Сравнение лития и флуоксетина у больных БАР

Background
Controversy exists over antidepressant use in rapid-cycling bipolar disorder.
Aims

Exploratory analysis of safety and efficacy of fluoxetine v. lithium monotherapy in individuals with rapid- v. non-rapid-cycling bipolar II disorder.

Method

Randomised, double-blind, placebo-controlled comparison of fluoxetine v. lithium monotherapy in patients initially stabilised on fluoxetine monotherapy (trial registration NCT00044616).

Results

The proportion of participants with depressive relapse was similar between the rapid- and non-rapid-cycling groups (P = 0.20). The odds of relapse were similar between groups (P = 0.36). The hazard of relapse was similar between groups (hazard ratio 0.87, 95% CI 0.40–1.91). Change in mania rating scores was similar between groups (P = 0.86). There was no difference between groups in the rate of syndromal (P = 0.27) or subsyndromal (P = 0.82) hypomania.

Conclusions

Depressive relapse and treatment-emergent mood conversion episode rates were similar for lithium and fluoxetine monotherapy and placebo during long-term, relapse-prevention therapy of rapid- and non-rapid-cycling bipolar II disorder.

Efficacy and mood conversion rate during long-term fluoxetine v. lithium monotherapy in rapid- and non-rapid-cycling bipolar II disorder

Эбселен как потенциальная замена литию

Lithium is the most effective mood stabilizer for the treatment of bipolar disorder, but it is toxic at only twice the therapeutic dosage and has many undesirable side effects. It is likely that a small molecule could be found with lithium-like efficacy but without toxicity through target-based drug discovery; however, therapeutic target of lithium remains equivocal. Inositol monophosphatase is a possible target but no bioavailable inhibitors exist. Here we report that the antioxidant ebselen inhibits inositol monophosphatase and induces lithium-like effects on mouse behaviour, which are reversed with inositol, consistent with a mechanism involving inhibition of inositol recycling. Ebselen is part of the National Institutes of Health Clinical Collection, a chemical library of bioavailable drugs considered clinically safe but without proven use. Therefore, ebselen represents a lithium mimetic with the potential both to validate inositol monophosphatase inhibition as a treatment for bipolar disorder and to serve as a treatment itself.

 A safe lithium mimetic for bipolar disorder.

Литий-индуцированный гиперпаратиреоз

Approximately 15% to 20% of patients receiving long-term lithium treatment show elevated calcium levels, although only a few of these patients also have significant elevations of PTH levels and clinical symptoms of hyperparathyroidism. Interestingly, lithium-associated clinical hyperparathyroidism is almost always caused by a single parathyroid adenoma rather than 4-gland hyperplasia.
...
Neuropsychiatric symptoms associated with primary hyperparathyroidism include anxiety as well as cognitive and psychotic presentations. However, the most common presentation is depression with associated apathy. In a prospective study of 34 patients with hyperparathyroidism, Velasco and colleagues6 found that approximately one-third of participants had no psychiatric symptoms, one-third had affective symptoms (with or without paranoia), and one-third had cognitive impairment. Affective symptoms were most common in patients with modest elevations in electrolyte levels, while cognitive deficits were more often related to higher calcium concentrations.

 Hyperparathyroidism Resulting From Lithium Treatment Remains Underrecognized

Роль минеральных веществ в патогенезе психических расстройств

Early studies showed that women affected by chronic depression sometimes have copper, zinc, and cesium deficiencies [37,38]. Later studies suggest that the presence of depression and other neuropsychiatric symptoms is due to the deposit of copper in the central nervous system [39]. Eggers et al. [40] used SPECT to demonstrate a reduction in thalamichypothalamic presynaptic dopamine and serotonin transporters due to the accumulation of copper. There was a negative correlation between the density of presynaptic dopamine transporters and the severity of depression as assessed using the Hamilton Rating Scale for Depression.

