Valproate treatment resistance

The combination of carbamazepine with lithium, valproate, and antipsychotics is often used for manic episodes in treatment-resistant patients. 

Lamotrigine is effective for the maintenance treatment of bipolar I disorder in adults. It has both antidepressant and mood-stabilizing effects, and it may have augmenting properties when combined with lithium or valproate. It has low rates of switching patients to mania. Although it is less effective for acute mania compared to lithium and valproate, it may be beneficial for the maintenance therapy of treatment-resistant bipolar I and II disorders, rapidcycling, and mixed states. It is often used for bipolar II patients. 

Post and Kramlinger (386) have also suggested that lithium added to carbamazepine may be useful in treatment-resistant mood-disordered patients. One possible basis for this approach is that carbamazepine, which has a tricyclic ring structure similar to imipramine, may sensitize postsynaptic serotonin receptors in a similar way to standard drugs such as imipramine. A mood stabilizer (e.g., lithium, valproate, carbamazepine) plus antidepressant may benefit some rapid cycling or mixed bipolar patients, attenuating the propensity to switch from mania to depression. 

Ontiveros A, Fontaine R. Sodium valproate and clonazepam for treatment-resistant panic disorder. J Psychiatr Neurosci 1992 17 78-80. 

Anticonvulsants in treatment-resistant cases (carbamazepine, valproate). 

For treatment-resistant patients who do not respond to SSRIs or TCAs, or to the combination of TCAs/SSRIs with benzodiazepines, other antidepressants have shown at least some beneficial effects in alleviating PD symptoms (e.g. mirtazapine, moclobemide, nefazodone, phenelzine, reboxetine, and venlafaxine). Other agents have also been reported to exert beneficial effects in PD, especially when combined with SSRIs/TCAs (lithium, pindolol, and propranolol). In cases where all treatments have failed, valproate or olanzapine should be considered.2 - ° In order to optimize treatment, patients should avoid or reduce the consumption of compounds that could potentially induce/exacerbate panic attacks (e.g. caffeine, alcohol, and nicotine) and should exercise regularly. i... 

At the borderline between semisynthesis and patterned synthesis, versatile total syntheses may provide access to diversified bioactive structures. Classically, analogues of the active drug are sought that avoid the resistance developed by pathogens and show reduced side effects. In lucky cases, chemical simplification has afforded the wonder drug. This is the case of sodium valproate (2-propylvaleric acid sodium salt), which was synthesized in the fall of the XIX century and nearly a hundred years later became a leading drug in the treatment of epilepsy. 

Side effects. Piracetam is well tolerated and there is a low incidence of reported side effects. Those that do occur, at a frequency of less than 10%, include dizziness, insomnia, nausea, gastrointestinal discomfort, weight gain, drowsiness and agitation. Piracetam is indicated only for the treatment of myoclonus, particularly cortical myoclonus. It is used as a second-line drug for patients who are resistant to valproate or the benzodiazepines. 

Bromide (1857) was the first drug to be used for the treatment of epilepsy, but it is now obsolete. Phenobarbital, introduced in 1912, controlled patients resistant to bromides. The next success was the discovery in 1938 of phenytoin (a hydantoin) which is structurally related to the barbiturates. Since then many other drugs have been discovered, but phenytoin still remains a drug of choice in the treatment of major epilepsy. Over the past ten years there has been a dramatic increase in the number of new anticonvulsant drugs (vigabatrin, gabapentin, lamotrigine, topiramate, oxcarbazepine, levetiracetam), but none has been shown to be superior to the major standard anticonvulsants (phenytoin, carbamazepine and sodium valproate). 

In 126 patients with carbamazepine-resistant or valproate-resistant epilepsy given lamotrigine, 50% during add-on therapy and 53% during lamotrigine monotherapy had at least 50% reduction in total seizures (15). There were adverse events in 49 patients, including respiratory tract infections n — 11), dizziness (n — 8), headache (n = 7), diplopia (n = 5), tremor (n = 5), somnolence (n — 4), insomnia (n = 4), nausea (n — 4), and weakness (n = 3). Treatment was discontinued in nine patients because of adverse events, in five cases because of rash. 

Jozwiak S, Terczynski A. Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in patients with carbamazepine- or valproate-resistant epilepsy. Seizure 2000 9(7) 486-92. 

In a study of adjunctive treatment with valproate in 47 patients with panic disorder, 35 of whom also had a bipolar disorder and 12 of whom were resistant to antidepressants, none had to interrupt treatment because of adverse events [305 ]. 

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