Withdrawal

There are many reasons that one might chose to withdraw from a psychiatric medication, ranging from health concerns to drug ineffectiveness.  Such a decision is complicated, can occur with or without the introduction of another treatment, and is highly personal.  The goal of this post is not to discuss the reasons for choosing to withdrawal but rather to discuss the process of successful withdrawal.

The process of withdrawing from a psych drug is not to be taken lightly.  Some people who have been through it say that it is more difficult by far than withdrawal from many legal and illegal drugs, including alcohol, cannabis, and tobacco.  Some people compare withdrawing from psych drugs to withdrawal from cocaine or meth which are both psychoactive drugs.  The difficulty in the process is further complicated by the lack of social support for, resources for, and understanding of psych drug withdrawal.  Most of the support and information that exists is anecdotal and found in the experiences of consumers who have experienced withdrawal.

Withdrawal can include anxiety, depersonalization, brain flashes, seizures, psychosis, pain, fatigue, mania, depression, and drug sensitivities, some of which can be worse that anything previously experienced.  Sometimes withdrawal is precipitated by health problems which only makes the experience more difficult.  For example, people who abruptly withdraw from Lithium due to kidney failure are at greatly increased risk of mania.  Furthermore, the negative withdrawal experiences can go on literally for years if a person experiences protracted withdrawal.  Some people think they have recovered, only to experience withdrawal-like issues ten years after they chose to abstain.

The previous paragraphs are meant to scare and (ironically) to comfort.  If you are thinking of withdrawing, please take care and beware of what you might confront.  If you are having an agonizing withdrawal, please know that you are not alone.  There are people who have lived through it and who can support you.  On the other hand, some people are able to easily withdraw, and they are to be envied.

Knowing all this, let us proceed with our eyes wide open to discuss a single drug: Zyprexa.  I choose this one due to my personal experience with it.  Again, I will not discuss my reasons for choosing to withdraw, nor will I say that other people must make the same choice.  It is often said that the higher the starting dose and the longer one took the drug, the harder the withdrawal may be.

A reasonable approach to withdrawal from Zyprexa is as follows:

1. Reduce the dosage slowly over many months.
2. Hold each dose for a week to a month before further reductions in dose (rule of thumb: reduce dose by about 10% of starting dose, for 30mg starting dose, reduce by 2.5-3mg per step).
3. The last few reductions are often the hardest, e.g. 5 mg to 2.5mg to 0mg.
4. If necessary, use a compound pharmacist to make specialized doses.
5. Zyprexa has a 1-2 day half-life depending on ones metabolism, making a difficult proposition out of dose averaging by alternating doses.  For a four day example, one might take 2.5mg, 0mg, 2.5mg, 0mg, to obtain an average dose of 1.75mg.  However, the drug has to remain in the body long enough for the doses to average, and for some people the Zyprexa half-life might be too short.

It should be noted that some people may need a long slow tail to the reductions before getting completely off.  Some people advise to only make reductions after a time period in which all the withdrawal symptoms have been absent for 2 weeks.  This can make for long hold times between reductions, and is easier to do if the withdrawal symptoms are physical or otherwise very obvious.

Things to know about Zyprexa withdrawal:

1. Target is 6-10 months abstinence.
2. Withdrawal can include: nausea, insomnia, anxiety, lack of self-confidence, paranoia, psychosis, weight loss, appetite changes, neuroleptic malignant syndrome, tardive dyskinesia (TD), tardive akathisia (TA), etc.
3. Reinstating, or increasing the dose to a previous level, can provide relief from withdrawal symptoms (indeed, the definition of a withdrawal symptom is one that almost always disappears upon reinstatement and that usually slowly disappears without reinstatement).
4. If one is switching to a new medication, drug interactions might also cause temporary side-effects.
5. Although some people find that they cannot withdrawal completely, there are options such as specialized dosing from a compound pharmacist that can ease withdrawal symptoms at the tail of the withdrawal

(The caveat, for antipsychotics, is that TD and TA can be permanent--existing after successful withdrawal--or transitory, but we have no way of predicting this.  The mechanisms involved in making TD and TA permanent are not known.)

