Ketamine Metabolite Linked to Rapid Antidepressant Effect

Model of crytalized ketamine molecule

Standard antidepressant therapies typically take two weeks or more to begin to act.

Ketamine is an anesthetic drug recently demonstrated to have a rapid antidepressant effect.

The mechanism for this effect is unknown. 

A recent mouse study of ketamine and metabolites of ketamine show some potentially groundbreaking insight for the treatment of depression.

This study found these significant findings:

• Ketamine like most organic compounds is made of boty an R and an S isomer that are mirror images 
• S ketamine is more potent in blocking NMDA receptors
• Blocking the metabolism of ketamine blocks the antidepressant effect suggesting an active metabolite is responsible for the physiological effect
• A key metabolite of ketamine named hydroxynorketamine appears to be the active agent in the antidepressant effect
• This active agent blocks the AMPA receptor rather than the NMDA receptor

These findings may lead to finding new drugs that can act like hydroxyketamine in producing a rapid antidepressant effect through the AMPA receptor.

The Science Daily link to this study can be found here.

Figure of ketamine is from the Wikipedia Commons File and authored by Ben Mills.

Follow the author on Twitter: @WRY999

Zanos, P., Moaddel, R., Morris, P., Georgiou, P., Fischell, J., Elmer, G., Alkondon, M., Yuan, P., Pribut, H., Singh, N., Dossou, K., Fang, Y., Huang, X., Mayo, C., Wainer, I., Albuquerque, E., Thompson, S., Thomas, C., Zarate Jr, C., & Gould, T. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature DOI: 10.1038/nature17998

Bipolar Disorder Guidelines: NICE Update

Clinicians treating bipolar disorder and patients with a bipolar disorder diagnosis are aided by the availability of expert opinion guidelines.

In the last post, I reviewed a study that found decreased rates of suicidal behavior in bipolar patients treated with antidepressant drugs.

This review prompted me to look for a recent consensus update on assessment and treatment of bipolar. One recent update came from the UK National Institute for Health and Care Excellence or NICE. This guideline is freely available and I will post a link at the end of this blog post.

I will focus on psychopharmacology in my review but the reader is encouraged to take a look at these excellent guidelines for other details.

The recommendations from the guideline for general maintenance treatment of bipolar disorder in adults in specialty care:

• Do not use gabapentin or topiramate
• Antipsychotic drugs
• Lithium therapy
• Valproate therapy
• Lamotrigine therapy

Recommendations for treatment of mania in specialty care:

• If manic bipolar patient is taking antidepressant consider stopping it
• Electroconvulsive therapy is an intervention that should be considered in those with severe and prolonged mania
• The further treatment of mania follows the maintenance list as above: antipsychotics (haldol, olanzapine, quetiapine or risperidon), lithium, valproate and lamotrigine

Recommendations for treatment of bipolar depression in specialty care:

• Make sure full psychological services are used as a base in treatment
• Add fluoxetine plus olanzapine or quetiapine on it's own
• If no response to initial antidepressant treatment consider a trial with lamotrigine

As you can see from these depression guidelines, the use of standard antidepressants in bipolar depression is not recommended. The exception to this is the use of fluoxetine (covered with olanzapine).

The full pdf guideline from NICE is 59 pages and I would encourage interested reader to go to the website and download the full guide. You can do that by clicking HERE .

Photo of baseball player Albert Pujols in spring training is from the author's files.

Follow the author on Twitter @WRY999

Kendall T, Morriss R, Mayo-Wilson E, Marcus E, & Guideline Development Group of the National Institute for Health and Care Excellence (2014). Assessment and management of bipolar disorder: summary of updated NICE guidance. BMJ (Clinical research ed.), 349 PMID: 25258392

Antidepressants Linked to Lower Suicide in Bipolar Disorder

Bipolar disorder is known to have a marked increased lifetime risk for suicide.

