Brain Dopamine–Serotonin Vesicular Transport Disease and Its Treatment

Known disorders of biogenic amine neuromediators (dopamine, norepinephrine, epinephrine, and serotonin) involve defects in nine enzymes1-9 and one transporter.10 Affected persons present in early childhood with symptoms referable to the affected neurotransmitter, and the disorders are diagnosed by measurement of neurotransmitter breakdown products in the cerebrospinal fluid (CSF). A deficiency in dopamine results in movement disorder; deficient norepinephrine or epinephrine causes autonomic dysfunction; and serotonin deficiency leads to sleep and psychiatric disturbances.2,3,6
We describe members of a family with symptoms of deficiencies in dopamine (dystonia, parkinsonism, and oculogyric crises), serotonin (sleep and mood disturbance), and epinephrine and norepinephrine (diaphoresis, temperature instability, ptosis, and postural hypotension), with no demonstrable deficiency of neurotransmitters in the CSF. Genome investigation revealed a mutation in the gene encoding VMAT2 that compromises transport of biogenic amines into synaptic vesicles, resulting in impairment of their synaptic transmission without detectable reductions in their amounts.

 Brain Dopamine–Serotonin Vesicular Transport Disease and Its Treatment

Гэмблинг вызваный прамипексолом

BACKGROUND: Dopamine agonists (DAs), long used in treating Parkinson’s disease and effective in relieving symptoms of restless legs syndrome, have frequently been reported to induce problematic compulsive behaviors (e.g., obsessive gambling, hypersexuality) in individuals who had never had difficulties with such behaviors before. OBJECTIVE: The authors report two cases that add to a small-but-growing literature suggesting that these drugs be dispensed with appropriate caution. METHOD: The authors describe two patients seen in a psychiatric setting—one, after a suicide attempt, and one with depression—both resulting from intractable compulsive gambling. RESULTS: In both instances, control of gambling was achieved: in one, when pramipexole was discontinued, and in the other, after substitution of ropinirole and addition of spiritual and support-group approaches. DISCUSSION: DAs stimulate pathways that govern reward behavior, including pleasure and addiction. Other reward behaviors, such as eating and sexual activity, may also be affected by DAs. These cases demonstrate a clear temporal relationship between initiation and behavioral change; patients and their caregivers should be alerted to the possibility of such changes.

Impact of Dopamine Agonists on Compulsive Behaviors: A Case Series of Pramipexole-Induced Pathological Gambling

Резистентное к лечению биполярное расстройство

In acute mania, antidepressants should be discontinued immediately. The focus should be on using evidence-based treatments for mania. Although lithium is not recommended for mixed episodes or for patients with many previous episodes, lithium and divalproex are often used before an atypical antipsychotic because they are thought to be safer with long-term use.
The most commonly recommended nonstandard treatments for treatment-resistant mania are clozapine and ECT, which have been shown to have efficacy.A combination of clozapine and ECT has also been suggested.
Several novel treatments have been studied using an augmentation approach in combination with standard treatments for treatment-resistant mania. These include donepezil, gabapentin, topiramate, mexiletine, and intravenous magnesium sulphate. The reported efficacy in these uncontrolled reports is confounded by the continuation of the previous treatments. One exception is tamoxifen, which, like lithium and valproate, inhibits protein kinase C and was found to have antimanic efficacy superior to placebo.
However, antidepressants (other than fluoxetine in combination with olanzapine) have not been shown to be efficacious in acute bipolar depression and may be associated with switching. In particular, antidepressants with norepinephrine activity including tricyclics and serotonin-norepinephrine reuptake inhibitors may have a greater risk of inducing switching than SSRIs.
For treatment-resistant acute bipolar depression, the dopaminergic agonist pramipexole and the wakefulness-promoting agent modafinil have been shown to have efficacy greater than placebo as augmentation to standard treatments.4,26 Other pharmacotherapies have been studied in uncontrolled augmentation, including donepezil, bupropion, riluzole, gabapentin, levetiracetam, and aripiprazole. Two brain-stimulating therapies—magnetic seizure therapy and repetitive transcranial magnetic stimulation (TMS)—have been studied as well.
Other approaches include augmentation with hypermetabolic thyroid supplementation, diltiazem, aripiprazole, topiramate, gabapentin, mexiletine, levetiracetam, and chromium, as well as vagus nerve stimulation. Efficacy has also been reported for levetiracetam monotherapy and a combination of topiramate and clozapine.

Treatment-Resistant Bipolar Disorder