While some of the withdrawal symptoms can feel like illness, it is important to recognize them as drug-related.  This recognition usually provides quick path to relief (reinstatement) and hope for decreased symptoms over time.  It may be tempting to try treating the withdrawal symptoms with yet another antipsychotic.  This may or may not work, while true withdrawal symptoms can usually be fixed by reinstating the original drug.  (The caveat is that it is possible for a withdrawal symptom to be resistant to reinstatement, but this seems to be rare.)  In my experience, an attempt to treat a Zyprexa withdrawal psychosis with Abilify failed, and the symptoms only responded to the reinstatement of Zyprexa.  On the other hand, some people have a much easier withdrawal if they are switching medications.  Indeed, switching medications can be a successful way to withdrawal, for example some people progressively switch from short-half-life benzodiazepine (benzo) to longer-half-life benzos before withdrawing completely.

There should be absolutely no shame in reinstating.  It is not failure.  It also does not preclude a later successful withdrawal.  Sometimes people have their hearts so set on being free of a drug that they forget to consider all their options.  Since reinstatement can reduce withdrawal symptoms, it can mitigate agony.  If one is withdrawing due to health reasons, the decision to reinstate must be carefully considered and the potential harms weighed.

There is also no shame in using another drug as a crutch to get through the hard parts.  For example, a person might take Benadryl or even a benzodiazepine to help ease insomnia.  While one should consider the risks of becoming dependent on yet another drug, short-term usage of even a highly-addictive benzo can be less risky than courting sleep-deprivation psychosis.

Of course, if you are one of those unlucky people who have multiple drug sensitivity, an extremely sensitive to all drugs, adding even a safe-seeming additional drug at low dose may not be wise.  Such a sensitivity could be transitory and limited to the withdrawal process or could be permanent.  Indeed, some people find that their withdrawal symptoms are better if they do not even use supplements (vitamins, minerals, etc.).  So, if you find your withdrawal experience worsening or becoming increasingly chaotic, you might look into multiple drug sensitivity and even supplement sensitivity as an explanation.

If only I had known all this before I first tried to withdraw from Zyprexa.
After many failed withdrawals (always followed by reinstatement), the keys to my successful withdrawal from Zyprexa were:

1. the insight of my psychiatrist who insisted that I taper slowly
2. the recognition that my reinstatement threshold was psychosis and that I could tough out the insomnia, the anxiety, the crashes in self-esteem, and the arbitrary suspicious thoughts that came and went for the first few months of abstinence.

I can happily say that I have passed the 6-month mark and believe that I have passed the dangerous portion of withdrawal.


It should be clear that while withdrawal from psychiatric drugs can be quite difficult for some people, there are also people who come through the process with little trouble.  There is little science to guide the process, and a person cannot know their likely situation before experiencing it.  Due to the degree of problems that can arise, many people who have experience with this process suggest proceeding slowly.  Slow can mean different things to different people, so it is important for each person to stay within their comfort level.  It is also important to research the particular drug from which you are withdrawing, in order to discover how slow other people take it, what the likely problems, and what other people's experiences are.  The resource, below, Coming Off Psychiatric Drugs is a basic reference that discusses many different drugs.


Resources:

Coming Off Psychiatric Drugs 

Beyond Meds

Long Silence

Please forgive the long silence on my part.  I have been busy this summer with moving around North America, taking a long vacation, and preparing myself to begin my new job.

I hope to resume my discussion of the HPA axis soon.  Until then, take care.

The HPA Axis and Circadian Rhythm in Bipolar

The relationship between bipolar and the circadian rhythm, although not well understood, is thoroughly discussed.  Many popular books on bipolar recommend regimented schedules in the hopes that having such a schedule might help control the sleep disturbances that sometimes come with bipolar.  In this post, we first continue the discussion of bipolar and the circadian rhythm.  Second, we discuss the hypothesis that HPA axis disregulation may mediate sleep disregulation in bipolar.  This last is a hypothesis, because it is speculative.