It was recently hypothesized that trace elements play an important role in the pathogenesis of

bipolar disorders by causing neurodegeneration [41]. Moreover, essential elements like vanadium have been implicated as a causative factor for bipolar mood disorder, while elevated vanadium and molybdenum levels have been reported in serum samples from bipolar mood disorder patients [41]. This latter study showed, using DSM-IV standard diagnostic criteria and classification into types I, II, and V according to the concept of Young and Klerman, that Na, K, P, Cu, Al, and Mn were elevated significantly in Bipolar I (Mania) (P < 0.001). In Bipolar II hypomania, Na, S, Al, and Mn were increased significantly (P < 0.02), while in Bipolar II depression, Na, K, Cu, and Al were increased significantly (P < 0.001). Finally, in Bipolar V, Na, Mg, P, Cu, and Al were increased significantly (P < 0.002) compared to a control group [41]. A recent study by Gonzales-Estecha and colleagues [21] found higher serum copper and zinc, blood lead and cadmium, and urine lead, cadmium, and thallium concentrations in patients diagnosed with bipolar disorders compared to a control group.

Increased neuronal oxidative stress (OxS) induces deleterious effects on signal transduction, structural plasticity and cellular resilience, mostly by inducing lipid peroxidation in membranes, proteins and genes [42]. It has been hypothesized that these pathological processes occur in critical brain circuits that regulate affective functioning, emotions, motoric behavior and pleasure involved in bipolar disorder (BD) [43,44].

The brain is particularly vulnerable to oxidative damage since it contains large amounts of polysaturated fatty acids and possesses low antioxidant capacity [45]. Several studies have demonstrated altered OxS parameters in the pathophysiology and therapeutics of BD, including changes in the levels of enzymes superoxide dismutase (SOD), catalase (CAT) and thiobarbituric acid reactive substances (TBARS) [46]. The well-known stabilizing agent Lithium was found to limit the enzyme activity, potentially lowering hydrogen peroxide and hydroxyl radical formation. Similarly, lithium was also shown to reverse increased OxS parameters in BD [43,47]. For instance, a decline in lipid peroxidation and an increase in CAT levels were observed in valproate and lithium-treated rats [42,48]. Accumulation of copper was shown to increase oxidative stress in bivalve species [49]. In skeletal muscle of Broilers Under Heat Stress, copper decreases because of dietary Selenium, Vitamin E, and their combination with an increase in antioxidant defense [50]. In humans accumulation of copper was associated with oxidative stress in allergic asthma patients, and introduction of nutritional supplement therapy accompanies improved oxidative stress, immune response, pulmonary function, and decrease in copper plasma levels [51]. On the other hands copper levels were elevated in several brain areas in a degenerative disease such as Niemann-Pick C [52]. Interestingly, Nieman-Pick C disease was specifically indicated to be associated with Bipolar Disorders [53]. If the results of our study are further confirmed, it will lend significant support to the hypothesis that minerals such as copper play an etiological role in psychiatric disorders, and WD may serve as a pathogenic model for the bipolar disorder. 

Bipolar disorders and Wilson’s disease

Литий и циркадные ритмы

According to Dr. Qing-Jun Meng in the university’s Faculty of Life Sciences, the extreme mood swings in bipolar disorder are associated with disruptions in circadian rhythms — the 24-hour rhythms controlled by our body clocks that govern our day and night activity.
“By tracking the dynamics of a key clock protein, we discovered that lithium increased the strength of the clockwork in cells up to threefold by blocking the actions of an enzyme called glycogen synthase kinase or GSK3,” he said.

Lithium Impacts Bipolar Disorder by Strengthening Body Clock 

Литий как препарат выбора для долгосрочной терапии БАР

Lithium is linked to thyroid and parathyroid abnormalities, weight gain, and an increased risk for reduced urinary concentrating ability, but the jury is still out on whether it causes birth defects, new research suggests.
The systematic review and meta-analysis of 385 randomized, controlled trials and observational studies also found scant evidence that lithium produced a clinically significant reduction in renal function in most patients and that the risk of end-stage renal failure among users of the drug is low.
"Lithium is the most effective long-term therapy for bipolar disorder, protecting against both depression and mania and reducing the risk of suicide and short-term mortality," Professor John R. Geddes, MD, University of Oxford and Warneford Hospital, Oxford, United Kingdom, and colleagues write.
"Because lithium has always been an unpatented, cheap drug, it is not commercially promoted and the potential for adverse effects has been a substantial deterrent to use," they write.
There have been concerns about lithium’s effect on renal function and its purported teratogenicity. Despite these concerns, there has not been an "adequate synthesis of the evidence for adverse effects," the authors note.