There has been limited study of the effect of specific interventions in the risk of suicidal behavior and completed suicide.

A recent study has added to our understanding of this topic using data from the Collaborative Depression Study or CDS.

The CDS is a large longitudinal stud funded by the NIMH that enrolled a large sample of subjects with bipolar I disorder, bipolar II disorder and unipolar depression.

Subject were followed intensely after a research diagnostic assessment every six months. Follow up interviews including information about antidepressant treatment, mood state, suicidal ideation and suicidal behaviors.  

This was a significantly ill cohort. Twenty-four subjects committed suicide during the five year period of follow up.

Subjects receiving drug treatment with bipolar disorder had statistically lower suicidal behavior (but not in the unipolar group). The estimated level of reduction of suicidal behavior by diagnosis group was:

• Bipolar I disorder: 54% reduction (95% confidence interval 31% to 69
• %)
• Bipolar II disorder: 35% reduction (95% confidence interval 1% to 57%)
• Unipolar disorder: 12% reduction (95% confidence interval 36% reduction to 22% increase)

The authors note some clinicians are less likely to use antidepressants in bipolar depression due to concern about inducing mania or more rapid cycling. They note their study supports a link between antidepressant use and reduced suicidality in bipolar disorder.

Many clinicians recommend chronic use of mood stabilizers with intermittent antidepressant use in bipolar disorder during depressive episode only. This may reduce potential risk for the use of antidepressants in bipolar disorder. The authors note some previous studies support a specific role for the mood stabilizing drug lithium to reduce suicide risk in bipolar disorder.

The psychopharmacologic treatment of bipolar disorder is a complicated process that needs to be customized to individual patient comorbidity, tolerance, medical comorbidity and past treatment response. Patients with bipolar disorder are best managed in a setting of expert medical care, family support and longitudinal monitoring. Patients are best served when they make decisions about drug treatment options in this type of setting.

The CDS cohort study was done prior to the evolution of the use of the novel antidepressant drug treatment lamotrigine in bipolar disorder.  Lamotrigine is an antiepileptic drug that is increasing used in bipolar disorder and is an FDA approved drug for maintenance therapy. The FDA also has approved aripiprazole and the combination of olanzapine plus fluoxetine for the treatment of depression in bipolar disorder.

Readers with more interest in the above study can access the free full-text manuscript by clicking on the PMID link in the citation below.

Slide showing symptoms in the manic phase of bipolar disorder is an original slide from the author's files. 

Follow the author on Twitter: @WRY999

Leon AC, Fiedorowicz JG, Solomon DA, Li C, Coryell WH, Endicott J, Fawcett J, & Keller MB (2014). Risk of suicidal behavior with antidepressants in bipolar and unipolar disorders. The Journal of clinical psychiatry, 75 (7), 720-7 PMID: 25093469

Add Exercise or an Antidepressant for Depression?

Although the psychological benefits of exercise are well recognized, the role of exercise in the treatment of psychological disorders is less clear.  Randomized control trials are limited and so clinicians are left without much data to advise patients on the proper role of exercise in a comprehensive treatment program.

Madukar Trivedi and colleagues recently published a study of exercise therapy in a group of individuals with major depressive who had not reached complete remission of depression despite treatment with a first-line pharmacological intervention using a selective serotonin reuptake inhibitors.

Subjects were randomized into a relatively high intensity aerobic program (16 kilocalories per kilogram per week) or a relatively low intensity program (4 kilocalories per kilogram per week) for 12 weeks through a program conducted at the nationally known The Cooper Institute in Dallas, Texas.

Here are the key outcome findings from the study:

• Both exercise groups showed improvement in depression scores over the trial
• There was a trend for the high-intensity group to have more improvement in depression
• High-intensity exercise appeared to produce higher remission rates in men
• High-intensity exercise appeared to produce higher remission rates in women without a family history of mental illness

Of note, the high-intensity group demonstrated a lower adherence rate than the low intensity group.