On the topic of mood disorders and the circadian rhythm, there is a review article:

C.A. McClung, Circadian Genes, Rhythms and the Biology of Mood Disorders. Pharmacol Ther. 114(2): 222–232, 2007.

Disruptions in biological rhythms are known to be strongly associated with mood disorders. .... Thus, it has long been hypothesized that abnormalities in the molecular clock underlie he development of these disorders.  In addition, nearly all of the successful treatments for mood disorders seem to affect circadian rhythms, and it appears that the shifts, resetting and stabilization of these rhythms produced by these treatments are important for therapeutic efficacy.  Though these associations have been known for many years, we are only now starting to understand the biology that underlies this connection.

That article is not specific to bipolar, and covers all the mood disorders.  There are plenty of articles that are more specific to bipolar, including studies of the genetics such as

McCarthy MJ, Nievergelt CM, Kelsoe JR, Welsh DK.  A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response.  PLoS One. 2012;7(2):e32091. doi: 10.1371/journal.pone.0032091. Epub 2012.

This study, using a meta-analysis approach, concluded that the core circadian clock genes that regulate the circadian rhythm are associated both with bipolar and with lithium drug response.  This is an important discovery because it provides a molecular basis for the association between sleep disturbances and bipolar.

An interpersonal therapy technique also deserves a nod.

E Frank, H A Swartz, D J Kupfer.  Interpersonal and social rhythm therapy: managing the chaos of bipolar disorder. Biological Psychiatry. 48(6):593–604, 2000.

Interpersonal and social rhythm therapy is an individual psychotherapy designed specifically for the treatment for bipolar disorder. Interpersonal and social rhythm therapy grew from a chronobiological model of bipolar disorder postulating that individuals with bipolar disorder have a genetic predisposition to circadian rhythm and sleep–wake cycle abnormalities that may be responsible, in part, for the symptomatic manifestations of the illness.

All of the above is well discussed, if not completely understood.  What is less discussed is the possibility that the HPA axis may mediate disturbances in the sleep cycle.  In support of forming that hypothesis, there is plenty of evidence that the circadian clock interacts with the HPA axis:

N. Nader, G. P. Chrousos, T. Kino.  Interactions of the circadian CLOCK system and the HPA axis.  Trends in Endocrinology and Metabolism, 21(5):277–286, 2010.

Organisms have developed concurrent behavioral and physiological adaptations to the strong influence of day/night cycles, as well as to unforeseen, random stress stimuli. These circadian and stress-related responses are achieved by two highly conserved and interrelated regulatory networks, the circadian CLOCK and stress systems, which respectively consist of oscillating molecular pacemakers, the Clock/Bmal1 transcription factors, and the hypothalamic–pituitary–adrenal (HPA) axis and its end-effector, the glucocorticoid receptor. These systems communicate with one another at different signaling levels and dysregulation of either system can lead to development of pathologic conditions.

When discussing other sleep conditions, it has been discovered that the HPA axis can play a role:

T. M. Buckley and A. F. Schatzberg. On the Interactions of the Hypothalamic-Pituitary-Adrenal (HPA) Axis and Sleep: Normal HPA Axis Activity and Circadian Rhythm, Exemplary Sleep Disorders.  The Journal of Clinical Endocrinology & Metabolism. 90(5):3106-3114. 2005. 

The hypothalamic-pituitary-adrenal (HPA) axis plays important roles in maintaining alertness and modulating sleep. Dysfunction of this axis at any level (CRH receptor, glucocorticoid receptor, or mineralocorticoid receptor) can disrupt sleep.

Following this discussion, I would put forward the following hypothesis: disruption in the HPA axis may mediate the development of sleep disturbances in bipolar.  Since we know that bipolar is associated with circadian rhythm disruptions and with HPA axis disregulation, it is reasonable to speculate that the two may have something to do with each other.