Lithium's Safety Examined

Малые дозы лития могут предупреждать проблемы с памятью при болезни Альцгеймера

Low-dose lithium appears to slow the progression of memory loss and cognitive decline in individuals with amnestic mild cognitive impairment (aMCI), a significant risk factor for Alzheimer's disease (AD), a new study suggests.

A randomized, placebo-controlled trial showed treatment with lithium, an old drug historically used to treat bipolar disorder (BD) and major depression, was associated with a significant decrease in cerebrospinal fluid (CSF) concentrations of phosphorylated tau (P-tau) and better cognitive performance in individuals with aMCI. Furthermore, the drug was well tolerated and had a side effect profile similar to placebo.

Old Drug May Hold New Promise in Alzheimer's Disease

Сезонное аффективное расстройство в рамках БАР и рекуррентной депрессии

Many see seasonal affective disorder (SAD) as synonymous with winter depression. However, depression is only half of the problem; spring and summer mania tend to be ignored. Beginning with winter depression, core symptoms resemble hibernation. People sleep more, eat more, and are less interested in usual activities. They are not sad in mood, typically, and may be unaware that their slowed down, uninterested behavior reflects a kind of depression.

Moreover, light itself is not the only cause of depression. Light interacts with a person's own sensitivity to depression. Some people, especially those with bipolar disorder or recurrent unipolar depression, are sensitive to changes in light, and will develop winter depression even in areas with reasonable light levels, such as Georgia or Italy. Others are insensitive to light, and will not develop SAD even in areas with low light levels, such as New England or Scandinavia.

This leads to another misconception about SAD. It is a diagnosis of exclusion, and should not be diagnosed in persons with bipolar disorder or recurrent unipolar depression. SAD means someone has only depression in the winter, and almost never has depression any other time of year.

Light entrains our circadian rhythms; it is what keeps us on regular sleep-wake cycles. When sleep is impaired and reduced, an antidepressant effect occurs, and, in sensitive persons, mania materializes. This is what takes place in the spring and summer when light greatly increases. Longer duration of sleep leads to depression in sensitive persons. Circadian cycles appear to be biologically abnormal in people with bipolar disorder and recurrent depression, hence their sensitivity to light. One of the effects of lithium, for instance, is to lengthen circadian cycles, which appear to be abnormally shortened in animal models of mania.

I've developed my own recommendations for both winter depression and summer mania, which one could call "light precautions." They are as follows, briefly.

In winter. Increase your exposure to light as much as possible. Go out for a walk at noon for up to an hour without any sunglasses on; sleep with all the blinds up.

In summer. Reduce your exposure to light as much as possible: Always wear sunglasses; get room-darkening shades; and sleep in as much darkness as possible. (It is key to adjust one's exposure to natural morning sunlight. It is amazing how many people who oversleep never think of pulling up their window shades, and how many people who don't sleep enough don't think about getting room-darkening window shades.)
Light Box Treatment

Light box treatment essentially replaces the sunlight that is missing in wintertime. Most light boxes provide about 10,000 lux of light, and are meant to be used in the mornings, which is when the sun would normally have risen earlier than it does in the depths of winter. Patients should read or eat breakfast while exposed to indirect light from the box at about arm's length for about 30 minutes daily. Just as one does not directly look at the sun, patients should not directly look at light boxes; this causes ocular damage.

The Truth About Seasonal Affective Disorder

Аффективные расстройства быстрого цикла ассоциированные с менструальным циклом

Affective fluctuations during menstruation have drawn considerable interest from researchers for a long time.1 Data indicates increased frequency of depression associated with menstrual period in adolescence,2 though there is limited information about the differences in the course or symptoms of bipolar disorder associated with menstrual period in adolescents. The question of the direction of mood shifts in the course of bipolar disorder with specific phases of menstrual cycle has been raised, albeit with limited and inconsistent results.3 We present a case of an adolescent female with cyclic affective changes akin to rapid cycling bipolar disorder starting in the premenstrual (luteal) period and subsiding with onset of menstruation, and we try to explore the biological underpinnings of inherent propensity for the development of bipolar disorder using quantitative electroencephalography (qEEG)

