Yonglin Gao

Tardive dysphoria: The role of long term antidepressant use in-inducing chronic depression

BACKGROUND Treatment-resistant and chronic depression appear to be increasing. The recent identification of antidepressant tachyphylaxis, the loss of antidepressant efficacy over time, is only a partial explanation. This is an emerging evidence that, in some individuals, persistent use of antidepressants may be prodepressant. METHODS A literature search of PubMed utilizing the terms: antidepressant tachyphylaxis, treatment-resistant depression, chronic depression, and antidepressant tolerance was performed, and relevant articles were used. RESULTS Depressed patients who ultimately become treatment resistant frequently have had a positive initial response to antidepressants and invariably have received these agents for prolonged time periods at high doses. Parallels between this course and tardive dyskinesia are noted. It is proposed that neuroplastic processes related to dendritic arborization may underlie the treatment resistant depression that occurs in the setting of chronic antidepressant use. Since the prodepressant effect is seen after prolonged antidepressant use, the term tardive dysphoria is proposed. CONCLUSIONS Tardive dysphoria, needs to be considered in studies of treatment resistant depression, and should be examined in blinded, randomized antidepressant discontinuation trials.

Memantine reduces mania-like symptoms in animal models

Memantine, a selective antagonist of the N-methyl-D-aspartate receptor, is approved for the treatment of moderate to severe Alzheimers disease. Ion dysregulation is thought to be involved in the pathophysiology of bipolar illness, suggesting that memantine may be effective in treating bipolar manic and/or depressive episodes. We utilized two preclinical models of mania that mimic pathophysiologic changes seen in bipolar illness to examine the potential efficacy of memantine in the treatment of this disorder. Locomotor hyperactivity of male Sprague-Dawley rats in an open field was induced with intracerebroventricular (ICV) administration of 10(-3) M ouabain. Memantine (2.5, 5 or 7.5mg/kg), lithium (6.75 mEq/kg), or vehicle were administered acutely via intraperitoneal injection immediately prior to ouabain, then chronically for 7 days (oral memantine 20, 30, and 40 mg/kg/day in water; lithium 2.4 g/kg food). In a second model of bipolar disorder, cycling between population spikes and epileptiform bursts was investigated in rat hippocampal slices treated with ouabain (3.3 μM) alone or in combination with memantine (0.5, 1.0, and 5.0 μM). Ouabain-induced hyperlocomotion was normalized with acute and chronic lithium and chronic use of memantine. Memantine delayed the onset of ouabain-induced-cycling in hippocampal slices. Memantine may have antimanic properties.

Effect of ouabain on sodium pump alpha-isoform expression in an animal model of mania.

While the pathophysiologic mechanisms of bipolar illness are unknown, a dysregulation of electrolytes, particularly intracellular sodium (Na) and calcium (Ca), are thought to contribute to the illness. Ouabain, a potent Na pump inhibitor, administered intracerebroventricularly (ICV), has been used previously to model mania. The current study evaluates the effect of ICV ouabain on Na pump isoform expression in rat brain. Animals received 5 microl ICV of either 10(-3) M ouabain or artificial cerebrospinal fluid (aCSF). They were then sacrificed 7 days after the ICV injection and specific brain areas were dissected and frozen until the assay (frontal cortex, hippocampus, and basal ganglia). The three isoforms of the alpha subunit of the Na pump that are expressed in the brain were quantified with immunoblot analysis with actin serving as internal control. The behavioral hyperactivity seen in rats receiving ICV ouabain is associated with an increase of expression of the glial-specific alpha2 isoform in the basal ganglia, and the neuron-specific alpha3 isoforms in the frontal cortex. These findings, in association with human post mortem studies finding that alpha2 is underexpressed in the temporal cortex of bipolar subjects, suggest that Na pump isoform expression may be of interest in the pathophysiology of mania.

Bipolar disorder: an update.