The HPA Axis in Bipolar

In the last post, I threw around the term HPA axis without describing what it is.  I will try to rectify that here.  The HPA axis, more correctly called by its full name the hypothalamic-pituitary-adrenal axis, is a part of the  neuroendocrine system.  The HPA Axis is largely involved in responses to stress---sometimes termed the 'flight or flight' response.  Stress is the input to the system and can come in the form of either physiological or psychological demands.  In either event, these stresses are input to the HPA axis through the neurons that connect to it, including those involved in mood regulation.

There is a nice review of the HPA axis for bipolar

Duffy A et al. Biological indicators of illness risk in offspring of bipolar parents: targeting the hypothalamic-pituitary-adrenal axis and immune system. Early Interv Psychiatry. 6(2):128-37.  2012.

How does the HPA axis work?  There is a nice picture of this process at Wikipedia.  What we know at the moment says that there are three major organs (in italics) involved in signalling cascade and feedback loop whereby the system self-regulates.  The signal cascade originates in the neurons connected to the paraventricular nucleus in the  hypothalamus which in turn produces vasopressin and corticotropin-releasing hormone (CRH).  The vasopressin and CRH work together to cause the pituitary gland to produce adrenocorticotropic hormone (ACTH).  In response to ACTH, the adrenal cortex produces glucocorticoid hormones (mainly cortisol in humans).  These glucocorticoid hormones in sufficient quantity suppress the activity of the hypothalamus and the pituitary gland which generate less CRH and ACTH.  The glucocorticoid hormones by suppression work to extinguish the stress-response.  It is important to note that cortisol has many functions throughout the body (including functions for the immune system), and most tissues have glucocorticoid receptors.

The previous paragraph is fairly detailed.  Why should we go through all this?  There are various times at which the HPA axis can be disregulated.  Specifically, we are interested in the form of disregulation called hyperactivity which is characterized by inhibited response to CRH and increased levels of cortisol in the saliva and blood.  We know that Cushing's syndrome is a disease where hyperactivity of the HPA axis can result in euphoria or even psychosis.  Additionally, many studies show strong evidence of a link between HPA axis disregulation and bipolar.  For example

Watson S et al. Hypothalamic-pituitary-adrenal axis function in patients with bipolar disorder. Br J Psychiatry.  184:496-502. 2004.

which shows a p-value of 0.001 for the presence of increased cortisol in the saliva of individuals with bipolar.  Just to remind everyone, the lower the p-value the likely that the result is real, and values below 0.05 are typically considered strong.  The p-value is the probability of the ranked cortisol levels in the saliva of the two groups (non-bipolar, and bipolar) under a random model of ranked cortisol levels.  The main point is that there are many papers such as the one cited here, and the result of statistically elevated cortisol levels in people with bipolar is a robust finding regardless of whether the people have active or remitted bipolar.

There are similar findings of increase cortisol levels in people with depression.

Daban et al. Hypothalamic-pituitary-adrenal axis and bipolar disorder.  Psychiatr Clin North Am. Jun;28(2):469-80. 2005.

Similarly depression can remit, but the HPA axis function might not return to normal.  Indeed, for people in remission, if the HPA axis function improves, and then a return to hyperactivity can predict the return of depression.  This relationship causes one to wonder if HPA axis hyperactivity should be taken into account when diagnosing mental illnesses.

Duffy et al. suggest that the HPA hyperactivity is due to the over production of CRH which results in a failure of the suppressing effect of cortisol.  They say that successful treatment with fluoxetine, amitriptyline, desipramine or electroconvulsive treatment returns CRH levels to normal.  They also speculate that Lithium is effecting one of these pathways.  Notice in this paragraph all the tentative words such as 'suggest' and 'speculate'.  These words indicate that much of this is hypothetical and has not been tested.  However, this is the opinion of experts formed from the most recent available data.

