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Some Ideas for Handling Treatment-Resistant Bipolar Disorder

Some Ideas for Handling Treatment-Resistant Bipolar Disorder



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Bipolar disorder is being better understood each day. There is also ongoing research into its treatment.

But successfully treating bipolar disorder can involve several medication trials, and it can take years to achieve remission. Even if remission is attained, recurrence is the rule — not the exception. It’s not uncommon for all first-line treatments to be exhausted.

People in this situation may be considered by mental health professionals to be treatment-resistant. Luckily, there are treatments that can be tried when first-line, and even second-line, treatments for bipolar disorder fail.

What is Treatment Resistance?

There is no consensus among clinicians and researchers on one definition of treatment resistance. Generally, patients in an acute state (manic, depressed or mixed) whose symptoms do not improve after at least two evidence-based medication trials are considered treatment-resistant in research studies. In the maintenance phase, patients are considered treatment-resistant if they continue cycling despite several adequate medication trials.

In some studies additional criteria must be met in order to truly be considered treatment-resistant. These include functional measures of remission.

Dr. Prakash Masand, psychiatrist and founder of Global Medical Education argues, however, that “Treatment-resistance is more common than most clinicians think since a sustained response to treatment rarely includes an assessment of functioning. When functioning and residual depression are taken into consideration, far more patients would be considered treatment-resistant.”

First-Line Treatments for Bipolar Disorder

First-line treatments for bipolar disorder have been shown to be the most reliable. They are approved by the Food and Drug Administration (FDA). First-line treatments vary, depending on the phase of bipolar disorder the patient is in.

First-line treatments for mania include:

  • Valproate (Depakote)
  • Carbamazepine (Tegretol, extended release)
  • Lithium
  • All atypical antipsychotics such as risperidone (Risperdal), quetiapine (Seroquel) and aripiprazole (Abilify)

In the depressed phase of bipolar disorder, only quetiapine and an olanzapine (Zyprexa)/fluoxetine (Prozac) combination are approved as first-line treatments, although lurasidone (Latuda) is awaiting FDA approval.

For mixed episodes of bipolar disorder, carbamazepine and most atypical antipsychotics are approved. For the maintenance phase of bipolar treatment, lamotrigine (Lamictal), lithium, aripiprazole and olanzapine are FDA-approved.

Second-Line Treatments for Bipolar Disorder

According to Dr. Masand, many treatments are still available for people considered treatment-resistant. “People should not give up hope just because several treatments have failed. We have many tools in the toolbox outside of first-line monotherapy treatment.”

Primary second-line treatments in bipolar disorder include adjunctive treatments such as the addition of an atypical antipsychotic to lithium or valproate or vice versa. Dr. Masand notes that “patients in a manic or mixed state may actually respond more quickly to lithium or an anticonvulsant combined with an atypical antipsychotic.”

And while antidepressants should never be used alone to treat bipolar disorder, adding them to an existing mood stabilizer or antipsychotic is considered a second-line treatment and is sometimes helpful for bipolar depression. “Additionally, adjunctive armodafinil (Provigil) may also be useful in bipolar depression,” Dr. Masand. said

Additional Treatments for Bipolar Disorder

There are additional therapies that can be considered even if both first-line and second-line treatments fail. According to Dr. Masand, third-line treatments include clozapine (Clozaril), electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), calcium channel blockers, high-dose thyroid augmentation, omega-3 fatty acids and other anticonvulsants.

“Novel treatments are also being researched,” Dr. Masand said. “Agents such as n-acetylcysteine, mexiletine (Mexitil), pramipexole (Mirapex), ketamine and others have shown promise for the treatment of the various phases of bipolar disorder. It’s also critical that all patients with bipolar disorder receive an adjunctive proven psychotherapy such as psychoeducation, family-focused therapy, interpersonal and social rhythm therapy or cognitive behavioral therapy (CBT), as relapse rates have been shown to be lower when therapy is added to medication treatment.”


Treatment Resistant Bipolar Disorder

This activity is designed for general, pediatric and geriatric psychiatrists, neurologists, nurse practitioners, physician assistants, nurses, psychologists, social workers, other mental health professionals and primary care clinicians who treat patients with bipolar disorder.

Supported by educational grants from:

Alkermes, Inc., and Sunovion Pharmaceuticals Inc.

Activity Information

Original Release Date: May 10, 2019
Expiration Date: May 10, 2020
Estimated Time to Complete Activity: 1.0 hour


The Newest Treatments for Treatment-Resistant Bipolar Depression: Part I, The Pharmaceuticals

According to the World Health Organization, bipolar disorder is the sixth leading cause of disability in the world. The illness is characterized by periods of overexcitement, or mania, followed by depression, with its reduced functioning. The National Alliance for the Mentally Ill adds the shocking statistic that approximately 25-50% of those with bipolar disorder (BD) attempt suicide at least once, one of the highest rates for any psychiatric disorder. One study found that, over a 12-month period, bipolar disorder was associated with 65.6 lost days per sick worker annual human capital loss per worker was averaged at $9619 for BD--and annual projections to the US labor force were $14.1 billion for BD [Kessler 2006]).

Yet one of the most challenging things when dealing with bipolar disorder is its resistance to treatment, for it's a disease that raises its ugly head again and again. Nearly 1 out of every 2 patients with BD will suffer a recurrence within their lifetimes--often within two years of their last episode (Chou, 2011).

Although the manic phase gets much of the ‘play,’ the majority of the bipolar patient’s disturbed time is spent in the depressed state. It’s a state of serious concerns for the patients functions more—more personal problems, more functional impairment, more comorbid physical problems, and—treaters’ biggest fear—more suicide attempts. (That’s before we add in costs to society with in-hospitalization and disability costs as well as occupational impairment expenditures.)

Fifteen years ago a depression was considered refractory (or treatment-resistant) after two 6-week trials of antidepressants. How things have changed. Perhaps you thought, like so many others, that a good dose of Paxil, or, failing that, perhaps Wellbutrin, was just what the doctor ordered. Not here. Turns out antidepressants are out. Back in 2007 researchers ran a study comparing subjects on mood stabilizer plus antidepressants versus mood stabilizer plus placebo. And the results were pretty disappointing: 23.5% of those on the antidepressants recovered--as did 27.3% on placebo (Sachs 2007). AND antidepressants run the danger of throwing bipolar patients into a manic episode, so they're really uncool. Rather inconvenient if you're trying desperately to treat depressed people--but the reality nonetheless.

Failures of patients with bipolar depression to respond to mood stabilizers—in addition to antidepressants—added to the discouragement of doctors and suffering patients. Doctors who had tired the mood stabilzers, givein the antipsychotics a whirl, desperately thought about the antidepressants. . . but then thought better of it--well, they need something else to try.

And the FDA offers them. . .two choices.