Abstract There has been a recent increase in the number of clinical trials and treatment options for bipolar disorder. This research has resulted in new treatment options. Most second-generation antipsychotics have demonstrated efficacy in the treatment of mania, both in monotherapy and as adjuncts to mood stabilizers. For bipolar depression, nearly all randomized, placebo-controlled studies have demonstrated that antidepressants do not provide any additional benefit to ongoing mood stabilizers. Additionally, antidepressants carry a risk of destabilization of bipolar disorder with an increase in mania, cycling, and chronic irritable dysphoria. Newer non-antidepressant treatments for depression include quetiapine, lamotrigine, modafinil, and pramipexole. These agents are effective for acute treatment and appear to be effective in maintenance. The least-studied phase of bipolar disorder is the maintenance phase. The use of multiple agents appears to be superior to monotherapy in relapse prevention. Despite the many advances in the pharmacotherapy of bipolar disorder, the overall prognosis of this severe illness does not appear to have changed.

Effect of ionic stress on apoptosis and the expression of TRPM2 in human olfactory neuroepithelial-derived progenitors

Abstract Objectives. Disturbed ion homeostasis and apoptosis have been implicated in the pathophysiology of bipolar disorder (BD). TRPM2, a nonselective cation channel, is involved in apoptosis and is possibly linked with BD. In this study, monensin, a sodium ionophore, was used to model the increase [Na+]in and [Ca2+]in seen in BD patients. Methods. Human olfactory neuroepithelial-derived progenitors (ONP), which possess neuronal markers, were utilized to investigate the effects of monensin on apoptosis and the response of TRPM2, and the effects of lithium on the cellular response to monensin. Monensin treatment for 6 h activated caspase-3, -7 and poly(ADP-ribose) polymerase (PARP), inducing apoptosis. Results. [Na+]in increased to twice the basal level and reached steady state after 2 h of 10−6 M monensin treatment, while [Ca2+]in rose after 6 h of the treatment. Monensin treatment for 24 h decreased expression of the long form of TRPM2, and increased expression of the short form. Lithium (1 mM) pretreatment reduced the [Na+]in and [Ca2+]in elevation caused by monensin, down-regulated the leveles of caspase-3, -7 and PARP, and reduced expression of TRPM2. Conclusions. Our findings suggest that the elevation of [Na+]in and [Ca2+]in induced ONP apoptosis and altered the expression of TRPM2. Lithium pretreatment attenuated the apoptosis induced by ionic stress.

Cariprazine exerts antimanic properties and interferes with dopamine D2 receptor β-arrestin interactions

Activation of dopamine D2 receptors (D2R) modulates G protein/cAMP‐dependent signaling and also engages Akt‐GSK‐3 signaling through D2R/β‐arrestin 2 scaffolding of Akt and PP2A. This G protein‐independent pathway may be important in mediating the antimanic effects of mood stabilizers and antipsychotics. The mood stabilizer lithium influences behavior and Akt/GSK‐3 signaling in mice and many antipsychotics have been shown to more potently antagonize the activity of the β‐arrestin‐2 pathway relative to the G protein‐dependent pathway. Cariprazine, an antipsychotic with potent D3R/D2R partial agonist activity and preferential binding to D3R, was investigated for its effects on the mediators of D2R pathways in vitro and its efficacy in animal models of mania. Effects on G protein‐dependent activity were measured via inhibition of isoproterenol‐induced cAMP production; effects on D2R/β‐arrestin 2 signaling were determined using bioluminescence resonance energy transfer (BRET). Cariprazine was tested in vivo for antimanic‐like activity, using the ouabain‐induced hyperactivity model in rats. Cariprazine was more potent than aripiprazole in inhibiting isoproterenol‐induced cAMP although both compounds showed similar maximum efficacy. In assays of D2R/β‐arrestin 2‐dependent interactions, cariprazine showed very weak partial agonist activity, unless the levels of receptor kinase were increased; as an antagonist it showed similar potency to haloperidol and ~fivefold greater potency than aripiprazole. In an animal model of mania, cariprazine showed similar efficacy as lithium in attenuating the effects of ouabain‐induced hyperactivity. In summary, the differential effects of cariprazine on D2R G protein and β‐arrestin 2 mediators of signal transduction pathways could contribute to its potent antimanic‐like activity.