Is the relationship between bipolar and the HPA axis overstated?  The relationship between the HPA axis and bipolar are not fully explained, yet.  We do not know if there is a causality to the link, or in what direction it might go.  We have some strong links between cortisol and bipolar, but we have yet to have solid data on the potential links between bipolar and the other hormones in the HPA axis.  We do not know whether it is the input to the HPA axis that is faulty or some part of the signal cascade in the HPA axis.  We do not know the temporal associations between HPA axis disregulation and bipolar mood states.  While it would be nice to predict that perturbations in cortisol levels correlates to extreme mood states, we simply do not have the data to draw any conclusions of this nature.

A Theory of Bipolar

The title of this post may be a bit more grand than the contents.  For instance there is not one theory and certainly not one coherent theory that tries to explain the whole phenomenon referred to as bipolar.  In this instance, I mean to describe the most coherent theory of bipolar that I see emerging from recent research.  Please bear in mind that the theory is not totally coherent and is missing some pieces of the puzzle.

Along the way of describing this emerging theory, I will try to use examples from my own experience and will suggest possible explanations for how things might fit together.  Please to not take any of these stories or suggestions as fact.  There is much research left to do on these topics, and my presentation could end up being a bit wrong.

What is the theory?  It suggests a mechanism for bipolar by joining two research threads:

1. HPA axis disregulation
2. circadian rhythm disturbances

The first one is the potential mechanism, and the second is correlated with the first.  Another feature of bipolar that is correlated with HPA axis disregulation alcoholism. There is strong evidence that the HPA axis is disregulated in alcoholism, and this provides a mechanism to explain the correlation between alcoholism and worsening bipolar symptoms.  In line with my previous posts about alcohol, I will emphasize that these correlations have only been found for alcohol abuse, not short-term light alcohol use.

I intend to follow this post with a series of posts that explore this hypothesized mechanism, the connection to the circadian rhythm, potential drug treatments, and practical steps to be taken.  More specifically:

1. I will attempt to explain the potential mechanism that results in HPA axis disregulation.  There is evidence, in the form of another disease, Cushing's Syndrome, that has the potential for mood symptoms, including depression, irritability, and sleeplessness, and is strongly correlated with HPA axis disregulation.  
2. I will explain as well as possible the connection between circadian rhythm disturbances and the HPA axis. 
3. I will try to explain the scant evidence for how the HPA axis disregulation due to alcoholism might interact with the HPA axis disregulation that is observed for bipolar.
4. I will mention a drug trial that was just finished for the drug Mifepristone that acts on the HPA axis and has been used for Cushing's Syndrome.  
5. I will do a post on what this research means from a practical perspective to a person living with bipolar and on what lessons I take from this research.

Credit

Credit is an issue that concerns everyone connected to academia from students to professors.  We have names for situations where due credit is not given: plagiarism.  The act of plagiarism can be committed by students, professors, and academic researchers.  While it is a serious offence, it is extremely common, in part due to there being a fuzzy boundary between what is plagiarism and what is not.

Why am I discussing this issue on a blog about mental health and academia?  I am writing about this, because I see my students struggle with it, and I myself struggle with it.  Indeed my struggles over this issue go so deep that they have been the subject of deep worries.  The reason behind these worries is that it is not sufficient to do good work, rather that work must be credited to the one doing the work.

Careers are made by proper credit and destroyed by improper credit.  Credit is the currency of academia, the currency of success, and some people advance their careers by taking credit for the work done by others.  There are professors who believe, correctly or incorrectly, that they are responsible for the work done by their subordinates.  There are labs where the culture is such that the supervisor takes credit for all the work published by people in that laboratory.  Some people do not believe that those actions are plagiarism.  I disagree.  I feel that such a policy is tantamount to the lower power individuals buying the support of the more senior people by essentially ghost writing papers for them.  I think these sorts of policies have no place in academia, because it is essentially plagiarism.