The authors note the size of the effect for adding exercise to single antidepressant drug appears similar in magnitude to that of offering a second antidepressant drug.  Second drugs commonly in use for the treatment of depression include antidepressants such as bupropion (Wellbutrin) or the newer atypical antidepressant drugs such as aripiprazole (Abilify).

For a 70 kilogram individual, 16 kilocalories per week of added exercise would be approximately 12 miles of walking per week.  The high intensity regimen in this study would approximate general exercise recommendations for physical health, (30 minutes per day of moderate exercise most days of the week).  So it seems reasonable to recommend this level of exercise for men with depression.  Lower levels of exercise may help some women with depression.  When higher levels of exercise prove difficult to attain, lower levels are better than none.

A key issue with exercise in depression is motivation and compliance.  Some individuals with severe depression face big hurdle in getting active.  For these individuals, use of a personal trainer or group exercise may provide the structure needed for higher exercise adherence.

Photo of Juno Beach Florida sun rise through filter from the author's collection.

Trivedi, M., Greer, T., Church, T., Carmody, T., Grannemann, B., Galper, D., Dunn, A., Earnest, C., Sunderajan, P., Henley, S., & Blair, S. (2011). Exercise as an Augmentation Treatment for Nonremitted Major Depressive Disorder The Journal of Clinical Psychiatry, 72 (05), 677-684 DOI: 10.4088/JCP.10m06743

Persistent Insomnia in Depression Responding to Antidepressants

Sleep problems commonly occur as part of a problem with mood disorders including depression.  Changes in sleep duration (insomnia or hypersomnia) are one of the criteria for the diagnosis of depression in the Diagnostic and Statistical Manual of Mental Disorders.  Although not absolutely required for the diagnosis, insomnia is a complaint in the the majority of subjects presenting for clinical trials in the treatment of depression.

The selective serotonin reuptake inhibitors (SSRIs) like fluoxetine (Prozac) have become one recommended strategy in the treatment of depression.  However, unlike other antidepressants, the SSRIs commonly do not have a sedative effect.  It is possible that when someone gets an antidepressant response to an SSRI, sleep disturbance also resolves.  However, in clinical practice, SSRIs commonly produce a partial remission of depression but fail to improve problems with insomnia.  So what does this type of response mean and what can be done for those with improvement in depression but residual sleep complaints.

Gulec and his research team from Turkey have some recent research on this topic posted online at the Journal of Affective Disorders.  They followed a group of adults with major depression treated naturalistically--i.e. treating psychiatrists could select the antidepressant drug although algorithms for dose and sequencing were followed.  Subjects were followed with research rating scales for a period of 52 weeks.  Some subjects responded and remained well.  Some subjects responded but had a recurrence of depression in the one year follow up period.  The key findings from the study:

• Persistent insomnia rates were high in those who had a recurrence of depression
• The recurrent groups showed the following rates of insomnia prior to recurrence: onset insomnia (difficult falling asleep) 58%, terminal insomnia (early morning awakening) 33% and middle of the night insomnia 8%.
• Only 26% of those subjects whose depression remained remitted throughout the 52 week follow up period endorsed any persistent insomnia complaint.

The authors note their study is consistent with other studies supporting insomnia as a marker for poor prognosis is depression.  Reynolds and colleagues found that subjects who remitted with an antidepressant drug (including improvement in subjective sleep) had had high rate of continued remission of depression with psychotherapy alone.  Those whose insomnia persisted were less likely to benefit from psychotherapy alone as a long term maintenance strategy.


So an important question is what to do when insomnia persists despite a general antidepressant response.  It appears this is a problem that is too important to ignore and hope it goes away.  Options appear to include adding a sedative antidepressant, switching to another antidepressant, adding a sedative hypnotic treatment for insomnia or adding cognitive behavioral treatment for insomnia.  Here there is little data to support one of these choices over the others.  A research study examining these types of options is needed to aid patients and their clinicians in the management of this common clinical situation.

