Instructions for use DEPAKINE CHRONO
The use of antiepileptic drugs may in rare cases be accompanied by the recurrence and development of more severe seizures or the episodic appearance of a new type of seizure in patients, these seizures are not dependent on the spontaneous fluctuations established in these patients. This primarily concerns simultaneously administered antiepileptic therapy, pharmacokinetic interactions with other drugs, toxicity, and overdose.
To avoid overdose, you should not use simultaneously other drugs whose metabolism produces valproic acid (including divalproate, valpromide).
There are extremely rare reports of severe and fatal cases of liver disease. In the vast majority of cases, such liver damage occurs within the first 6 months of treatment, usually between 2 and 12 weeks, and most often with combination therapy with antiepileptic drugs. At increased risk are infants and children under 3 years of age with severe epilepsy, especially those associated with brain damage, mental retardation, and/or congenital metabolic or degenerative diseases. Over the age of 3 years, the frequency of such complications decreases significantly and gradually decreases with age.
Early diagnosis of liver lesions is based primarily on clinical examination. In particular, you should take into account 2 types of symptoms that may precede jaundice, especially in patients at risk:
- on the one hand, nonspecific general symptoms, usually appearing suddenly, such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain;
- on the other hand, relapse of epileptic seizures, despite adequate treatment.
It is recommended to inform the patient, and if it is a child, then his family, that if these clinical symptoms develop, you should immediately consult a doctor. In such cases, in addition to clinical examination, a liver function test should be immediately performed.
In order to timely detect liver dysfunction, it is necessary to periodically monitor liver function during the first 6 months of treatment, especially in patients at risk. Among the standard parameters, the most important are tests reflecting the protein-synthetic function of the liver and especially the prothrombin index. If a pathologically low level of prothrombin is detected, especially in combination with other laboratory test results (significant decrease in the level of fibrinogen and blood coagulation factors, increase in the level of bilirubin and transaminases), treatment with Depakin Chrono should be suspended. If the patient has been prescribed salicylates (concomitant therapy), as a precautionary measure, their use should also be discontinued, since they are metabolized along the same route.
In extremely rare cases, severe forms of pancreatitis were observed, which in some cases led to death. These cases were observed regardless of the patient's age or duration of treatment, although younger children appear to be at increased risk.
Pancreatitis with an unfavorable outcome was usually observed in young children, in patients with severe epilepsy, brain damage, or when using complex anticonvulsant therapy. Insufficiency of liver function in pancreatitis increases the risk of death.
When treating with Depakine Chrono, as with other antiepileptic drugs, a slight, isolated and temporary increase in transaminase levels may be observed, especially at the beginning of treatment in the absence of any clinical symptoms. In this case, it is recommended to do a more complete laboratory examination (including determination of the prothrombin index), if necessary, adjust the dose and repeat the tests depending on changes in parameters.
For asymptomatic thrombocytopenia, reducing the dose of sodium valproate usually achieves regression of thrombocytopenia if the platelet count and epilepsy control allow.
The condition of patients who experience an increase in body weight during therapy with Depakine Chrono should be monitored, because this is a risk factor for the development of polycystic ovary syndrome.
Patients should be warned about the risk of weight gain early in treatment and the need to follow an appropriate diet.
Before starting therapy or surgery in the case of hematomas or spontaneous bleeding, it is recommended to conduct a hematological blood test (determine the blood count, including platelet count, bleeding time and coagulation tests).
In patients with renal failure, it is recommended to take into account the increased concentration of free form of valproic acid in the serum and reduce the dose.
In case of acute abdominal pain and gastrointestinal symptoms (nausea, vomiting and/or anorexia), it is necessary to conduct diagnostic tests for the presence of pancreatitis and, in case of elevated levels of pancreatic enzymes, discontinue the drug and prescribe alternative therapy.
Sodium valproate is not recommended for use in patients with carbamide cycle enzyme deficiency. In such patients, several cases of hyperammonemia accompanied by stupor and/or coma have been described.
Although it has been shown that during treatment with Depakine Chrono, dysfunction of the immune system is extremely rare, the potential benefits of therapy and the risks should be assessed if it is necessary to use the drug in patients suffering from SLE.
Patients should be warned about the risk of weight gain early in treatment; To minimize this effect, the patient should follow an appropriate diet.
Use in pediatrics
In children with unexplained gastrointestinal symptoms (anorexia, vomiting, episodes of cytolysis), a history of lethargy or coma, mental retardation, or a family history of death of a newborn or young child, metabolic studies, especially ammonemia, should be performed before initiating treatment with sodium valproate. on an empty stomach and after meals.