Coming back the students, I have heard my students express concern over the credit on their group projects.  Invariably, it is the students who are succeeding in class that find themselves in a group with weaker contributors and that find themselves carrying their weaker classmates along.  Not only can the extra burden of work be onerous, but also the assignment of credit in the form of a project grade can seem unfair.  Is it not plagiarism if the weaker student takes equal credit for the project?

So, how should we deal with these issues?  In the case of researchers, we need more strict rules defining what is plagiarism in research and more frequent use of ethical sanctions on individuals who violate the ethical rules.  Individuals in low power situations, such as graduate students and post-doctoral fellows, should have ways of speaking up about mis-credited work without fearing for their jobs or degrees.

As for students, they, too, should have ways of speaking up.  For example as part of grading projects, the professor can ask for the students' input on how much each person of the group contributed, including themselves.  While most of the responses will have an inflated self-assessment, the average over the responses of several group members should be more reliable.  (Because of the inflation, there is some difficulty when considering groups of one or two people.) However, grading mechanisms such as this can help give credit where credit is due.

Because of the amount of extreme worry that can result from mis-attributed credit.  I call on all of us to try our hardest to be fair.  We shouldn't just be more than fair to ourselves.  In the wording of Orson Welles our current situation is the following:

All animals are equal, but some are more equal than others.

Let us try to be at least as fair to our subordinate and our students, as we are to ourselves.  Let us have strict definitions of what a research contribution is.  Let us not accept having our name on a paper that we did not contribute to.  Let us be open about who contributed what to each paper, and let us give credit where it is due.   Let us not have our judgement about credit be clouded by (potential) acclaim.  And, let us remember that some of us, perhaps those with the greatest ability to contribute to scientific progress, are even more sensitive to unfairness and mis-attribution of credit than other people are.  While many people brush these issues off and play the credit game as it is, there are others, like myself, who are greatly pained by the status quo.

Accepting a Job Offer

Commensurate with the post on academic interviewing, I am pleased to report that I have secured my first faculty position!  This is a tenure track job at a major research university in North America.

Why is this exciting?  I survived both the interviewing procedure and the negotiations for the terms on my contract.

I have previously described the interviewing process, which I survived to the best of my ability.  I had some 13 interviews that left my head spinning and my internal clock totally confused due to the multiple trips across time zones in North America.  You might be thinking to yourself that 3 time zones is not much, and indeed for one trip it is not much.  But if you factor in the 11 trips back and forth across 3 time zones in three months, this gets to be a bit excessive.  At any rate, my head was spinning. At the time I thought I had 3 more interviews which were subsequently cancelled.

Arriving home after the 13th interview, I found myself in a situation where I had one verbal job offer (in academia job offers are usually verbal first and written in paper second), and I was anxiously waiting news from 4 other places.  Over the space of the next 3 weeks, I received 3 additional job offers and 1 rejection.  Why does this matter?  Well the waiting is hard, and the timing even harder.  Unfortunately each paper offer comes with a deadline by which one must either reply or ask for an extension.  In my case the original deadline was not long enough to hear from the 4 other places, so I wasted some political capital on asking for an extension.  In addition to this, I was negotiation slightly better contract terms for myself with the employer of my choosing.  All the while I was waiting for the 4 other places to get back to me.  The hope was that someone else would give me a better offer than the original offer.  (All this is very stressful.)  In the end, I accepted the offer from the original place while having 3 back-up offers that I ended up rejecting.

I must say that these negotiations are not easy on someone who has low grade psychotic symptoms that include paranoia.  How exactly is it hard?  Well if you are prone to paranoid thinking, you may not believe that people are playing it straight during sensitive job negotiations.  This is precisely what happened to me.  I noticed the paranoia early and upped the dose of a medication in an attempt to handle these symptoms.  I am happy to report the success of these actions, as I quickly restored my normal thought patterns and successfully negotiated a contract with the university of my choosing.

Three cheers for getting a job!  Three cheers for negotiating the terms of the job! And, three cheers for surviving the interviews!

I will very soon be a professor in a science field!