That's right. There are precisely two FDA-approved treatments for bipolar depression: a drug called Symbyax, which is a combination of Zyprexa, an antipsychotic, and Prozac, an (need I really say this?) antidepressant, that Eli Lilly kindly mixes together, approved since 2004. Then Seroquel, another antipsychotic, approved 3 years later.

It doesn't exactly leave doctors with a large bag of tricks. So researchers have been studying drugs to treat bipolar depression people never thought they'd never see in the mental health field at all. Traveling the road less traveled by, they've looked far and wide--at Parkinson's, narcolepsy (of course!), Lou Gehrig's disease, and-- even a date rape drug. Here's a starting list of what's cutting edge in treating refractory bipolar depression:

Riluzole : Researchers continue to explore riluzole (Rilutek as marketed by Sanofi-Aventis), currently FDA-approved to treat the paralyzing disorder ALS, or Lou Gehrig's Disease. Recent studies in bipolar disorder have discovered that glutamate, an excitatory neurotransmittor found in abundance in the body, might possibly play a more significant role than seratonin in mood regulation. Bipolar depression (along with ALS) is correlated with higher levels of glutamate activity in the brain.

Riluzole researchers were quite familiar with how the neurotransmitter worked, not from ALS--but from spending quality time with rats. In rat brains, riluzole both inhibits the release of glutamate while simultaneously significantly increasing glutamate uptake. And when researchres left the rat lab and headed to humans, results were promising, as well.

The best-known study--admittedly a small one—gave riluzole to 14 subjects with bipolar depression for 6-12 weeks. Sure enough, the drug decreased glutamate release and --as theorized--subjects had "a significant reduction in depression symptoms” (Brennan et al, 2006).

Celecoxib: Known quite well as Celebrex, the arthritis drug made by Pfizer and used by millions to treat their pain, celecoxib is an acknowledged "long shot" in the treatment of bipolar depression--but it's still in the game.

Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID)-- like Advil. Both drugs work by reducing compounds known as prostaglandins, which contribute to inflammation in the body, causing anything from pain and fever to chronic peptic ulcer to Crohn's disease, hepatitis--arthritis--and more.

Enter our hero celecoxib. It blocks the enzyme that makes prostaglandins, yielding, ultimately, lower inflammation and pain. And it seems that, although we didn't know this for years, depressed patients (both those with unipolar and bipolar depression) have levels of prostaglandins that are abnormal over time.

The major study included both the psychiatrist of the "long shot" fame and 28 bipolar patients currently experiencing either a mixed or depressive episode. Patients stayed on their medicine regimen, but were randomized to receive placebo or Celebrex for a 6-week trial.

Results were both positive and fast. The patients taking Celebrex had lower scores on a depression rating scale starting in the first week of treatment. Conclude the authors, "Our findings suggest that adjunctive treatment with celecoxib may produce a rapid-onset antidepressant effect in BD patients experiencing depressive or mixed episodes" (Nery et al., 2008).

Pramipexole , (Mirapex) has been used to treat Parkinson's disease since 1997. It’s what’s called a dopamine 'agonist,' which mobilizes the brain's dopamine receptors, helping to balance the amount of dopamine in the brain.

For those of you still in the early stages of neurotransmitter familiarity, let me encourage you to add this one to your repertoire. Dopamine affects satisfaction, enjoyment and motivation--and that wonderful sense of achievement you feel when you've done something well. [It probably comes as no surprise that both food and sex release dopamine (Imran Siddiqui 2005)]. In other words, it's the brain's "pleasure chemical."

Nor surprisingly, then, dopamine also controls motivation, something we only recently discovered. It doesn't just sit back and help us 'feel good' once we've, say, eaten that pack of M&Ms--it actually causes us to initiate an action (to hop in the car to drive to CVS)--and then to persevere, to keep at it (to wait in that never-ending line, while the woman at the front pulls out 32 coupons, some out of date--but she's negotiating their use), until we achieve what we want-- M&Ms!

As recently as January of this year researchers explained, "It was believed that dopamine regulated pleasure and reward and that we release it when we obtain something that satisfies us, but in fact the latest scientific evidence shows that this neurotransmitter acts before that, it actually encourages us to act. In other words, dopamine is released in order to achieve something good or to avoid something evil" (Asociación RUVID 2013).

And such a view of dopamine clearly suggests possible treatments of depression and bipolar depression, so researchers were right on it. Mirapex could do its 'agonist' thing with dopamine and make a difference in the lives of those suffering from bipolar depression. Always used as an adjunct to a mood stabilizer or antipsychotics or both, results were still good. In 2000, Sporn and colleagues found that 50% of those on pramipexole improved (based on their scales), in 2004 a study "showed marked responses that were sustained at least through 12 week follow-up" (Goldberg et al, 2004). As recently as 2010, researchers found that "[f]or all patients, . . . the total profile of depressive symptoms improved significantly within 4 weeks and remained significantly improved for as long as 36 weeks” (El-Mallakh et al).

Not too shabby, I'd say. And sure makes dopamine look like a major player.

Modafinil As someone who's been a sleepy-head her whole life, I'm truly intrigued by this one. It's better known by its brand name, Provigil, which treats shift sleep work disorder, and sleepiness due to obstructive sleep apnea and to narcolepsy. It does so effectively enough that maker Cephalon has made a pretty penny off of its use. I can only begin to imagine how happy the company is now that some psychiatrists are using the drug for unipolar and bipolar depression, also.

I must say that I appreciate honestly, so when I went to ferret out how modafinil worked, and I checked in with Mark Frye, who did some of the groundbreaking work on modafinil and bipolar depression, I wasn’t disappointed when I turned up this: "Modafinil's wakefulness-promoting mechamism of action is unknown" (Frye et al 2007). Simple enough. And it looks like we haven't come too far in the past few years either, but what I can tell you is that modafinil seems to (we're not all sure here), assist in releasing dopamine, and also acts kind of like a psychostimulant, like, say, amphetamine--but a lot less powerful (CPA 2008).

There's a fair amount of evidence that modafinil can make a difference in other forms of depression--but it's mostly the kind of evidence that scientists sneer at--the studies might be open-label, or not double-blinded. The major, most rigorous study of the drug to date (yes, it's Dr. Frye's), published in 2007 after studying 85 patients for 6 weeks, did observe a clear antidepressant effect, although, interestingly enough, the subjects had no reduction in their level of sleepiness, often a diagnostic of depression (Frye et al 2007).

However, researchers wondered if they had under-dosed the drug, and perhaps with higher doses would have come greater wakefulness. Either way, they felt they had something that might very well "improve symptoms of bipolar depression without mood destabilization."

Although there are more compounds being looked at for treatment-refractory bipolar depression seemingly all the time, and the suffering should hold out hope, I close my piece with perhaps the oddest of the ideas out there (and keep in mind that I haven't dealt with Aricept, used to treat Alzheimer's, tamoxifen (yes, for breast cancer--and I haven't even started with anything that has the word 'magnet' in its treatment formulation), so you know researchers and doctors are really looking everywhere.