The simultaneous administration of salicylate derivatives to children should be avoided due to possible hepatotoxicity.
Impact on the ability to drive vehicles and operate machinery
During treatment, patients should be warned about the possible occurrence of temporary drowsiness and the need to be careful when driving vehicles and other activities that require high concentration and speed of psychomotor reactions (especially when using combined anticonvulsant therapy).
PsyAndNeuro.ru
We present to your attention a review translation of the first clinical recommendations in the history of psychiatry for the treatment of mixed conditions in bipolar affective disorder of the World Federation of Societies of Biological Psychiatry, prepared jointly by the scientific Internet portal “Psychiatry & Neuroscience” and the Clinic of Psychiatry and Addiction Medicine Doctor SAN.
Mixed conditions have attracted the attention of specialists only recently. The interest is largely due to their high prevalence and poor prognosis. 70% of patients with manic symptoms also have symptoms of depression. Observations of such mixed states support the idea that bipolar disorder is by no means “madness in two forms,” an illness in which two polar states—manic and depressive—are clearly separated.
It's time to create a guideline that focuses exclusively on mixed disorders. Current recommendations include extrapolations from studies that have examined cases of pure mania. Based on these extrapolations, recommendations were made for mixed conditions. However, mixed depression (depression with hypo/manic symptoms) was rarely taken into account.
The presence of depressive symptoms in the manic phase was noted at the beginning of the 19th century. German scientists. In the middle of the 19th century. transition states observed at the end of depression and the onset of mania have been described. In transitional states, the symptoms of mania and depression are mixed.
The first systematic description of mixed states was made by Kraepelin and Weingandt in 1899. Their description proceeds from the fact that between pure mania and pure depression there are subtypes in which the features of depression and mania are mixed in different combinations.
The main problem in treating mixed conditions is that there is still no common definition of what they are. The diagnostic criteria of DSM-IV, ICD-10 and DSM-V are summarized in Table 1. This guideline, which is based on the diagnostic criteria of DSM-IV, refers to the following situations:
- immediate treatment of a manic episode with three or more depressive symptoms, including anxiety, irritability, and agitation
- immediate treatment of a bipolar depressive episode with three or more hypomanic or manic symptoms
- continuation of treatment and prevention of recurrence of a mixed episode
- preventing a mixed episode after a manic or depressive episode
Due to the lack of a common understanding of mixed conditions, data on their prevalence varies greatly. Mixed conditions are noted to become more frequent as bipolar disorder progresses, especially in women. The gender proportion, according to some sources, appears to be 60:40 in favor of women. Manic patients with mixed conditions are more likely to be admitted to the hospital and spend more time there. It has also been noted that patients with mixed conditions are more likely to abuse substances.
Table 1. Diagnostic criteria for mixed conditions
| ICD-10 (F38 (single episode) and F31.6) | DSM-V mixed manic traits specifier | Specifier for mixed depressive traits in DSM-V | |
| Symptoms | The episode is characterized by a mixture or sudden change (over several hours) of hypomanic, manic and depressive symptoms | Manic or hypomanic episode with at least three of the six core depressive symptoms present on more than half the days of the episode | Major depressive episode with at least three of seven core manic/hypomanic symptoms observed on more than half of the days of the depressive episode |
| Duration criterion | Manic and depressive symptoms must occur most of the time for at least two weeks | One week for a manic episode, four days for a hypomanic episode | Two weeks (criterion for depression) |
| Severity | Not specified. | No specifications except: if there are symptoms to diagnose mania and depression simultaneously, the diagnosis should be “manic episode with mixed features”, due to the clinical severity and the deterioration that mania brings. | No specification except: if there are symptoms to diagnose mania and depression simultaneously, the diagnosis should be “manic episode with mixed features” |
| Criteria for inclusion/exclusion | The episode is not associated with substance use (F1) or organic mental disorder (F0). For F31.6: there must be a history of at least one documented hypomanic or manic episode (F30.-), depressive episode (F32.-) or mixed affective episode (F38.00). | Mixed states are not associated with surfactants. | Mixed states are not associated with surfactants. |
A – Strong evidence from controlled studies
A category is assigned if there are: two or more double-blind, parallel group, randomized controlled trials (RCTs) showing superiority over placebo (or in the case of psychotherapy, superiority to “psychological placebo”), or one or more positive RCTs showing superior to or as effective as a comparator, with three groups of participants and a placebo control, or in a well-designed experiment (where a standard comparator exists).