Photo of Moth Hovering Over Flower Courtesy of Tim Yates

Gulec M, Selvi Y, Boysan M, Aydin A, Besiroglu L, & Agargun MY (2011). Ongoing or re-emerging subjective insomnia symptoms after full/partial remission or recovery of major depressive disorder mainly with the selective serotonin reuptake inhibitors and risk of relapse or recurrence: A 52-week follow-up study. Journal of affective disorders PMID: 21684011

Reynolds CF 3rd, Frank E, Houck PR, Mazumdar S, Dew MA, Cornes C, Buysse DJ, Begley A, & Kupfer DJ (1997). Which elderly patients with remitted depression remain well with continued interpersonal psychotherapy after discontinuation of antidepressant medication? The American journal of psychiatry, 154 (7), 958-62 PMID: 9210746

What Do Antidepressants Do in Healthy Brains?

The easiest answer to the title question is “cause side effects”.  A more important theoretical and practical aspect of this question is: Do antidepressants have a general property experienced by everyone or are their effects only seen in the presence of depression?  Antidepressant drugs have research support for a variety of non-depression indications including: chronic pain, fibromyalgia, migraine prophylaxis, irritable bowel syndrome and pathological crying and laughing.  So there are quite a few non-depressed individuals taking antidepressants making the title question is important.

Serretti and colleagues from Italy recently summarized published research on this issue.  Additionally, they performed some meta-analyses when appropriate to look for effects across studies.   They note the review suggests that antidepressant effects in the normal or healthy brain may be different under acute than under chronic treatment.   They authors conclude there is some evidence that antidepressants increase social behaviors and reduce negative effects in the healthy brain.  They structure their review based on antidepressant class and I will note the highlights of their paper by class.

Studies of Selective Serotonin Reuptake Inhibitors (SSRIs)

The selective serotonin reuptake inhibitors (i.e fluoxetine (Prozac), sertraline (Zoloft), escitalopram (Lexapro)) are the most commonly prescribed class of antidepressants.   SSRIs do not reduce sub-threshold symptoms of anxiety or depression as measured by the State-Trait Anxiety Inventory (STAI) and the Beck Depression Inventory (BDI).  They do tend to reduce negative affect as measured by the Positive and Negative Affect scale.  In addition, SSRIs do reduce the amount time spent in REM sleep in healthy individuals.  The clinical implication of this is unknown. Escitalopram appears to decrease activation in several fMRI tasks with some evidence for decreased activation of the amygdala compared to baseline activation.

Studies of Norepinephrine Reuptake Inhibitors (NRIs)

This class of drug is represented by reboxetine, an antidepressant not found in the United States.  The drug atomoxetine (Strattera) used for attention deficit hyperactivity disorder (ADHD) is sometimes assigned to this class of compound.  A single dose of reboxetine appears to influence social behavior by increasing cooperativeness in communication, reducing focus on self and reduced anxiety ratings.  It also appears to enhance recognition of positive environmental stimuli such as processing happy facial expressions and positive words.  Some of these effects persist over at least one or two weeks.  Brain imaging studies show reduced amygdala responses to fearful faces.

Studies of Serotonin and Norepinephrine Reuptake Inhibitors (SSNRIs)

This class of agents includes the compounds venlafaxine (Effexor), desvenlafaxine (Pristiq) and duloxetine (Cymbalta).   There are many fewer studies involving these agents as researchers tend to often one to focus a single neurotransmitter.   A single dose study of duloxetine demonstrated showed enhanced recognition of both happy and sad faces.  Early responses to these compounds tend to reflect transient side effects rather than a specific brain response in healthy individuals. 