There was high spectral power in low frequency (theta band) over the right temporal region which was further corroborated by LORETA and revealed high signal density over the right temporal region for the same frequency band

A review3 presented findings of 24 prospective studies of affective fluctuations during the menstrual cycle. In most cases the authors found that negative moods marked by irritability, restlessness, anxiety, tension, migraine, sleep disturbance, and impaired concentration occurred more often during the premenstrual and menstrual phases than at other times in the cycle. There were only a few cases of positive moods—such as an increased feeling of well-being, elation, pleasantness, and activation—during the follicular and midcycle phases.3 This case presents with positive mood state, though irritability and headache were present as seen in premenstrual syndrome (PMS). This is an atypical presentation of PMS as opposed to the more common occurrence of elated moods during midcycle; in our case it occurred in premenstrual phase.7 It has been reported that whereas menstrual problems appear to occur more frequently in younger than in older women, premenstrual symptoms occur more often in older women. This suggests a relation between age and menstrual symptoms.

The overlap in symptomatology between PMS and cyclothymia, often considered to be a variant of manic-depressive illness, has given rise to therapeutic trials of lithium carbonate in women with PMS, with mixed results.14 Lithium treatment has been beneficial in controlling premenstrual affective changes, and this led us to use the same in our case.

Rapid Cycling Associated With Menstrual Periods in an Adolescent: Electrophysiological Underpinnings for Bipolarity

Нейротоксичность лития при нормальных концентрациях

To the Editor: Lithium is used with great success in the treatment and prophylaxis of bipolar disorders, unipolar recurrent depression, and endogenous depression that is resistant to conventional treatment. It is also known to be neurotoxic at higher serum levels. In rare cases patients develop symptoms of intoxication even with normal lithium levels.

Case Report

A 61-year-old man with history of bipolar disorder that was managed with lithium for more than 20 years presented with complaints of psychomotor slowdown, unsteady gait, memory deficits, restlessness, sleep disorder, and severe tremor in his hand that prevented him from eating or drinking properly. These symptoms had begun in the previous week. There was no recent history of fever, respiratory, gastrointestinal, or urinary complaints. He was medicated with lithium, 800 mg/day, and fluvoxamine, 200 mg/day, and the dosage of his medication had remained unchanged over the last year.

Neurological examination showed psychomotor slowdown, inattention, temporal disorientation, severe episodic memory impairment, motor and verbal perseveration, slurred speech, and hypophonia. Symmetrical global and segmental bradykinesia and lead-pipe rigidity, as well as tremor at rest, intention, and posture, were also evident. His gait was abnormal with shuffling small steps and a hunched-forward upper body.

An analytic study revealed no abnormalities, including CBC, renal, thyroid and hepatic function, and PCR. Lithium serum levels were normal (1.0 mmol/liter).

EEG showed diffuse slow background activity, mainly at 5–6 Hz, with periods of greater lentification at 3 Hz, which is compatible with moderate to severe encephalopathy. A brain CT was normal. The patient was admitted and lithium was stopped. There was remarkable clinical improvement over the next days, and he was discharged at day 5, asymptomatic and on valproic acid (300 mg/day).

Lithium Neurotoxicity at Normal Serum Levels

PHQ-9

Table 3. PHQ-9

1. Over the past 2 weeks, how often have you been bothered by any of the following problems?
	Not at all (0)	Several days (1)	More than half the days (2)	Nearly every day (3)
a. Little interest or pleasure in doing things
b. Feeling down, depressed, or hopeless
c. Trouble falling/staying asleep, sleeping too much
d. Feeling tired or having little energy
e. Poor appetite or overeating
f. Feeling bad about yourself -- or that you are a failure or have let yourself or your family down
g. Trouble concentrating on things, such as reading the newspaper or watching television
h. Moving or speaking so slowly that other people could have noticed. Or the opposite -- being so fidgety or restless that you have been moving around a lot more than usual
i. Thoughts that you would be better off dead or of hurting yourself in some way
2. If you checked off any problem on this questionnaire so far, how difficult have these problems made it for you to do your work, take care of things at home, or get along with other people?
	Not difficult at all	Somewhat difficult	Very difficult	Extremely difficult