Current and Emerging Therapies for the Management of Bipolar Disorders

Bipolar disorder is a complex condition to treat because agents that may be effective for a specific phase may not be effective for other phases, or may even worsen the overall course of the illness. Over the last decade there has been an increase in research activity in the treatment of bipolar illness. There are now several agents that are well established for the treatment of acute mania (lithium, divalproex, carbamazepine, nearly all antipsychotics), acute bipolar depression (lamotrigine, quetiapine, olanzapine/fluoxetine combination), and relapse prevention (lithium, lamotrigine, divalproex, most second generation antipsychotics). There are also novel treatments that are being studied for all three phases. These include eslicarbazepine, cariprazine, MEM-1003, memantine, tamoxifen and pentazocine for acute mania; pramipexole, modafinil, armodafinil, divalproex, lurasidone, agomelatine, cariprazine, lisedexamfetamine, riluzole, RG-2417, bifeprunox, ropinirole, GSK1014802, and magnetic stimulation for bipolar depression; and asenapine, lurasidone, and cariprazine for relapse prevention. Additionally, there are accumulating data that antidepressants, particularly serotoninergic ones, are not particularly effective in acute bipolar depression and may worsen the course of the illness.

Positron emission tomography with fluorodeoxyglucose-F18 in an animal model of mania

Intracerebroventricular (ICV) administration of ouabain to young adult rats has been suggested to model human bipolar mania. In the human condition, mania and bipolar depression are both associated with reductions in frontal cerebral metabolism. We utilized [(18)F]-fluorodeoxyglucose [(18)FDG] positron emission tomography (PET) to visualize glucose uptake in animals receiving ICV ouabain. Animals received 5 microl of 10(-)(3) M ouabain ICV, were anesthetized with isoflurane inhalation, and administered intraperitoneally with 0.5 mCi of (18)FDG. PET data were collected over 20 min 1 hour later. Additionally, the effect of lithium was examined in animals receiving lithium in their diet for 1 week before the ICV ouabain injection. Data were analyzed with IDL Virtual Machine software. Brain glucose utilization as measured by (18)FDG uptake was significantly reduced in animals receiving ICV ouabain compared with those receiving equal volumes of artificial cerebrospinal fluid. Pretreatment with lithium normalized (18)FDG uptake. These results mirror human studies.