If there are studies that are negative (studies that do not show superiority over placebo or that show inferior efficacy compared to the comparator), each study must have at least two additional studies with positive results or a meta-analysis of all available studies showing superiority over placebo and higher efficacy compared to the comparator drug. Research must meet established methodological standards.
B – Limited strength of evidence from controlled studies
A category is assigned if there is: one or more RCTs showing superiority over placebo (or in the case of psychotherapy, superiority over “psychological placebo”) or a randomized controlled comparison with standard treatment without placebo control with a sample size sufficient for the experiment or an a priori designed analysis subgroup included in the study protocol, and for every one negative result (studies not showing superiority over placebo or showing inferior efficacy compared with the comparator) there must be at least one additional positive result or a meta-analysis of all available studies showing superiority over placebo and higher efficacy compared to the comparator drug.
C – Evidence from uncontrolled studies or case reports, expert opinion, post hoc analysis of RCTs
A category is assigned if there are: one or more naturalistic open-label studies with a positive result (with a minimum number of patients evaluated) or a comparison with a reference product in a sample of insufficient size for a comparative experiment and no controlled studies with a negative result or clinical cases: one or more than one positive result and there are no controlled studies with a negative result or there is a post hoc analysis of an RCT (not planned a priori as part of the study protocol) or there are expert opinions
D - Conflicting results
RCTs with positive results are inferior or approximately equal in number to RCTs with negative results.
E – Negative evidence
Most RCTs or exploratory studies show no superiority over placebo (or, in the case of psychotherapy, superiority over “psychological placebo”) or lower efficacy compared to the comparator.
F – Lack of evidence
No studies have been conducted to demonstrate effectiveness or ineffectiveness.
Recommendation levels (RG):
1 – Category of evidence A and good risk/benefit ratio
2 – Category of evidence A and average risk/benefit ratio
3 – Category of evidence B
4 – Evidence category C
5 – Evidence category D
Additional Evidence (FE)
++ – Some supporting additional evidence, such as a meta-analysis or studies with a positive result, that do not meet the criteria for an “A” or “B” category of evidence
+ – Some supporting additional evidence, such as limited data from open studies
0 – Inconsistent data or missing data
(-) – Some disconfirming additional evidence, such as limited disconfirming data from open-label studies/Some disconfirming additional evidence, such as a negative meta-analysis or studies with a negative result that do not meet the criteria for an “A” or “B” evidence category ”
Safety and Tolerability (ST)
++ – Very good
+ – Good
0 – Advantages and disadvantages equal or no data
(-) – There are problems/Serious problems
Table 2. CE and RG for immediate treatment of mixed conditions
MM: mixed manic; DM: mixed depressive; MS: manic symptoms; DS: depressive symptoms; M: mania; D: depression; Mx: mixed episode; MIE: first manic episode; DIE: first depressive episode; MxIE: first episode of mixed state; CE: category of evidence; FE: additional evidence; ST: safety and tolerability; RG: recommendation level.
| CE for acute episodes of DM (monotherapy) | FE for treatment | ST for treatment | RG for immediate treatment of mixed conditions | |
| Asenapine | E for MS C for DS | F | + | 4 for MM (monotherapy, DS only) |
| Antidepressants | F | F | – | Not recommended |
| Aripiprazole | B for MS B for DS | F | 0 | 3 for MM (monotherapy) |
| Valproic acid | C for MS | F | + | 4 for MM (monotherapy) |
| Gabapentin | F | F | + | 4 for MM (combination therapy) |
| Ziprasidone | C for MS C for DS | F | + | 4 for MM (monotherapy) 3 for DM (combination therapy) |
| Carbamazepine | C for MS C for DS | C for DS | – | 4 for MM (monotherapy) 4 for DM (monotherapy, only for DS) |
| Cariprazine | C for MS F for DS | F | + | 4 for MM (monotherapy for MS only) |
| Quetiapine | E | F | 0 | 3 for MM (combined therapy, for DS) 4 for MM (combined therapy, for MS) |
| Clozapine | C for MS | F | – | 4 for MM (monotherapy, combination therapy, MS only) |
| Lamotrigine | F | F | + | Not recommended |
| Lithium | F | F | – | Not recommended |
| Lurasidone | F | C | + | 4 for DM (monotherapy) |
| Oxcarbazepine | F | F | + | 4 for MM (in combination with lithium) |
| Olanzapine | A for MS C for DS | C | + | 2 for MM (monotherapy) 2 for MM (in combination with valproic acid) 4 for DM (monotherapy) |
| Paliperidone | B for MS E for DS | F | 0 | 3 for MM (monotherapy) |
| Risperidone | C | F | 0 | 4 for MM (monotherapy) |
| Typical antipsychotics | C | F | 0 | 4 for MM (monotherapy) |
| Topiramate | F | F | 0 | 5 for MM (combination therapy) |
| ECT | F | F | – | 4 for MM (combination therapy) 4 for DM (combination therapy) |
Table 3. CE and RG for maintenance therapy after a mixed episode and for its prevention
MM: mixed manic; DM: mixed depressive; M: mania; D: depression; Mx: mixed episode; MIE: first manic episode; DIE: first depressive episode; MxIE: first episode of mixed state; CE: category of evidence; FE: additional evidence; ST: safety and tolerability; RG: recommendation level.