Table 4. Interpretation of PHQ-9 Results

Score/ Symptom Level	Treatment
0-4 No depression	Consider other diagnoses
5-9 Minimal	▪ Consider other diagnoses ▪ If diagnosis is depression, watchful waiting is appropriate initial management
10-14 Mild	▪ Consider watchful waiting ▪ If active treatment is needed, medication or psychotherapy is equally effective; consider function score in choosing treatment
15-19 Moderate	▪ Active treatment with medication or psychotherapy is recommended ▪ Medication or psychotherapy is equally effective
20-27 Severe	▪ Medication treatment is recommended ▪For many people, psychotherapy is useful as an additional treatment ▪ People with severe symptoms often benefit from consultation with a psychiatrist

Data from Kroenke K, Spitzer R. Psychiatr Ann. 2002;32:509-521.

A number of combinations have some benefit in selected patients, including:

• Lithium augmentation at stage 3 of STAR*D resulted in remissions in 15.9%.^[84] Lithium in combination with SSRIs and TCAs also has been effective in placebo-controlled studies, most involving small numbers of subjects. Such treatment requires monitoring of lithium levels, because there is a small difference between therapeutic and toxic levels.^[85]
• Thyroid hormone, and particularly triiodothyronine, has been studied for augmentation with the TCAs. In the STAR*D study, at step 3, augmentation with triiodothyronine led to a remission rate of 24.7%.^[84] Placebo-controlled studies have involved small numbers of subjects and have had mixed results.^[86]
• A heterocyclic-SSRI combination in 1 small study produced more rapid treatment onset and increased the likelihood of remission.^[87] In the study, a combination of fluoxetine and desipramine (a norepinephrine reuptake inhibitor) was more effective in achieving remission than either drug used as monotherapy: 53.8% for the combination, compared with 7.1% and 0%, respectively. However, such combinations can produce the serotonin syndrome, which is potentially life-threatening, and the dose of the heterocyclic must be adjusted using blood levels because SSRIs increase TCA levels through CYP-450 isoenzyme interactions (eg, fluoxetine increases the levels of desipramine 3- to 4-fold).^[88] Consequently, this augmentation strategy should rarely be considered in primary care.
• Mirtazapine has recently been evaluated in combination therapy with an SSRI (fluoxetine), an SNRI (venlafaxine), or bupropion.^[89] The investigators found that all 3 combinations were more effective than fluoxetine alone in achieving remission (52%, 58%, 46%, respectively, compared with 25%). In patients who responded, double-blind discontinuation resulted in relapse in about 40%. Of note, treatment was initiated with these combinations, rather than mirtazapine being used as an augmenting agent in those not initially responding.
• Methylfolate and folate have been used to augment SSRIs, resulting in increased rates of remission, particularly in women.^[90] The degree to which the response is due to folate deficiency, and whether methylfolate is of greater benefit due to its increased ability to cross the blood-brain barrier, are subject to further research.
• Antidepressants and hypnotics have been used together, with early improvement not only in sleep measures, but also in rates of depression remission.^[91]
• Stimulant drugs have been used as augmentation of heterocyclics or SSRIs.^[92] Of note, in individuals with comorbid medical illness, amphetamine stimulants should be used with caution, particularly if cardiac disease is potentially present.

Clinical and Pharmacologic Strategies to Achieve Remission in Depression

Распространённость и факторы риска развития маниакальных и гипоманиакальных состояний при терапии антидепрессантами

Antidepressant-induced manias have been reported with all major antidepressant classes in a subgroup of about 20-40% of bipolar patients. Lithium may confer better protection against this outcome when compared with other standard mood stabilizers, although switch rates have been reported with comparable frequencies on or off mood stabilizers. Evidence across studies most consistently supports an elevated risk in patients with (i) previous antidepressant-induced manias, (ii) a bipolar family history, and (iii) exposure to multiple antidepressant trials.