Antidepressant-Induced Tardive Dysphoria

pressive illness at the age of 45. He was homozygous for the short form of the serotonin transporter. He was treated off and on until the age of 59 and had been on an antidepressant continuously until the age of 67. Over the previous 2 years he had been depressed without any relief by medication or 2 electroconvulsive treatments. His medications at the time of evaluation included paroxetine 10 mg daily, venlafaxine 75 mg daily and clonazepam 3 mg daily. His 17-item Hamilton depression score was 22. Over the subsequent 6 months, he was started on bupropion and then tapered off all antidepressants, including the bupropion. His Hamilton depression score dropped to 18. The patient was not satisfied with his progress and sought another opinion to restart antidepressants. One year later, on duloxetine 60 mg daily, he continued to complain of unremitting depression. A possible prodepressant effect of antidepressants has been previously proposed. Fava [5, 18] was the first to suggest that an antidepressant-related neurobiochemical mechanism of increasing vulnerability to depression might play a role in worsening the long-term outcome of the illness. Others have also proposed similar ideas [6, 19] . Understanding of potential mechanisms of this phenomenon can be gleaned from observations regarding the short form of the serotonin transporter (5HTTR) [20] . The short form of the 5HTTR is a 44-base deletion in the promoter of the SLC6A4 gene, which codes for the 5HTTR protein [20] . This deletion reduces expression of the 5HTTR protein so that subjects with the short form express about half as many serotonin reuptake pumps in the membrane compared to those without the short form [20] . Subjects with the short form (heterozygotes and homozygotes) are more likely to become depressed in the setting of adversity than people with the long form [20] . Additionally, they are less likely to respond well to antidepressants, with reports of no response, delayed response, increased side effects and increased rapid cycling in bipolar individuals [20] . It is not clear how the increased risk for these changes comes about, but neuroplastic changes may be important. Modification of serotonergic neurotransmission alters arborization of the dendritic tree of serotonergic neurons [21, 22] . For example, mice that lack the serotonin transporter have fewer serotonergic neurons and reduced serotonergic function and express more behaviors associated with anxiety and depression [23] . Fifty percent expression of the 5HTTR that occurs with the short form resembles the 60–80% serotonin transporter inhibition that is required for an antidepressant response [24, 25] . It would be expected that individuals with either genetic reduction in 5HTTR or prolonged pharmacological blockage of 5HTTR would reduce serotonergic arborization, and this may play a role in the increased recurrence of depression in the setting of adversity, poor antidepressant response, increased side effects and increased rapid cycling in bipolar individuals. Patients with both risk factors, i.e. with the short form of the 5HTTR and prolonged The prevalence of treatment-resistant depression (TRD) appears to be increasing. A recent meta-analysis found TRD to be a problem in nearly 40% of depressed patients, a dramatic increase from the 1990s when it was reported to affect 10–15% of patients [1, 2] . While this difference may be related to differences in how the studies were performed, if correct, it would suggest a process in which TRD is occurring in response to environmental, biological or clinical factors. Psychiatrists do not have control over environmental factors, but we do have direct control over clinical factors and hence a duty to examine these. For example, TRD may be related to inadequate dosing of antidepressants [3] or antidepressant tolerance [4] . Alternatively, there are reasons to believe that antidepressant treatment itself may contribute to a chronic depressive syndrome [5, 6] . TRD may be related to the phenomenon of tachyphylaxis. Such patients experience an initial good response to antidepressants that is lost over time with repeated or continuous antidepressant administration [4, 7–9] . Attempts to treat these individuals frequently results in poor response [10] . While the incidence of tachyphylaxis is unknown, in a prospective study, Solomon et al. [11] found that relapse occurred in 25% of 171 episodes. However, antidepressants may play a more active role in the recurrence of depression in some of these patients. Even early reports noted worrisome phenomena. Mildly depressed patients may actually worsen over time when treated with imipramine [12] . Anxious patients who do not have a history of a mood disorder may develop depression after prolonged treatment with antidepressants for their anxiety disorder [13, 14] . Twenty-seven percent of patients without any history of a mood disorder who had received antidepressants for an average of 29 months for panic disorder developed a cyclothymic illness that persisted for 1 year after antidepressant discontinuation [15] . Normal controls receiving antidepressants in research studies were reported to experience depression [16] . In a study of 15 subjects (11 with unipolar and 4 with bipolar illness) with apparent tachyphylaxis, Sharma [17] found that discontinuation of antidepressants (and continuation of mood stabilizers) was associated with improvement. We report a case of antidepressant discontinuation in a TRD patient. He was a 67-year-old white man with onset of major deReceived: April 21, 2008 Accepted after revision: June 7, 2010 Published online: November 18, 2010

BDNF expression in lymphoblastoid cell lines carrying BDNF SNPs associated with bipolar disorder.

Objective To determine whether single nucleotide polymorphisms (SNPs) of the brain-derived neurotrophic factor (BDNF) that have been associated with bipolar illness are associated with physiological dysfunction. Methods Lymphoblastoid cell lines (n=30) obtained from bipolar I individuals carrying zero, one, or two copies of a BDNF SNP associated with bipolar illness (rs12273363) were utilized. Results Proapoptotic stressors of serum deprivation alone, or serum deprivation combined with the sodium ionophore, monensin, did not alter intracellular proBDNF. Monensin treatment increased mature-BDNF (mBDNF) protein levels (P<0.05). There were no differences related to the presence of SNP or copy number. Conclusion rs12273363 does not appear to have functional consequences that would involve its role in bipolar illness.