Ketamine Okay, let's face it, you’d think that any med that's also known as a date rate drug wouldn’t have people standing in line to take it. Except that this club drug is different from almost any other treatment for bipolar depression: when administered properly, ketamine alleviates the depression within minutes.

It really is worth a look. A dissociative anesthetic (and we'll come back to that, because people don't necessarily like disassociating), it was developed in the 1960s, and mainly used as a veterinary anesthetic.

But it hasn't spent its whole life innocently putting rabbits to sleep. Sneaking out of the veterinary OR, it's found a home on the street and in clubs, reinventing itself as "K," "Special K"," or "cat Valium," and inducing out-of-body sensations in those who take it--and doing triple-duty as a date-rape drug. It has the perfect profile for such--it's odorless, tasteless, and causes amnesia in the one who takes it. But wouldn’t it be nice if it had a fourth use, one that could change people's lives within minutes?

It just might. The idea of using ketamine for depression is fairly new. First came a study in 2000 on 'regular' depression, one with only 7 subjects, but it strongly indicated that ketamine had anti-depressant effects. More small-scale studies followed, but there were no results of any rigorous (you remember from above, one with all the words scientists love: "randomized,” placebo-controlled,” “double-blind crossover") studies on ketamine's effect on bipolar depression until as late as 2010. In that year we met a research team led by Dr. Carlos A. Zarate Jr, Chief, Section on the Neurobiology and Treatment of Mood Disorders and Chief of Experimental Therapeutics and Pathophysiology Branch at the National Institute of Mental Health. I'd tell you some more of his jobs, but I imagine you're getting restless.

We return to the study with the intriguing title "A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.” (Don't be thrown by all that "N-methyl-D-aspartate antagonist" stuff--it just means that ketamine is an anesthetic that works to inhibit [that's the 'antagonize'] the action of N-methyl-D-aspartate receptors, which are types of glutamate receptors. Apparently blocking these receptors improves the brain’s electrical flow, which, in turn, reduces depression.) Here, researchers found that, within 40 minutes of administering ketamine to their subjects, depressive symptoms significantly improved--for 71% of those given the drug.

The clearest downside of ketamine--well-known to doctors and researchers? The improvement lasts a only days.

As expected, the most common adverse effect was dissociation. This can be distressing to people, as it includes vivid and wild dreams, visual hallucinations, delirium, disorientation, and confusion--but such symptoms do usually pass within an hour.

Just last year the journal Biological Psychiatry published an article once again establishing ketamine's efficacy in bipolar depression--and, this time, in suicide. Dr. Zarate and his fellow researchers declared that they found a "rapid and robust antidepressant response" (2012), and, beyond that, they found the drug "rapidly improved suicidal ideation"

Despite the fact that a number of areas of concern remain in using ketamine to regularly treat those with bipolar depression (there's the dissociative 'trip,' the drug can lead to dependence, and long-term use can cause abnormalities in the brain), Dr. Zarate seems pretty sure he's onto a good thing: he's applied for patent for the use of ketamine in major depression.

In a 1989 issue Psychological Review, the authors develop an entire theory of depression that is based on hopelessness-—and it is a lot to ask someone in the depths of despair to hold out hope for a treatment so new it’s still in clinical trials. But there really is cause for hope for the person with treatment refractory bipolar depression. Researchers have new ideas all the time for ways to treat bipolar depression, and they’re putting them to the test. More cutting-edge psychiatrists are already using a number of the treatments in this post—and for some, as they travel “the road less traveled by”, they bring their patients along with them—and that can “make all the difference.”


Background

Despite growing evidence for the effectiveness of new pharmacological strategies in bipolar disorder (BD), the number of studies on pharmacotherapy of treatment-resistant cases is scarce. One of the medications used for this indication is clozapine. Although clozapine lacks regulatory approval for use in any phase of BD, it has been shown to be useful in treatment-resistant BD (TRBD), decreasing the number of hospitalizations (1) and is associated with symptomatic and functional improvement (2). Clozapine probably reduces aggressive behavior in young patients with TRBD (3), and it seems to be effective in reducing the number of hospitalizations and emergency room (ER) visits, including the ones due to self-harm and overdose (4). One case report presents its antidepressant effect (5) and another its anti-suicidal effect (6).

Suicidal ideation and behaviors in BD consist a significant clinical problem (7, 8). Suicide accounts for 15% to 20% of deaths among BD patients (9, 10). The ratio of suicidal attempts among BD patients is much lower (∼ 𢄣:1) than that in the general population (�:1) however, it has a high lethality (11). Suicidal acts appear mostly in association with severe depressive or mixed states. For today, there are no approved pharmacological interventions for suicidality in BD. Clozapine has been shown to have specific anti-suicidal properties in patients with schizophrenia (12�). Some authors have suggested that clozapine’s anti-suicidal properties could extend beyond schizophrenia to BD (8, 13).

This case series represents three bipolar patients with severe suicidal ideation who responded to clozapine as an add-on treatment.

Case 1

A 26-year-old single Caucasian female was admitted to an inpatient psychiatry unit. She was diagnosed with BD manic episodes with psychotic symptoms according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. She had a 5-year history of BD with three hospitalizations due to manic episodes, including one involuntary. She also had four episodes of depression and one mixed episode. In the course of her illness, she hardly had any remissions.

On admission, she presented an elevated mood, increased energy and motor activity, loud and aggressive behavior, flights of ideas, tangentiality, delusions of grandiosity, and a decrease in sleep and appetite. She had to be restrained because of self-aggression (banging her head against the wall). She had quit her treatment (olanzapine, lithium, fluoxetine, and lorazepam) a few months earlier without consulting her psychiatrist. Initially, she was treated with haloperidol intramuscularly (up to 20 mg) and olanzapine intramuscularly (up to 20 mg), then zuclopenthixol 50 mg intramuscularly and aripiprazole up to 30 mg with no satisfactory effects. Next, she was treated with valproic acid intravenously up to 3,200 mg with a good antimanic effect, but the drug had to be withdrawn due to thrombocytopenia. Moreover, the patient refused to take lithium carbonate due to the � taste of the drug” (in Poland, available lithium carbonate tablets are not coated). Subsequently, she was treated with olanzapine 20 mg together with aripiprazole 30 mg that caused a remission of the manic symptoms, but after about 2 weeks, the patient’s mood had worsened she became extremely irritable and revealed suicidal thoughts.

At this time, clozapine 100 mg was introduced, and the dose was increased to 200 mg the next day. We observed the resolution of the suicidal thoughts and mood normalization during the first 2�ys of clozapine treatment. Unfortunately, there was no improvement as far as her insight, and after a few days, the patient refused to take any medication and was discharged at her own demand.