Other agents: Noradrenergic and specific serotenergic antidepressants (NaSSAs), tricyclic antidepressants, monoamine oxidase inhibitors

This miscellaneous class would include mirtazapine (Remeron), amitriptyline (Elavil), and phenelzine (Parnate).  Mirtazapine appears to have some sedative side effects in healthy individuals and along with amitriptyline (and other tricyclics) have the potential to impair psychomotor performance including driving performance.  Tricyclic antidepressants also (like SSRIs) share the ability to reduce REM sleep duration in healthy individuals.

The authors conclude that this review tends to confirm that the human response to antidepressants is similar to the response in rats.  Early exposure to antidepressants tends to increase anxiety but over time anxiety behaviors tend to decrease to below baseline.  Early anti-depressant exposure reduces socializing behaviors in rats but increases them in the long term.   There are very few human studies that have been carried out for more than a week or two.  This means the long-term effect of exposure to antidepressants agents is unknown.


The brain imaging data suggest that antidepressants influence emotional experience and processing in healthy individuals.  There is a variety of individual variation in emotional experience and processing, but the antidepressants appear to move healthy individuals along this domain.

One interesting aspect of this issue is that we know very little about the comparison of side effect patterns in non-depressed individuals.  Do healthy controls experience the same type of side effects to the same degree as depressed individuals?  We have a wealth of data comparing side effects of antidepressants compared to control within depressed populations.  But the volume of data comparing side effects between depressed individuals and non-depressed is small.

Molecular model of the antidepressant escitalopram (Lexapro) courtesy of Creative Commons author Ben Mills.

Serretti A, Calati R, Goracci A, Di Simplicio M, Castrogiovanni P, & De Ronchi D (2010). Antidepressants in healthy subjects: what are the psychotropic/psychological effects? European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 20 (7), 433-53 PMID: 20079613

Drug Development for Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a common and chronic gastrointestinal disorder.  Symptoms include abdominal pain and cramping accompanied by diarrhea and/or constipation.  Estimated to effect 10 to 15% of the population, current drug treatment modalities are fail to relieve symptoms in many patients.  There is considerable interest in novel drugs that might more effectively control symptoms while producing limited side effects. 

A recent review of treatments for irritable bowel syndrome has been authored by Chang and Talley from the Mayo Clinic.  Dr. Chang works in a program identified as Enteric NeuroScience.  This designation highlights the importance of neuroscience issues in IBS.  Here are my notes from the review:

FDA Approved Drugs in the U.S.
Alosetron (Lotronex)--nerve receptor agonist initially approved for women with IBS and severe diarrhea and then removed from market due to risk of constipation, bowel obstruction and ischemic colitis.  Now re-approved but only by prescription from a limited number of physicians participating in monitoring program.
Lubiprostone (Amitiza)--chloride channel activator approved only in women with IBS accompanied by constipation

Nonapproved Drugs
Anticholinergic (antispasmodic)
    Scopoloamine also known as hyoscine is an alkaloid drug that has muscarinic antogist effects.  Effective in reducing cramping in some IBS patients.  May cause dry mouth and blurred vision especially at higher doses.
    Peppermint oil: a natural product that appears to have some scientific support for reducing cramping in IBS. 
Antidepressants
Tricyclic antidepressants: older antidepressants such as imipramine and doxepin reduce IBS symptoms in some individuals.  Effect may be due to anticholinergic effect seen with these older antidepressants.
Selective serotonin re-uptake inhibitors: new selective serotonin re-uptake inhibitors help some with IBS, but also can worsen diarrhea and cramping.
Serotonin norepinephrine re-uptake inhibitors--combine re-uptake blocking of both the serotonin and norepinephrine.  Limited study of these agents in IBS but may be promising as they appear to reduce pain in other clinical conditions.  Duloxetine (Cymbalta) clinical trial results pending

