the United States. Of course, the expansion of those claimed and determined to be depressed does not sadden the makers of these drugs used to treat this mental disorder one bit, I’m sure.

    Some have said that so many more people seek treatment now for what they believe is a major depressive disorder they are experiencing, when in fact it may be possibly intense sadness, perhaps, due to a loss of some sort in their lives. There is a difference, and health care providers should have the appropriate tools and knowledge to discriminate between the two states of mental conditions.

    Sadness is not a medical problem. Symptoms associated with an unfavorable mental state need to be excessive and chronic to be considered to have in fact the medical problem of a major depressive disorder, as stated by others.

    In Time magazine’s June 16th 2008 cover story, it was reported that the military personnel in the Iraq war are pounding down SSRIs often. Every time there is a new war, there is a new drug, it seems. Yet the story may illustrate the frequent usage of these types of medications in a variety of different areas for different reasons.

    Some reasons may be valid and appropriate, yet others perhaps may not be reasonable for such medicinal therapy. However, as illustrated in this situation, they appear to be accepted as a treatment option without reservation.

    In regards to those pharmaceutical companies who make and market such psychotropic drugs in the manner that their manufacturers do is largely unknown to others, such as with screenings performed essentially by front groups, and so forth. However, what is known is that the psychiatry specialty, as they often treats and manages depressed patients, is the one specialty that receives the most monetary funding that is paid to them by these certain pharmaceutical companies for ultimately what they hope will be continued and additional support of the psychotropic meds that they currently promote to these doctors.

    Needless to say, the desire and the aspect of the pharmaceutical industry clearly is primarily concerned with encouraging as much use out of their products as possible- with both doctors and patients being the route of that increased use they desperately hope will occur.

    Regardless, SSRIs and SRNIs are the preferred treatment methods if depression or other mood disorders that are suspected and determined by the health care providers who treat such patients. Yet these drugs discussed clearly are not the only treatments, medicinally or otherwise, for depression and other related and suspected mental disease states, moods, or disorders. Patients should be aware of this fact as well as caregivers. And they may not be aware of the options available to them.
    For example, tens of millions of prescriptions are written by health care providers for these types of medications for their patients.

    These drugs are not inexpensive, either, as it is not unusual for a patient to pay greater than one hundred dollars to have their prescription filled for only a month’s worth of these particular drugs.

    Presently, there are about ten different SSRI/SRNI meds available, many of which are now generic, yet essentially, they appear to be similar in regards to their efficacy and adverse events. The newest one, a SNRI called Pristiq, was approved in 2008, and is believed to be launched as a treatment for menopause.
    The first one of these SSRI meds was Prozac, which was available in 1988, and the drug was greatly praised for its ability to transform the lives of those who consumed this medication in the years that followed. Some termed Prozac, ‘the happy pill’.

    In addition, as the years went by and more drugs in this class became available, Prozac was the one of preference for many doctors for children. A favorable book was published specifically regarding this medication soon after it became so popular with others.

    Furthermore, these meds have received upon request of their makers to the FDA to have additional indications besides depression for these types of drugs they produce and market, and the indications they have received are for some really questionable conditions, such as social phobia and premenstrual syndrome.

    Also included with indications that now exist with these types of medications are the quite devastating conditions of what may be mild anxiety and shyness, yet the makers of these drugs consider such patients as having chronic anxiety with severe anxiety disorder, which others have said is rather obsurd.

    And it gets worse with the indications received for these types of drugs, which now include Obsessive-Compulsive Disorder, Panic Disorder, Agoraphobia, Post Traumatic Stress Disorder, Bulimia, and any form of stress disorders in general. I understand they are seeking indications for pain management as well with these SSRI or SRNI pharmaceuticals.

    Likely, they will get the indication for their drugs to treat such creative cognitive states apparently others have in great numbers.

    With some of these indications for these classes of drugs, I question as to whether or not they are actual and treatable disease states or medical problems. Yet with additional indications for particular drugs in these classes of medications, one can be assured that the market for these drugs will continue to grow- as more are prescribed to those patients who are progressively asking for them specifically for relief they anticipate they will receive from taking these drugs.

    What such patients are not aware of is that studies have shown that this class of medications is only effective in roughly half of those who take them. And some of the indications granted to drugs in these classes of medications may be considered disease mongering tacitly performed by the makers and marketers of these drugs to again grow the market share for particular drugs of this type.

    This is combined with drug companies who make these types of meds either forming or creating front groups in order to have more diagnosed with various medical problems that may not exist so their medication can be utilized more.

    And as mentioned earlier, such pharmaceutical companies have been known to either create or support front groups to ultimately encourage who may be normal people to get evaluated for the diseases indicated with these medications. Of course, such tactics implemented by such pharmaceutical companies are deceptive, inappropriate, unreasonable, unnecessary, and potentially if not actually dangerous to others.