Case 2

A 26-year-old Caucasian female was admitted to the inpatient psychiatry unit due to severe bipolar I depression with comorbid borderline personality disorder and epilepsy. During the course of her illness, she was hospitalized four times due to depressive episodes and had two manic episodes without hospitalization. The current depressive episode lasted 6 months prior to admission. She had a low mood and extreme lack of energy, anhedonia, psychomotor retardation, reduced sleep, and suicidal thoughts. She was treated with valproate at a maximum of 1,300 mg/day for 9 weeks (serum level 70 mg/l), but the drug was withdrawn due to hair loss and tremor and lack of effect. Aripiprazole at a max of 30 mg/day for 6 weeks that also did not cause any improvement was administered, and then, we used quetiapine at a max of 550 mg/day that caused partial mood stabilization and also severe constipation causing withdrawal. Additionally, the patient was taking lamotrigine 400 mg/day and lithium carbonate 1,000 mg/day during the whole hospitalization. During treatment with lithium carbonate, we introduced eight intravenously ketamine doses (0.5 mg/kg) that caused an immediate mood improvement lasting about a week. Next, we used risperidone 4 mg without any clinical effect. We added topiramate at a max of 400 mg hoping for a further mood stabilizing effect and weight reduction (the patient had gained 10 kg during the year before hospitalization, and it was a significant problem for her). Next, we introduced fluoxetine at a max of 60 mg/day plus 5-mg olanzapine for 10 weeks—which was associated with a mild antidepressant effect.

Finally, we used clozapine at a max of 100 mg for 8 weeks that caused gradual mood and energy normalization and the withdrawal of suicidal thoughts. The patient was discharged on lamotrigine 400 mg, lithium carbonate 750 mg, clozapine 100 mg, and topiramate 400 mg. During the whole time of her hospitalization, the patient had psychodynamic psychotherapy twice a week and continued it after discharge.

Case 3

A 42-year-old Caucasian female was admitted to the inpatient psychiatry unit due to a severe depressive episode in the course of BD. Before admission, she had quarreled with her husband, and under the influence of ethanol, she had tried to commit suicide by cutting her wrist. She had never been hospitalized in a psychiatric unit before. During hospitalization, she was treated with venlafaxine 375 mg, lamotrigine 200 mg, and quetiapine 200 mg with a small improvement of her depressive symptoms but no effect on her suicidal ideations. The patient stayed at the hospital for 10�ys, subsequently withdrawing consent for further hospitalization𠅌laiming her mental state had much improved. The next day, she came to our outpatient clinic still presenting active suicidal thoughts and depressive symptoms. She refused to be hospitalized but agreed to take medication at home with the close supervision of her family and frequent ambulatory visits (three times a week). The patient had been diagnosed with BD type I 21 years ago. During her illness, she had three episodes of major depression, two manic episodes, and one mixed episode. The current depressive episode lasted 2 months before admission and was related to a relationship crisis due to her marital relations. She had a low mood and anhedonia, psychomotor retardation, reduced sleep, and active, persistent suicidal thoughts that were the leading cause of her concern at the moment.

She agreed to be treated with clozapine up to 100 mg as an add-on treatment to previous drugs. During the next two weeks, the patient improved significantly, with the most prominent anti-suicidal effect after 10�ys of clozapine treatment. Although she was still depressed, she did not express any suicidal thoughts, and this effect was present as long as the clozapine was subscribed. Two months later, due to sedation, she tried to decrease the dose of clozapine to 25 mg/day, but suicidal thoughts returned. Since then (2 years), she has been taking clozapine as an add-on treatment with a good clinical effect.

The previously discussed cases constitute the part of the clozapine registry approved by the independent ethics committee of the Medical University of Gdansk (approval number NKEBN/355/2016). The previously mentioned cases are presented according to guidelines for disguising case material.


Lamotrigine Rechallenge in Treatment-Resistant Bipolar Disorder

Background: Although lamotrigine may be useful for treating patients with treatment-resistant bipolar disorder, some lamotrigine-associated adverse effects, including mild to moderate skin rash, may prevent the continuation of treatment.

Methods: We investigated lamotrigine rechallenge for the treatment o f b ipolar disorder. The present study was based on retrospective chart review of outpatients with bipolar disorder ( DSM-5 criteria) who visited the hospital’s psychiatric department between July 2011 and August 2017. The review revealed 12 patients with bipolar disorder who underwent lamotrigine rechallenge following lamotrigine discontinuation due to various adverse reactions, including skin rash. None o f t he patients showed Stevens-Johnson syndrome. All patients suffered from treatment-resistant bipolar disorder that was refractory to treatments other than lamotrigine. For each patient, the severity o f t he adverse reaction to lamotrigine was weighed against the potential for therapeutic benefit.

Results: In 9 of 12 cases, a positive outcome of lamotrigine rechallenge was observed. In all cases with initial skin rash with very slow titration of lamotrigine, rechallenge was successful with no recurrence of the rash. In the 3 cases for which lamotrigine was unsuccessful, lamotrigine was discontinued owing to movement disorders, ie, oral dyskinesia and action tremor, and liver dysfunction, respectively.

Conclusions: The present results suggest that lamotrigine rechallenge may be a viable option for treatment-resistant bipolar disorder.

Prim Care Companion CNS Disord 201820(2):17m02231

To cite: Inaba T, Sogawa R, Mizoguchi Y, et al. Lamotrigine rechallenge in treatment-resistant bipolar disorder. Prim Care Companion CNS Disord. 201820(2):17m02231.

To share: https://doi.org/ 10.4088/PCC.17m02231

© Copyright 2018 Physicians Postgraduate Press, Inc.

a Department of Psychiatry, Faculty of Medicine, Saga University, Saga, Japan

b Department of Pharmacy, Saga University Hospital, Saga, Japan

c Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

* Corresponding author: Akira Monji, MD, Saga University, Department of Psychiatry, Nabeshima 5-1-1, Saga-city, Saga 849-8501, Japan ([email protected]) .

L amotrigine is a structurally novel anticonvulsant that was approved by the US Food and Drug Administration for the treatment of epilepsy in 1994. Lamotrigine is generally well tolerated by children and adults. 1 The mechanism of action o f l amotrigine involves sodium channel blocking and may entail the activation of N -methyl- d -aspartate receptors. 2 Lamotrigine is also beneficial for the treatment of psychiatric disorders, especially mood disorders. Evidence supports lamotrigine as an effective maintenance treatment for bipolar disorder, particularly in the prevention of depressive episodes. 1 In acute bipolar depression, there is modest support for its efficacy from meta-analysis, 1 especially in more severely depressed subjects. A double-blind randomized controlled trial 3 in unipolar depression reported benefits on subsets of symptoms and improved response in the more severely depressed subjects. Although the preventive effect o f l amotrigine on recurrence or relapse of mood episodes in bipolar I disorder has been established in clinical studies, it has recently been reported that lamotrigine may be more suitable for maintenance treatment in bipolar II disorder than in bipolar I disorder. 2 Another recent report 5 suggested that lamotrigine alone or in combination with quetiapine may be effective in the prevention of postpartum depression in women with bipolar II disorder.