ANTIDEPRESSANT-INDUCED MANIA: AN OVERVIEW OF CURRENT CONTROVERSIES

Switches to hypomania or mania occurred in 27% of all patients (N = 12) (and in 24% of the subgroup of patients treated with SSRIs [8/33]); 16% (N = 7) experienced manic episodes, and 11% (N = 5) experienced hypomanic episodes. Sex, age, diagnosis (bipolar I vs. bipolar II), and additional treatment did not affect the risk of switching. The incidence of mood switches seemed not to differ between patients receiving an anticonvulsant and those receiving no mood stabilizer. In contrast, mood switches were less frequent in patients receiving lithium (15%, 4/26) than in patients not treated with lithium (44%, 8/18; p = .04). The number of previous manic episodes did not affect the probability of switching, whereas a high score on the hyperthymia component of the Semistructured Affective Temperament Interview was associated with a greater risk of switching (p = .008).

Antidepressant-induced mania in bipolar patients: identification of risk factors.

Antidepressant-induced mania or hypomania was evident in 39.6% (21/53) of the study group. Patients who developed manic features soon after starting an antidepressant had more antidepressant trials per year than those who did not (p < .05). A history of substance abuse and/or dependence was associated with substantially increased risk for antidepressant-induced mania (odds ratio = 6.99, 95% CI = 1.57 to 32.28, p = .007). Concomitant mood stabilizers were not uniformly associated with protection against inductions of mania during antidepressant trials.

The association between substance abuse and antidepressant-induced mania in bipolar disorder: a preliminary study

Эффективность лития и вальпроатов при повторных маниакальных обострениях

A larger number of previous episodes of affective disorder was associated with poor antimanic response to lithium but not to divalproex. This differential treatment response did not result from current rapid cycling or mixed states.

Explanations for reduced response to lithium in subjects with many previous episodes include the following: 1) Lithium resistance may develop with repeated episodes (2). Reduced response to lithium prophylaxis has been reported in patients with many episodes and early onset (3) and in those with more than three previous manic episodes (11). 2) Multiple lithium discontinuations could result in refractoriness to lithium. Most patients, however, have similar responses before and after lithium is discontinued (12, 13). Furthermore, in this study, previous response to lithium predicted current response (4). 3) A group of patients may have frequent episodes that were always lithium resistant, representing an inherently unstable subtype of bipolar disorder. If this proves true, early identification of such patients will be valuable in establishing lifetime treatment strategies.

These results are related only to treatment of acute mania. Further studies are needed to determine whether these relationships extend to maintenance treatment.

Differential Effect of Number of Previous Episodes of Affective Disorder on Response to Lithium or Divalproex in Acute Mania

STAR*D

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was a longitudinal, multi-center, 5-year study of common strategies for treating depression. To date, it is the United States’ largest National Institute of Mental Health funded study including over 4,000 patients. This four level trial compared traditional augmentation strategies with switching agents (Slide 2).30-34 Unlike most depression studies, in STAR*D the outcome measure was full remission.
In Level 1, the initial monotherapy phase, citalopram (mean dose of 41.8 mg) was effective at achieving remission for only ~30% of subjects. This finding has been accepted as an accurate reflection of clinical experience with any initial monotherapy. The remaining 70% were randomized to either receive bupropion or buspirone augmentation, or switched to one of three antidepressants as monotherapy—bupropion, venlafaxine, or sertraline. Augmentation resulted in a 30% response, while switching antidepressants resulted in ~20% of patients achieving remission. Level 3 included those non-remitters from Level 2 who were then randomized to either T3 or lithium augmentation, resulting in remission rates of 25% and 16% respectively. A Level 3 switch to nortriptyline (NTP) or mirtazapine (MTZ) was in general less successful than Level 3 augmentation, with 20% of NTP patients and 12% of MTZ patients remitting. Level 4 treatment options (monoamine oxidase inhibitors [MAOIs] or venlafaxine–mirtazapine-combination therapy) were provided to patients who had not responded satisfactorily to previous levels of the treatment protocol, and very few experienced full remission (14% and 7% respectively).12,35


An overall analysis of STAR*D results indicates that the chances of achieving and maintaining remission in patients with difficult-to-treat depression diminishes with every additional strategy needed. Those who fully remit early in the course of treatment have a better chance of remaining well than those who experience only symptomatic improvement. STAR*D does not tell us which treatment works better as a first or second adjunct, simply that the greatest chance of recovery appears to lie with the first two sequential treatments.