    Perhaps of greater concern and danger with these particular psychotropic medications involve the adverse effects associated with these types of drugs, which include suicidal thoughts and actions, violence- including acts of homicide, and aggression- and this is only to name a few. Such events are devastating and have been demonstrated by those who have or are taking these types of drugs. It has been reported that the makers of such drugs are suspected to have known about these toxic and dangerous effects of their drugs and did not share them with the public in a timely and critical manner until forced to do so.
    While most SSRIs and SNRIs are approved for use in adults only, prescribing these meds to children and adolescents has drawn the most attention and debate with others for understandable reasons, which have included those in the medical profession as well as citizen watchdog groups.

    The reasons for this attention are due to the potential off-label use of these meds in this population of children, yet what may be most shocking is the fact that some of the makers of these meds did not release clinical study information about the risks of suicide as well as the other adverse events related to such populations, combined with the true decreased efficacy of SSRIs in general, which is believed to be only less than 10 percent more effective than a placebo.

    Paxil caught the attention of the government regarding this issue of data suppression some time ago, this hiding of such important information- Elliot Spitzer specifically was the catalyst for this awareness, as I recall. Furthermore, that drug is in the spotlight once again years later. Some believe the drug maker knew about possible risk to the youth as early as 1991. Yet did not disclose such danger associated with their drug to the public or the FDA, and this was done with intent.

    And there are very serious questions about the use of SSRIs in children and adolescents regarding the possible damaging effects of these meds on them as they get older- these children and teenagers who are prescribed these drugs. Others are asking if this is really necessary- and are these drugs doing more harm than good for their children.

    For example, do the SSRIs correct or create brain states considered not within normal limits, which in effect would possibly cause harm rather than benefit a patient on such a drug? Are adolescents really depressed, or just experiencing what was once considered normal teenage angst? Do SSRIs have an effect on the brain development and their self identity of such young people? Do adolescents in particular become dangerous or bizarre due to SSRIs interfering with the myelination occurring within their still developing brains?

    No one seems to know the correct answer to such questions, yet the danger associated with the use of SSRIs does in fact exist, as demonstrated by others. It is observed in some who take such drugs, but not all who take these drugs.

    Yet health care providers possibly should be much more aware of these possibilities, possibly, along with the black box warning now on SSRI prescribing information for the youth that has existed since 1994. There are other medications health care providers could prescribe for such patients that have no less benefit for them then the serotonin drugs discussed.

    Finally, if SSRIs or SNRIs are discontinued by a patient rapidly, abruptly, and without medical supervision, withdrawals experienced by many of these patients are believed to be quite brutal that follow soon after this drug is not taken anymore by a former patient. This in itself may be a catalyst for one to consider or attempt suicide, others have suggested. Many are aware and understand that discontinuing these SSRIs and SSNIs leaves the brain in a state of neurochemical instability for some great length of time as the neurons need to recalibrate after existing in a brain over-saturated with serotonin and neuron alteration.

    This occurs to some degree with any psychotropic medication, yet the withdrawals can reach a state of danger for the victim in some classes of meds such as SSRIs and SNRIs, it is believed. And this seems to concern many, yet does not inhibit health care providers for continuing to select such therapy with these drugs for their patients.

    SSRIs and SRNIs have been claimed by doctors as well as patients to be extremely beneficial for the patient’s well -being regarding their apparent mental issues that resolve in time. Yet overall, the factors associated with this class of medications may outweigh any perceived benefit for the patient taking such a drug that can harm themselves and others.
    Before these medications mentioned were developed, doctors praised trycyclics, another class of anti-depressants mentioned earlier, in a similar manner since their advent in the 1950.

    Considering the lack of efficacy that has been demonstrated objectively with these new serotonin specific psychotropics, along with the deadly adverse events with these SSRI and SSNI meds only recently brought to the attention of others, other pharmacological and non- pharmacological treatment options should probably be considered, but that is up to the discretion of the prescriber.

    And the perception of the benefits derived by these types of drugs may be flawed, as there has been no decrease in incidences of suicide or remission of depression since these drugs have been available, many have concluded.

    Yet antidepressants in general have been considered by others to create amotivational syndrome, which is a lack of interest in various activities, as well as creating a state of flat affect of users of antidepressants.

    Furthermore, recent studies have suggested that the supplement, St. John’s Wart, has shown to be as effective as medicine for major depression. Deficiencies in vitamins B12 and Folate have been suggested as a cause for depression as well. One study showed that a small jog performed by a depressed patient offered similar if not greater relief than a SSRI drug.

    It is my hope that such a prescriber rules out possible other etiologies for their patients’ mental conditions before they conclude that such a patient is suffering from true mental illness requiring the medications mentioned earlier, such as asking their patients about life stressors and other medications these patients have taken or are presently taking. Because at times, a doctor can in fact do harm without intent.

    “I use to care, but now I take a pill for that.” —

    Author unknown*

    Dan Abshear

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