Some lamotrigine-associated adverse effects, such as skin rash, may prevent continuation of lamotrigine treatment, particularly in the first 2 months of treatment during ongoing or completion of lamotrigine titration. 6 Tak et al 7 compared the adverse effects of lamotrigine in adolescent epilepsy patients and adolescent psychiatric patients. They reported that within 7 weeks of initiation of lamotrigine, the likelihood of developing a rash was not significantly different between psychiatric and nonpsychiatric patients. 7 A recent report 8 has demonstrated that psychiatrists, neurosurgeons, and pediatricians should strictly comply with the guidelines for the proper use of lamotrigine and that allergologists should endeavor to ensure the early detection of severe lamotrigine-induced skin eruptions.

Several reports 9-16 have described the outcome of lamotrigine rechallenge following a skin rash in the treatment of either epilepsy or psychiatric disorders. There may be racial differences in susceptibility to adverse effects of lamotrigine, and probably also to rechallenge of lamotrigine. Here, we report on lamotrigine rechallenge in the treatment of bipolar disorder after discontinuation of lamotrigine due to various adverse effects, including skin rash.

Between July 2011 and August 2017, we retrospectively reviewed charts from the psychiatric department of our hospital for outpatients with bipolar disorder. Among this group, we were looking for patients who had experienced an adverse reaction to lamotrigine on initial exposure to the drug ( Table 1 ), even though lamotrigine had been titrated according to the manufacturer suggested protocol, and who had discontinued the drug because of the reaction. We found all of the patients had been diagnosed by the same psychiatrist (T.I.) according to the DSM-5 classification, and all of the patients were Japanese and thus have the same ethnic traits. Lamotrigine had been used in combination with other drugs, such as antipsychotics, antidepressants, other anticonvulsants, and benzodiazepines, and patients’ prescription regimens had been maintained during the rechallenge.

  • Lamotrigine is an effective maintenance treatment for bipolar disorder, particularly in the prevention of depressive episodes.
  • Some lamotrigine-associated adverse effects, such as skin rash, may prevent continuation of lamotrigine treatment, particularly in the first 2 months of treatment during ongoing or completion of lamotrigine titration.
  • Lamotrigine rechallenge with very slow titration may be a viable option for bipolar disorder that is treatment resistant against drugs other than lamotrigine.

For those who had skin rash as their reason for lamotrigine discontinuation, grade of the rash was based on the intensity and location of the outbreak according to the classification system of Serrani Azcurra. 16 For example, Grade 1 is "Macular or papular outbreak or erythema without related symptoms" Grade 2 is "Macular or papular outbreak or erythema with itching or other related symptoms. Localized peeling or other lesions that cover < 50% of body surface area" and Grade 5 is "Severe life-threatening Stevens-Johnson syndrome." 16

Because our patients suffered from treatment-resistant bipolar disorder that was refractory to treatments other than lamotrigine, they were offered lamotrigine rechallenge by their responsible physician (A.M.). For each patient, the severity of the adverse reaction to lamotrigine was weighed against the potential for therapeutic benefit with the drug. Informed consent had been obtained at that time for all those considered appropriate for rechallenge.

Twelve patients fit our criteria their clinical data are shown in Table 1 . In all cases, adverse effects showed improvement after withdrawal of lamotrigine. In 5 of 12 cases, the reason for initial lamotrigine discontinuation was skin rash. Four patients showed a Grade 1 skin rash and 1 patient showed a Grade 2 skin rash. None of the patients showed Stevens-Johnson syndrome. In 9 of 12 cases, a positive outcome following lamotrigine rechallenge was observed in psychiatric symptoms. In all cases with an initial skin rash, lamotrigine rechallenge was successful with no recurrence of the rash. In 3 of 12 cases, lamotrigine rechallenge was discontinued because of oral dyskinesia, action tremor, and liver dysfunction, respectively.

To our knowledge, few reports have described lamotrigine rechallenge for the treatment of bipolar disorder following skin rash. In case studies of single patients, reports are mixed. Buzan and Dubovsky 10 reported an unsuccessful case of lamotrigine rechallenge, while Manfredi et al 12 reported a successful case of lamotrigine rechallenge. In a larger study of a group of 27 patients with bipolar disorder, Aiken and Orr 15 investigated the efficacy of lamotrigine rechallenge and reported a positive outcome in 21 cases. Another study 16 of 10 patients with bipolar disorder undergoing rechallenge reported that 8 patients had a positive outcome. These 2 reports 15,16 that included groups of patients support the use of lamotrigine rechallenge as a viable option for treatment-resistant bipolar disorder following a benign lamotrigine-induced rash, and they demonstrated that lamotrigine rechallenge should be avoided within 4 weeks of the initial rash.

In the present study, we investigated lamotrigine rechallenge in several patients with bipolar disorder that was resistant to treatments other than lamotrigine. These patients had discontinued their treatment owing to various adverse effects induced by lamotrigine, including skin rash. In all of the cases with initial skin rash, lamotrigine rechallenge with very slow titration of lamotrigine occurring for several weeks was successful and there were no recurrences of the rash.

In some cases (case 1 and case 4 in Table 1 ), maximum doses of lamotrigine in rechallenge were lower than those of lamotrigine in the first challenge however, psychiatric symptoms were ameliorated in these cases. The reason for these results should be clarified in future studies. The present results suggest that lamotrigine rechallenge is a viable option for treatment-resistant bipolar disorder. However, the clinicians should consider the ethnicity of the patients because there might be different reactions of lamotrigine in other populations.

In 3 cases, lamotrigine rechallenge was unsuccessful. In 2 of them, patients experienced movement disorders such as oral dyskinesia and action tremor twice during the treatment of lamotrigine. This side effect is surprising as lamotrigine has rarely been linked to the development of movement disorders 17 although, a few studies 18 reporting on adverse effects following long-term use of lamotrigine report movement disorders among the symptoms experienced. Mackay et al 18 reported that early in lamotrigine treatment, adverse effects experienced by epileptic patients included skin rash and Stevens-Johnson syndrome. Lamotrigine rechallenge may have unacceptable risk in patients who had previously had severe (Stevens-Johnson syndrome) rash with lamotrigine. However, after more than 6 months of treatment, adverse effects experienced included mood disorder, ataxia, visual blurring, and diplopia. 18 Other reports 19-21 demonstrated late neurologic disturbances induced by lamotrigine in epileptic patients, including ataxia, headache, oculogyric crises, involuntary eye blinking, and tic disorder. Therefore, clinicians should bear in mind the potential for movement disorders induced by lamotrigine, as seen in the present study.

This study was limited by its small number of subjects and use of a retrospective design. Future prospective studies with more subjects are necessary to draw more definitive conclusions.

Submitted: October 13, 2017 accepted January 18, 2018.

Published online: March 29, 2018.

Potential conflicts of interest: The authors declare no conflicts of interest.

Funding/support: No external funding was received in support of the present study.