| CE to prevent recurrent episode (monotherapy) | CE to prevent a mixed episode after a manic or depressive episode (monotherapy) | ST for long term treatment | RG for maintenance therapy | |
| Asenapine | F | F | + | Not recommended |
| Antidepressants | F | F | 0 | Not recommended |
| Aripiprazole | F | E (MIE) F (DIE) | + | 4 to prevent D after MxIE (combination therapy) |
| Valproic acid | E | B | – | 3 to prevent a mixed episode after an episode of undetermined type (monotherapy) or after a manic or mixed episode |
| Gabapentin | F | F | + | Not recommended |
| Ziprasidone | C | F | + | 4 to prevent mania after MxIE (monotherapy) |
| Carbamazepine | F | E | – | Not recommended |
| Cariprazine | F | F | + | Not recommended |
| Quetiapine | B (for manic, depressed, any type) | E | – | 2 to prevent a new episode after MxIE (combination therapy) 3 to prevent a new episode after MxIE (monotherapy) |
| Clozapine | F | F | – | Not recommended |
| Lamotrigine | F | E | ++ | Not recommended |
| Lithium | B for all types B for manic | D | – | 3 to prevent a new manic episode and an episode of any type after MxIE (monotherapy) 5 to prevent a mixed episode after the first episode of any type |
| Lurasidone | F | F | + | Not recommended |
| Oxcarbazepine | F | F | 0 | Not recommended |
| Olanzapine | B | D | – | 3 to prevent a new episode after MxIE (monotherapy) |
| Paliperidone | F | F | 0 | Not recommended |
| Risperidone | F | F | – | 4 to prevent a new episode after MxIE (combination therapy) |
| Typical antipsychotics | F | F | – | Not recommended |
| Topiramate | F | F | 0 | Not recommended |
| ECT | F | F | – | 4 to prevent a new episode after MxIE (combination therapy) |
Several drugs are effective in treating patients with mixed conditions. But none of these drugs works equally well at all stages of treatment or in all subgroups of patients. There are still more questions than answers regarding the treatment of mixed conditions.
For the immediate treatment of mixed mania, olanzapine, paliperidone, and aripiprazole are the best proven medications. For mixed bipolar depression, ziprasidone alone has been shown to be effective in combination therapy (levels of recommendation 1-3). Level 4 recommendation categories include carbamazepine, lurasidone, olanzapine, and ECT.
Thus, for mixed bipolar depression, there are no drugs with convincing evidence. Additionally, ziprasidone has only been studied in bipolar II disorder.
Quetiapine, lithium and olanzapine (as monotherapy and in combinations) are best suited to prevent a new episode of mixed conditions.
Little is known about how to prevent a mixed episode after a primary manic, mixed, or depressive episode. But at least valproic acid, olanzapine and lithium show some effectiveness.
As a result, it turns out that olanzapine (as monotherapy and in combination) is the drug that is suitable for most situations and subgroups of patients. It can also be assumed that combination therapy is more effective than monotherapy in the treatment of mixed conditions.
It is believed that valproic acid is more effective than lithium in mixed conditions. In the absence of reliable data on lithium, it can be assumed, although with a low recommendation category, that this is true for immediate treatment. As with mania and depression, clozapine and ECT are options that should be considered when all other treatments have failed.
The material was prepared with the support of the Doctor SAN clinic, a leading private psychiatric clinic and one of the best drug treatment hospitals in the North-West region.
Translation: Filippov D.S.
Translation editor: Kasyanov E.D.