The Role of L-methylfolate in Depressive Disorders

Литий vs флуоксетин в профилактике депрессивных фаз при БАР

These findings suggest that long-term fluoxetine monotherapy may provide superior relapse-prevention benefit relative to lithium monotherapy after recovery from bipolar II major depressive episode without an increase in hypomanic mood conversion episodes.

Efficacy and Safety of Long-Term Fluoxetine Versus Lithium Monotherapy of Bipolar II Disorder: A Randomized, Double-Blind, Placebo-Substitution Study

Новое в механизме действия лития

Though it has been prescribed for over 50 years to treat bipolar disorder, there are still many questions regarding exactly how lithium works. However, in a study appearing in this month's Journal of Lipid Research, researchers have provided solid evidence that lithium reduces brain inflammation by adjusting the metabolism of the health-protective omega-3-fatty acid called DHA.

Uncovering Lithium's Mode of Action

Антидепрессанты при БАР

"Although some might argue that the precise relative risk of antidepressant-induced mania or hypomania is unknown (eg, considering intervening factors such as the natural illness course), recent literature suggests that the emergence of mania or hypomania can be reasonably attributed to antidepressant use in no more than 10% to 25% of patients with bipolar disorder"

"One large randomized trial showed comparable antidepressant efficacy with a mood stabilizer plus adjunctive venlafaxine (43%) vs sertraline (55%) vs bupropion (49%) over 10 weeks,14 but the lack of a mood stabilizer monotherapy comparison group limits the ability to anticipate whether adjunctive antidepressants increase response or remission rates more than mood stabilizers alone. Adjunctive imipramine,13 paroxetine,12,13,15 and bupropion12 yield no greater improvement in depressive symptoms than is seen with optimally dosed mood stabilizers alone."

"The largest dataset on this topic—the randomized controlled data from Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)12—found that the risk for treatment-emergent manic switch with paroxetine or bupropion was almost identical (about 10%) with or without an FDA-approved antimanic agent.

In a retrospective study, Henry et al6 found that cotherapy with lithium but not divalproex or carbamazepine protects against antidepressant-induced mania, and that switch rates to mania were the same whether or not an antidepressant was taken with an anticonvulsant. In a naturalistic retrospective study (n=158), Bottlender et al24 revealed that mood stabilizers (lithium, carbamazepine, or divalproex) prevented switches from depression to mania during treatment with TCAs but not SSRIs or MAOIs.

I favor incorporating lithium or other antimanic agents in the regimens of patients with bipolar depression not primarily to guard against antidepressant-induced mania but more for pharmacodynamic synergy—complementary mechanisms of action that collectively may produce more substantial antidepressant effects—especially when the patient’s illness course has included manic or hypomanic features in the preceding year."

"Wehr et al25 reported that antidepressants may accelerate cycling frequency (ie, inter-episode durations become shorter) in a small subgroup (N=10) of patients. By contrast, use of TCAs was not more likely in the weeks preceding shifts from depression to mania or hypomania in a 14-year follow-up study of bipolar rapid cycling from the NIMH Collaborative Depression Study.26 In fact, rapid-cycling patients spent more weeks depressed when taking lithium without a TCA than with."

Antidepressants in bipolar disorder: 7 myths and realities

Preventing Bipolar I Relapse: Results of the BALANCE Trial

Preventing Bipolar I Relapse: Results of the BALANCE Trial

Relapse rates were high overall, but better with lithium–valproate combination or lithium monotherapy than with valproate monotherapy.

Most treatment guidelines for bipolar disorder list lithium and valproate as first-line mood stabilizers, although lithium prescriptions have declined recently. In a randomized, open-label, multisite, international, 2-year trial, researchers compared the effectiveness of lithium, valproate, and their combination in preventing relapse.

First, 459 nonacutely ill patients with bipolar I disorder (74% without history of mood-stabilizer maintenance) received the combination at minimally effective doses (typically, for 4–8 weeks). The 330 participants who tolerated combination treatment were then randomized to continue the combination or to receive either monotherapy (the other drug was gradually withdrawn). Treatment groups were balanced for multiple illness characteristics.