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3. Barbee JG, Thompson TR, Jamhour NJ, et al. A double-blind placebo-controlled trial of lamotrigine as an antidepressant augmentation agent in treatment-refractory unipolar depression. J  Clin Psychiatry. 201172(10):1405-1412. PubMed CrossRef

4. Terao T, Ishida A, Kimura T, et al. Preventive effects of lamotrigine in bipolar II versus bipolar I disorder. J Clin Psychi atry . 201778(8):e1000-e1005. PubMed CrossRef

5. Sharma V, Sommerdyk C. Lamotrigine in the prevention of bipolar II postpartum depression. Prim Care Com panion CNS Disord . 201618(6):doi:10.4088/PCC.16l01964. PubMed CrossRef

6 . Abe Y, Yasugawa S, Miyamoto K, et al. Valproate as a risk factor for lamotrigine discontinuation. J Affect Disord . 2013150(3):1197-1199. PubMed CrossRef

7. Tak H-J, Ahn J-H, Kim K-W, et al. Rash in psychiatric and nonpsychiatric adolescent patients receiving lamotrigine in Korea: a retrospective cohort study. Psychiatry Inves tig . 20129(2):174-179. PubMed CrossRef

8. Saeki H, Yamada K, Morikawa N, et al. Severe drug eruptions due to lamotrigine in Japan based on data from the relief system of the Pharmaceuticals and Medical Devices Agency. Allergol Int . 201766(1):156-158. PubMed CrossRef

9. Tavernor SJ, Wong ICK, Newton R, et al. Rechallenge with lamotrigine after initial rash. Seizure . 19954(1):67-71. PubMed CrossRef

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16. Serrani Azcurra DJL. Lamotrigine rechallenge after a skin rash: a combined study of open cases and a meta-analysis. Rev Psiquiatr S alud Ment (Barc.) . 20136(4):144-149. PubMed CrossRef

17. Yang JH, Chung SW, Kim JS. Action tremor associated with lamotrigine monotherapy. J Mo v Disord . 20103(1):18-19. PubMed CrossRef

18. Mackay FJ, Wilton LV, Pearce GL, et al. Safety of long-term lamotrigine in epilepsy. Ep ilepsia . 199738(8):881-886. PubMed CrossRef

19. Sotero de Menezes MA, Rho JM, Murphy P, et al. Lamotrigine-induced tic disorder: report of five pediatric cases. Epilepsia . 200041(7):862-867. PubMed CrossRef

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21. Thome-Souza S, Moreira B, Valente KD. Late adverse effects of the co-administration of valproate and lamotrigine. Pediatr Neurol . 201247(1):47-50. PubMed CrossRef


Long-term maintenance treatment

Lithium, introduced by John Cade in 1949, remains the best established long-term treatment for bipolar disorder. 49 Although the metal has been in clinical use for more than 50 years, the most convincing evidence of long-term efficacy comes from randomised clinical trials in which lithium was included as an active comparator. 50 A meta-analysis of five placebo-controlled lithium maintenance trials (n=770) showed that lithium reduces the risk of manic relapses by 38% (RR 0띢, 95% CI 0띐𠄰랄) and depressive relapse by 28% (0띲, 0띀𠄰랕). 50 Lithium is the only known anti-suicidal treatment with randomised evidence of a reduction in the risk of suicide of more than 50%. 51 However, the benefits of lithium are restricted by adverse effects and a low therapeutic index. 52 Although little evidence exists of a clinically substantial reduction in renal function in most patients, the risk of end-stage renal failure remains unclear. The risk of congenital malformations in the babies of mothers who have taken lithium during pregnancy is uncertain, but probably lower than previously thought. The balance of risks should be considered before lithium is withdrawn during pregnancy. In addition to known effects of lithium on the thyroid, the risk of hyperparathyroidism is increased and calcium concentrations should be checked before and during treatment. 52

The limitations of lithium mean that alternatives are often needed for long-term treatment. A pooled analysis of two randomised lamotrigine versus placebo trials reported a 36% reduction for lamotrigine in the risk of relapse over 18 months. 53 Despite the dramatic increase in the use of valproate in the past two decades, 54 placebo-controlled evidence for valproate in long-term prevention remains scarce. 55 Moreover, the BALANCE trial found that lithium was better than valproate in the prevention of mood episodes (RR 0띱, 95% CI 0띑𠄱뜀), but a combined analysis finds heterogeneity between studies. Combination treatment with lithium plus valproate is better than treatment with valproate monotherapy (0띙, 0띂𠄰랃). 56

Enrichment designs are standard in continuation trials sponsored by industry. Enrichment selects patients with known acute response to, or who can tolerate, the investigational agent. Patients are then randomly assigned to either continue the investigational agent during the active trial or switch to placebo or an active comparator. The enrichment design can answer questions about the continued benefits of the investigational medicine, but is not a fair test of the comparator agents that do not have the prerandomisation selection. For example, one trial protocol treated 2438 patients with quetiapine for 4� weeks 1226 (50%) who responded to treatment were randomly allocated to continue quetiapine or to switch to placebo or lithium (0୶𠄱୲ mEq/L). 40 Over 104 weeks, time-to-recurrence of any mood event was significantly longer for patients given quetiapine versus placebo and for patients given lithium versus placebo.

Because antipsychotics are the most potent treatments in acute mania, 9 in many clinical situations, it will seem reasonable to continue them after remission from the acute episode. 30 However, there are few long-term trials, most use enrichment designs, and none have the same degree of independent replication of efficacy as lithium. Thus, the role of antipsychotics as long-term mood stabilisers remains uncertain.


Treatment-Resistant Bipolar Disorder

Most of the literature on treatment-resistant bipolar disorder is related to treatment of acute episodes of mania or depression. There is no formal universal definition of treatment resistance proposed criteria have included a specific number of failed medication trials, incomplete or unsatisfactory response to treatment (usually determined by symptom rating scales), unsuccessful response for a specified duration of treatment, failure to respond to a phase of bipolar disorder, poor response to all medication and nonmedicinal interventions, or lack of response to only “evidence-based” (usually FDA-approved) medications for bipolar disorder.

It should be noted that the FDA has approved both vagus nerve stimulation (VNS) and transcranial magnetic stimulation (TMS) for treatment-resistant depression: VNS, if the patient has failed 4 or more different medication trials and TMS after only 1 adequate medication trial. We consider a patient with bipolar disorder treatment resistant if trials of all medications approved by the FDA for bipolar disorder have failed. 1

This article focuses on treatment resistance to medications in adult male and non-pregnant adult female outpatients with any type of DSM-5 diagnosed bipolar disorder.