Drug development targets in IBS
Treatment of visceral hypersensitivity
    Kappa-opioid receptor agonists-k-opioid receptor stimulus reduces pain from the gut while not producing constipation characteristic of other opioid
    Endocannabinoids- cannabinoids receptors CB1 and CB2 potential targets as activation may reduce pain and hypermotility
    Transient receptor potential vanilloid type 1 (TRPV1)-a receptor that is located throughout nervous system and mediates sensation and pain
    Beta 3 adrenoreceptor agonists-activation inhibits cholinergic GI contractions and increases release of somatostation.  Potentially helpful for inhibiting diarrhea
    Neurokinin antagonists-Neurokinin 1 receptor antagonists reduce IBS subjects emotional response to rectosigmoid distention
Centrally acting agents
    Dextofisopam-benzodiazepine receptor binding agent that modulates autonomic function
Cholecystokinin (CCK) antagonists 
   CCK1 antagonism stimulates GI motility and may be helpful in treating IBS associated with constipation
Inflammatory drug targets
    Protease-activated receptors-Mast cells release serine proteases that stimulate GI receptors and may play role in visceral hypersensitivty and inflammatory bowel diseases and IBS

A review of clinical trials for IBS at ClinicalTrials.gov shows the following:
Completed trials: duloxetine, mosapride citrate, dextofisopam, crofelemer, itopride HCL, renzapride, asimadoline, alosetron, BMS-562086, mesalazine, St. Johns wort, talnetant
Recruiting: Saccharomyces boulardii, JNJ-27018966, Probaclac, Probiotic

Model of the chemical scopolamine shared under auspices of  Creative Commons Attribution-Share Alike 3.0 Unported by author Giorgiogp2

Chang JY, & Talley NJ (2010). Current and emerging therapies in irritable bowel syndrome: from pathophysiology to treatment. Trends in pharmacological sciences, 31 (7), 326-34 PMID: 20554042

Seeking Depression Information on the Internet

The internet has grown as a source of health information for both clinicians and their patients.  Patients with mental disorders may be particularly drawn to using the internet for information due to the stigma associated with these disorders.  This makes it important for health educators to understand the demographic pattern of searches for health information including depression and other mental disorders.  A recent research study of those seeking information about depression provides some insight into the volume and pattern of web searches for "depression".  Fu et al conducted an interesting study that examined the number and pattern of internet searches for depression.  The authors used the following design in their study:

• Query for all AOL users web searches between March and May 2006
• Keyword depression with exclusion of obvious confounders, i.e. "great depression"
• Limited to U.S. AOL users
• Review of database of 21 million web queries.

The key results from their study included:

• 3 of every 1000 internet searches sought depression-related information
• 1.16 million search for "depression" estimated per month in the U.S.
• The most common search areas related to depression were 1. general information 28%, 2. identification/managment 18%, 3. pharmaceutical company depression website 11%, 4. depression-related psychiatric comorbidities, i.e. anxiety disorder or bipolar disorder 7%, 5. female and pregnancy-related depression 5%, 6. teen depression 5%, 7. suicide 0.6%.

This study probably underestimates the volume of internet searches related to depression as some individual likely type in the name of a depression drug or other more specific information in their query.

The authors note the volume of public searches for depression should stimulate high-quality education for the disorder.  Health educators with high-quality, evidence-based information should also work to keep their information at the top of search engine queries.  There is a significant amount of misinformation about depression and mental disorders on the internet.  There needs to be an effort to make sure individuals searching "depression" get to sites that provide them the information they need to help them make good decisions about their symptoms and disorders.

Here are some of the web sites that I feel provide high-quality evidence-based information for the general public:

National Institute of Mental Health
Mayo Clinic
WebMD
Google Health
Drugs.com
National Association of Cognitive-Behavioral Therapists

If you have personal experience with sites that you would like to recommend, feel free to post your recommendations in the comments section.

Pricky Pear from Enchanted Rock State Natural Area in Texas courtesy of Yates Photography.

Fu KW, Wong PW, & Yip PS (2010). What do internet users seek to know about depression from web searches? A descriptive study of 21 million web queries. The Journal of clinical psychiatry, 71 (9), 1246-7 PMID: 20923627