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Therapy of bipolar disorders is a rapidly evolving field. Lithium has efficacy in classic bipolar disorders whereas divalproex sodium and carbamazepine may have broader spectrum efficacy that includes non-classic bipolar disorder. In the last 10 years, a series of anticonvulsants have been approved for marketing in the United States. Gabapentin has indirect γ-aminobuytric acid-ergic actions, is generally well tolerated, and appears to have anxiolytic, analgesic, and hypnotic effects. Lamotrigine has antiglutamatergic actions and is generally well tolerated (aside from rash in 1 in 10, and serious rash in 1 in 1,000 patients). Lamotrigine is indicated for maintance treatment in bipolar disorder. Emerging evidence suggests lamotrigine may have utility in bipolar disorder patients with depression and treatment-refractory rapid cycling, as well as analgesic effects. Topiramate and zonisamide may allow both weight loss, while topiramate may have specific efficacy in bulimia, binge eating disorder, and alcohol dependence. Two small studies found oxcarbazepine had similar efficacy to lithium and haloperidol in acute mania. Phenytoin, an older anticonvulsant, may have adjunctive acute mania efficacy. Levetiracetam, a newer anticonvulsant, may be worth exploring and has minimal drug-drug interactions. None of these newer agents has been shown effective in a large placebo controlled trial for acute mania. Although the clinical profiles of these newer anticonvulsants do not appear to overlap markedly with divalproex and carbamazepine (except perhaps for oxcarbazepine), these novel agents may still offer important new options in relieving a variety of specific target symptoms in patients with bipolar disorder.
Animal models of depression and psychopharmacological mechanisms of action suggest the importance of the gamma-amino butyric acid (GABA) system in the pathophysiology of mood disorders. Mood stabilizers have overlapping effects on GABAergic neurotransmission, and antidepressant use has been associated with alterations in GABAB receptor function. Magnetic resonance spectroscopy (MRS) provides an opportunity to noninvasively assess cerebral GABA concentrations in anterior paralimbic circuits that have been implicated in mood disorders.
In bipolar disorder patients and healthy control subjects, we used MRS with a modified GABA-edited point resolved spectroscopy sequence (TE 68 ms, TR 1500 ms, 512 averages, total scan time 26 min) to assess GABA in an 18-cm3 occipital voxel. In addition, in another cohort of bipolar disorder patients and healthy control subjects, we similarly assessed GABA in a 12.5-cm3 medial prefrontal/anterior cingulate (MPF/AC) voxel. The concentration of GABA was referenced to creatine (Cr) from unedited spectra.
In bipolar patients and controls, we consistently detected 3.0 p.p.m. GABA peaks in occipital lobe and MPF/AC. In 16 bipolar (nine bipolar I and seven bipolar II) disorder patients, compared with six healthy control subjects, mean occipital GABA/Cr concentration was 61% higher. In addition, in 15 bipolar (five bipolar I, nine bipolar II, and one bipolar not otherwise specified) disorder patients, compared with six healthy control subjects, mean MPF/AC GABA/Cr concentration tended to be 41% higher.
Patients with bipolar disorders may have increased cerebral GABA concentrations. Although this was more evident in the occipital lobe, MPC/AC GABA disturbance may be of greater potential interest in view the more established role of MPF/AC in affective processing. Additional studies are warranted to assess changes in GABAergic neurotransmission and the influences of diagnosis, mood state, and medication status in bipolar disorder patients.
John O. Brooks III, Department of Psychiatry David Geffen School of Medicine University of California, Los Angeles Los Angeles, CA, USA,
Po W. Wang, Department of Psychiatry Mount Sinai School of Medicine New York, NY, USA and Medical Department Brookhaven National Laboratory Upton, NY, USA,
Terence A. Ketter, Department of Psychiatry and Behavioral Sciences Stanford University School of Medicine Stanford, CA, USA
There are a number of potential neurochemical alterations in the dorsolateral prefrontal circuit that are related to the clinical expression of bipolar disorder. This chapter focuses on translational studies that integrate neurochemical and neuroanatomical information to better understand the pathophysiology of bipolar disorders. There are three major frontal-subcortical circuits that constitute the corticolimbic network: dorsolateral prefrontal, lateral orbitofrontal, and anterior cingulate. Several techniques have been developed that allow for non-invasive assessment of neurochemistry. Ligand-specific positron emission tomography (PET) and single photon emission computed tomography (SPECT) permit regional measurement of monoamines and other neurochemicals, which are thought to be crucial to affective processes. There have been numerous findings of peripheral serotonergic dysfunction in bipolar disorder, including decreased serotonergic reuptake in platelets. The neurochemistry of corticolimbic circuits presents additional challenges for clarifying the neurochemical basis of dysregulation that has been observed in functional neuroimaging studies.
Terence A. Ketter, Bipolar Disorders Clinic, Stanford, University School of Medicine, Stanford, USA,
Po W. Wang, Department of Psychiatry and Behavioral Sciences, Bipolar Disorders Clinic, Stanford, University School of Medicine, California, USA
As noted by Parker, management of Bipolar II Disorder is challenging for several reasons, including the scarcity of controlled data to inform evidence-based care. Such limited data mean that clinicians commonly extrapolate information regarding BP I and/or (unipolar) major depressive disorder, and view BP II as an intermediate category. Such an approach has strengths and limitations. One notable limitation is that it may underemphasise the heterogeneity of BP II, a condition with substantial inter-patient variability.
Thus, some patients with BP II may have an illness more like major depressive disorder: relatively infrequent recurrent pure (with minimal mixed features) depressive episodes, rare hypomanias, and – with antidepressants – they experience relief of depression without treatment-emergent affective switch (TEAS) into hypomania or accelerating episodes. Antidepressants may be considered foundational treatments for this presentation. In academic centres with specialty clinics, such patients are more likely referred to major depressive disorder clinics, where clinicians may view antidepressants as the treatment of choice for this type of BP II.
However, other patients with BP II may have an illness more akin to BP I. These patients experience relatively frequent recurrent depressive episodes that include mixed features (in some instances with concurrent depression and hypomania, i.e. dysphoric hypomania), common hypomanias and, in some instances, rapid cycling. Antidepressants give inadequate relief of their depression and can confer TEAS, and/or cycle acceleration. For these patients, mood stabilisers or atypical antipsychotics – not antidepressants – may be considered foundational treatments.
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