Possible contributing factors to treatment resistance

Although the severity of the bipolar disorder and the degree of response to medical treatments are usually considered predominantly under genetic or other endogenous influences, several non-biological factors often contribute significantly to treatment resistance (Table 1). Some of these factors can be successfully addressed, often resulting in a better prognosis. For clinical purposes, it is more useful to conceptualize bipolar disorder as a spectrum condition rather than a true “bipolar” disorder, since this approach may lead to more accurate recognition of the active symptoms of the current episode. Such recognition is crucial because these findings, rather than the diagnostic subtype of the bipolar disorder as defined by DSM-5, should determine the choice of medications, especially because the diagnosis of MDD has been redefined in DSM-5 to include some hypomanic/manic symptoms.

13 Contributing Factors to Treatment-Resistant Bipolar Disorder

Some clinicians find symptom checklists or scales helpful in supplementing findings on the mental status examination. Symptom recognition is especially important when medicating patients who have bipolar disorder with mixed symptoms because failure to recognize less obvious or “soft” hypomanic symptoms (insomnia, anxiety, irritability, rapid thoughts, and rumination) can lead to prescribing antidepressants, which will offer no therapeutic benefit and may even worsen activation symptoms. (The reader is referred to 3 helpful and thoughtful references for a more thorough discussion of this important clinical issue. 2-4 )

Before medications are initiated, several potential obstacles to successful treatment of bipolar disorder should be addressed, especially for outpatients. Significant others of the patient should be included in the initial evaluation and during the course of treatment if necessary, especially if the patient is unable to recognize or communicate symptomatology well.

Patients who use even small or moderate amounts of alcohol or recreational drugs (including marijuana) should be informed that any continued use can interfere with the therapeutic effects of prescribed bipolar medications. Concurrent use of some psychiatric (antidepressants) and non-psychiatric (eg, steroids, opioids) mood-destabilizing medications should be discontinued to determine whether they are opposing the therapeutic effects of antimanic agents.

Volitional unhealthy lifestyle behaviors can also have an adverse effect on the prognosis of bipolar disorder. Patients should be informed that controllable poor sleep habits (staying up late on the internet), predictable and avoidable stressful situations, and irregular medication compliance can neutralize or outweigh the positive effects of prescribed medications. Moreover, frequent exercise and the stability of regular routines, such as healthy eating habits and good sleep hygiene, can enhance treatment outcomes.

Chronic insomnia and chronic anxiety

A significant number of patients with bipolar disorder, especially those with mixed symptoms, experience chronic insomnia and chronic daytime anxiety, often for years without interruption. These symptoms are not true mood symptoms and may be related to an overactivated generalized hyperarousal state that might be caused by a systemic dysfunction of the hypothalamic-pituitary-adrenal axis. 5,6 Aggressive medication treatment of these 2 persistent symptoms is indicated because both are associated with a diminished prognosis, and both can cause impaired daytime functioning and distress. In addition, chronic insomnia in bipolar disorder is associated with impaired cognition, worsening of hypomanic/manic symptoms, and increased risk of suicide. 7,8

In most cases, the benefits of maintenance treatment, even with benzodiazepines, usually outweigh the risks if the patient does not have a history of substance abuse and is monitored closely. Most large-scale surveys of different classes of medications taken by patients with bipolar disorder reveal that benzodiazepines are prescribed for a substantial number of patients, probably because their chronic insomnia and anxiety symptoms are not adequately controlled by maintenance mood-stabilizing medications alone.

Psychotherapy

Although medications are the mainstay of treatment of bipolar disorder, some patients benefit from adjunct psychosocial interventions, which can be provided by the treating psychiatrist or by a non-MD counselor working in parallel with the prescribing physician. According to some studies, the following psychotherapeutic modalities with pharmacotherapy can be helpful in reducing the risk of relapse, improving treatment compliance, and decreasing the number and duration of hospitalizations: psychoeducation, cognitive behavioral therapy, interpersonal and social rhythm therapy, family counseling, and functional rehabilitation training. 9 Referrals for this specialized treatment should be made to mental health professionals who have experience and expertise in working with bipolar disorder.

The art of psychopharmacology

The psychiatrist who provides pharmacological treatment for patients with bipolar disorder can improve the prognosis for treatment-resistant bipolar disorder by skillful and strategic management of medications. Helpful general prescribing principles are listed in Table 2. A significant number of psychiatric outpatients are sensitive to and respond to lower than standard doses of CNS medications. For this reason, starting doses for any psychiatric medication prescribed for the first time to outpatients should be very conservative, and increases in doses should be small and gradual. A good example is lithium, which can be effective and better tolerated in outpatient monotherapy or as an adjunct agent at doses that produce a blood lithium level of 0.5 mmol/L or lower. 2 We have had success utilizing a compounding pharmacy to produce medications for sensitive patients at strengths lower than the manufacturer’s recommended minimum doses.

Most patients with bipolar disorder require polypharmacy. In these cases, the prescribing physician should not change more than one medication at a time because the cause of any positive or negative effects will be unclear if more than one medicine is changed simultaneously. The cost and accessibility of a bipolar disorder medication should be considered and discussed with the patient before it is initiated because some expensive brand products may not be covered by the patient’s health insurance, or the high copay may be unaffordable. Providing samples to initiate treatment can be helpful in these situations.

Patients who have bipolar disorder should be alerted to the risk of a switch to hypomania/mania when antidepressants are initiated, even when they are being added to an antimanic medication. Furthermore, it is important for the treating psychiatrist to be aware of the risk-to-benefit ratio when introducing antidepressants in different treatment situations. Helpful consensus recommendations for the use of antidepressants in bipolar disorder have been provided by a task force convened by the International Society for Bipolar Disorders and are listed in Table 3. 10

Consensus treatment guidelines

During the past several years, multiple formal consensus guidelines for medical treatment of bipolar disorder have been published, usually by a group of academicians and experts on psychiatric organization committees from different countries. Most of these guidelines are organized into different tiers of preferred treatments that are ranked according to evidence-based supporting published research data and the strength of methodology utilized in each study.

More recent guidelines include neuromodulation interventions such as TMS, VNS, adjunctive ketamine with ECT, and deep brain stimulation, although none of these modalities are FDA approved for bipolar disorder. These newer brain stimulation treatments for depressive episodes of bipolar disorder show encouraging, but limited, results. 11 Nonetheless, we have treated a few medication-refractory depressed bipolar patients successfully with both VNS and TMS.

Most psychiatrists who treat bipolar disorder are aware that many patients do not respond to FDA- approved medications for bipolar disorder and that trials of off-label, less-often prescribed agents are acceptable and preferable to no further treatment, especially for patients who refuse ECT or in whom ECT has failed. (The reader is referred to 2 publications as helpful references that include both FDA-approved and off-label options for treatment-resistant bipolar disorder. 12,13 ) Our proposed guidelines for treatment options are listed in order of preference for the 3 main phases of bipolar disorder in Table 4.