Drug adherence was good, and follow-up covered 589.8 person-years. Relapse, defined as intervention for a new mood episode, occurred in 54% of combination-treatment recipients, 59% of lithium recipients, and 69% of valproate recipients. Combination treatment and lithium were statistically similar to each other in efficacy and superior to valproate. Combination therapy appeared most effective in preventing manic episodes and lithium in preventing depressive episodes. Results were not affected by baseline severity, polarity of the most recent episode, drug doses, blood levels, or when events in the first 3 months were excluded.

Comment: This study suggests that the most effective agents for preventing relapse are lithium–valproate combination and lithium monotherapy (numbers needed to treat, 7 and 10, compared with valproate alone). However, the high relapse rates suggest a serious need for new treatments.

Study limitations include the open treatment allocation, and the absence of both a placebo group and a systematic assessment of symptoms. Its strengths are its real-world design, diverse patient population, presence of a clinical endpoint (i.e., need for treatment change), and enrollment of patients who tolerated both drugs (in contrast to some previous studies).

Lithium is often underused. Its use may have declined because of clinicians' concerns about thyroid and renal effects, their reluctance to do the necessary monitoring, or the vigorous marketing of valproate. These results clarify that more patients should be given lithium, probably alone initially and then in combination with valproate.

— Peter Roy-Byrne, MD

Published in Journal Watch Psychiatry January 11, 2010

Citation(s):

Geddes JR et al. for the BALANCE Investigators and Collaborators. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): A randomised open-label trial. Lancet 2009 Dec 23; [e-pub ahead of print]. (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2809%2961828-6/fulltext)

http://psychiatry.jwatch.org/cgi/content/full/2010/111/1

Комбинирование клозапина с ламотриджином

Schizophrenia patients routinely are treated with polypharmacy--often with antidepressants or anticonvulsants--in attempts to improve negative symptoms, aggression, and impulsivity. Most adjuncts, however--including divalproex, antidepressants, and lithium--have shown very small, inconsistent, or no effects. The only agent with a recent meta-analysis supporting its use as augmentation in treatment-resistant schizophrenia is lamotrigine, an anticonvulsant approved for use in epilepsy...

Clozapine Augmentation with Lamotrigine

Резистентные к лечению депрессии

Antidepressants can be grouped into 6 major categories: tricyclic antidepressants (TCAs), SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), serotonin neurotransmitter (5-HT2)-receptor antagonists (eg, nefazodone, trazodone), and novel agents (eg, mirtazapine, bupropion). If a patient fails to respond to one antidepressant class, it makes sense (at least conceptually) to switch to another, although most guidelines acknowledge that 2 failed trials of SSRIs may be justifiable before switching classes.
For example, in a study by Thase and colleagues,10 58 patients failed a trial of fluoxetine; however, there was a 76% response rate to citalopram among completers. Although this study was not blinded, it is interesting that citalopram (which is believed to be the most selective of the SSRIs) was effective when another SSRI was not.
Antidepressants that are associated with discontinuation symptoms (eg, paroxetine, venlafaxine, duloxetine) may produce discontinuation syndromes when stopped that can be erroneously attributed to adverse effects of the new drug, particularly if the new drug does not possess a significant degree of serotonin reuptake inhibition.
In a study by Zarate and colleagues,21 the onset of the antidepressant effect of ketamine occurred within 2 hours. Unfortunately, the drug must be given by intravenous infusion, but because the effect persisted for 7 days, ketamine treatment may be useful if given as a series.
Another NMDA-receptor antagonist now available in the United States is memantine (FDA-approved for Alzheimer disease). Memantine was shown to be effective in an open-label study in major depression. In a double-blind, randomized trial it showed comparable effects to escitalopram in patients with major depression and alcohol dependence.
Randomized controlled trials have supported the superior efficacy of a TCA/SSRI combination, as well as a mirtazapine/SSRI combination; open studies have done the same for TCA/MAOI and SSRI/bupropion combinations.
As with lithium, a recent review concluded that the trial data that support the efficacy of T3 augmentation are of better quality with TCAs than with SSRIs

Treatment-Resistant Depression