True treatment failures

In most difficult bipolar disorder treatment cases, patients eventually have an acceptable response to one or more of the many currently available FDA-approved or off-label treatment options. Rarely, the clinician is faced with a true treatment failure after all known options have been exhausted. In these situations, the following interventions can be considered:

• A second opinion consultation by an experienced psychiatrist who specializes in bipolar disorder

• More emphasis on psychotherapy

• Referral to the patient’s primary care physician to rule out a medical cause of mood symptoms

In many instances, patients with treatment-refractory symptoms are satisfied with a partial benefit from a medical treatment, while they are waiting for the next new treatment for bipolar disorder to become available, if the response is noticeably better than no treatment, especially for the most uncomfortable and disabling symptoms. Lastly, the literature supports the use of 2 more treatments, ECT and clozapine, when all other options have failed. 14

Disclosures:

Dr. Charles Schaffer is Clinical Professor, Department of Psychiatry and Behavioral Science, UC Davis School of Medicine Dr. Linda Schaffer is in private practice and Ms. Howe is Dr. Charles Schaffer’s research assistant.

The authors report no conflicts of interest concerning the subject matter of this article.

References:

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2. Phelps J. A Spectrum Approach to Mood Disorders: Not Fully Bipolar But Not Unipolar: Practical Management. New York: WW Norton & Company 2016.

3. Ketter TA, ed. Handbook of Diagnosis and Treatment of Bipolar Disorders. Washington, DC: American Psychiatric Publishing Inc 2010.

4. Akiskal HS. The prevalent clinical spectrum of bipolar disorders: beyond DSM-IV. J Clin Psychopharmacol. 199616:4S-14S.

5. Daban C, Vieta E, Mackin P, Young AH. Hypothalamic-pituitary-adrenal axis and bipolar disorder. Psychiatr Clin North Am. 200528:469-480.

6. Riemann D, Spiegelhalder K, Feige B, et al. The hyperarousal model of insomnia: a review of the concept and its evidence. Sleep Med Rev. 201014:19-31.

7. Wehr TA, Sack DA, Rosenthal NE. Sleep reduction as a final common pathway in the genesis of mania. Am J Psychiatry. 1987144:201-204.

8. Pawlak J, Dmitrzak-Weglarz M, Skibinska M, et al. Suicide attempts and clinical risk factors in patients with bipolar and unipolar affective disorders. Gen Hosp Psychiatry. 201335:427-432.

9. Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet. 2016387:1561-1572.

10. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013170:1249-1262.

11. Oldani L, Altamura AC, Abdelghani M, Young AH. Brain stimulation treatments in bipolar disorder: a review of the current literature. World J Biol Psychiatry. 201617:482-494.

12. Ketter TA, ed. Advances in Treatment of Bipolar Disorders. Washington, DC: American Psychiatric Publishing 2015.

13. Poon SH, Sim K, Baldessarini RJ. Pharmacological approaches for treatment-resistant bipolar disorder. Curr Neuropharmacol. 201513:592-604.

14. Li X-B, Tang Y-L, Wang C-Y, de Leon J. Clozapine for treatment-resistant bipolar disorder: a systematic review. Bipolar Disord. 201517:235-247.


Other Steps You Can Take

Making lifestyle changes is an important part of treating major depressive disorder. There are a number of things that you can do to help supplement your treatment and find relief. Some of these changes can help alleviate symptoms in the short-term and aid in your long-term recovery.

Exercise May Be Helpful

Research has shown that regular physical activity can not only help prevent depression, it can also help alleviate symptoms. The idea that exercise may actually help treat depressive symptoms has been the subject of debate, but some evidence suggests that the beneficial effects may have actually been underestimated.

A meta-analysis of the research concluded that exercise has a large and significant beneficial effect on depression (including major depressive disorder), supporting the idea that exercise is an evidence-based depression treatment.

Stick to a Schedule

It can also be helpful to resume some of the activities that you enjoyed before you began experiencing symptoms of depression. Depression can not only cause you to lose interest in the things you used to be passionate about it can also make it difficult to stay on top of daily chores like doing the dishes or laundry. Seeing these things pile up makes it even more difficult to feel upbeat and motivated.

So when you are trying to manage your symptoms, focus on doing small things each day that will help restore your routines and sense of normalcy. If you have fallen out of a routine, create some sort of schedule that provides structure in your day.

Get Enough Sleep

Insomnia and other sleep disturbances are common symptoms of depression. Antidepressants may help with those symptoms, but you may also want to try relaxation techniques or have your doctor prescribe a medication to help with your sleeping difficulties.

Research has shown that sleep disturbances are a risk factor for depression. Insomnia also increases the duration and severity of depression and makes relapse more likely.

A Word From Verywell

In addition to doing these things, it is important that you always take your medicine as prescribed, communicate with your doctor or therapist about how you are feeling, and give your treatment time to work.

Major depressive disorder is a serious condition, but it is treatable. It may take some time to find the right approach for your needs, but understanding what you can expect in terms of treatment effects can help you better recognize how your treatment is working.


Trajtimet e linjës së dytë për çrregullimin bipolar

Sipas Dr. Masand, shumë trajtime janë ende në dispozicion për njerëzit që konsiderohen rezistentë ndaj trajtimit. “Njerëzit nuk duhet të heqin dorë nga shpresa vetëm sepse disa trajtime kanë dështuar. Ne kemi shumë mjete në kutinë e mjeteve jashtë trajtimit të rreshtit të parë të monoterapisë. ”

Trajtimet primare të linjës së dytë në çrregullimin bipolar përfshijnë trajtime ndihmëse të tilla si shtimi i një antipsikotik atipik në litium ose valproate ose anasjelltas. Dr. Masand vëren se "pacientët në gjendje maniake ose të përzier mund të reagojnë më shpejt ndaj litiumit ose një antikonvulsiv të kombinuar me një antipsikotik atipik".

Dhe ndërsa ilaqet kundër depresionit nuk duhet të përdoren kurrë vetëm për të trajtuar çrregullimin bipolar, shtimi i tyre në një stabilizues ekzistues të humorit ose antipsikotik konsiderohet një trajtim i linjës së dytë dhe ndonjëherë është i dobishëm për depresionin bipolar. "Për më tepër, armodafinil ndihmës (Provigil) mund të jetë gjithashtu i dobishëm në depresionin bipolar," Dr. Masand. tha


It's unfortunate, but it happens. Some people are simply misdiagnosed. You might actually have another condition, like bipolar disorder, an anxiety disorder, or a substance-induced mood disorder, and not treatment-resistant depression.

That's why it's so important to work with an expert. You might want to ask your doctor if they're consulted with anyone else. Or take your medical records to another doctor and get a second opinion.

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American Psychiatric Association, Practice Guideline for the Treatment of Patients with Major Depression, 2000.

American Psychological Association, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision, 2000.

Cadieux, R.J. American Family Physician, December 1998.

Depression and Bipolar Support Alliance: "Treatment Challenges: Finding Your Way To Wellness."

Fochtmann, L.J. and Gelenberg, A.J., Focus, Winter, 2005.

Keller, M.B., Journal of Clinical Psychiatry, 2005.

National Institute of Mental Health, Press Release, "Mutant Gene Linked To Treatment Resistant Depression."