Role of BDNF in bipolar and unipolar disorder: Clinical and theoretical implications

JOURNAL OF PSYCHIATRIC RESEARCH

Journal of Psychiatric Research 41 (2007) 979–990

www.elsevier.com/locate/jpsychires

Review

Role of BDNF in bipolar and unipolar disorder: Clinical and theoretical implications Robert M. Post

*

Penn State School of Medicine, Hershey, PA and 3502 Turner Lane, Chevy Chase, MD, 20815, United States Received 3 May 2006; received in revised form 16 September 2006; accepted 21 September 2006

Abstract A number of lines of converging evidence suggest that brain-derived neurotrophic factor (BDNF) may play a role in the onset and treatment of bipolar disorder. We review pertinent data on BDNF from several different areas of preclinical and clinical investigation that suggest novel theoretical and treatment implications for the recurrent affective disorders. Data from several recent studies have also converged showing that the val66met allele of BDNF, a common single nucleotide polymorphism (SNP), is associated with selective minor deficits in cognitive functioning in subjects with schizophrenia, bipolar illness, and normal controls. Yet, paradoxically, the better functioning val66val allele of BDNF appears to be associated with an increased risk for bipolar disorder and perhaps early onset or rapid cycling. All the primary antidepressant modalities, as well as the mood stabilizers lithium and valproate, increase BDNF. Stressors decrease BDNF and this effect can be blocked by antidepressants. Serum BDNF is low in proportion to the severity of mania and depression and increases with clinical improvement. Assessment of the val66val BDNF allele and a range of other SNPs as potential vulnerability factors for bipolar illness and its early onset could facilitate studies of early intervention, help reduce long delays between the onset of first symptoms and the first treatment, and help in the prediction of individual patient’s likelihood of responding to a given treatment. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: BDNF; Bipolar disorder; Unipolar disorder; Polymorphism; Val66val; Val66met; ProBDNF

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Environmental impacts on BDNF expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Stressors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Psychotropic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Emerging genetic findings for common alleles of proBDNF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. The val66met allele of BDNF and cognitive dysfunction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. The val66val BDNF allele and the incidence of bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Positive association studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Negative bipolar association studies and other illness associations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. The BDNF alleles and early age of bipolar onset or rapid cycling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Theoretical and clinical implications of BDNF alterations in unipolar and bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . 4.1. Prediction of treatment response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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0022-3956/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2006.09.009

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4.2. Early intervention to alter the poor prognosis of childhood-onset bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Countering stigma with new data on neurobiology and treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Medication effects on the neurobiology of bipolar illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Brain-derived neurotrophic factor (BDNF) is implicated in a variety of neural processes as a function of stage of development in both animals and humans. Initially, BDNF is important for neurogenesis (birth of new neurons), neuronal survival, and normal maturation of neural developmental pathways. Eventually in the adult, it is not only important for synaptic plasticity and dendritic growth, but also is essential to long-term memory. BDNF acts at one of a series of neurotrophic factor receptors that are tyrosine kinases (Trks), and that have important intracellular and transcriptional effects on a variety of neurochemical systems, via mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3-K), and phospholipase C (PLC) a signal transduction pathways (Patapoutian and Reichardt, 2001). BDNF acts at the Trk B receptor, whereas nerve growth factor (NGF) acts at the Trk A receptor, and neurotrophins 4 and 5 (NT4/5) act at the Trk C receptor (Green and Craddock, 2005). One method used to study the importance of BDNF in animal studies is to genetically remove or ‘‘knock-out’’ one copy of the BDNF gene in certain animal strains, particularly mice. Animals that have one copy of the BDNF gene deleted or ‘‘knocked-out’’ and therefore are heterozygous for the presence of the BDNF gene (BDNF+/ ) are severely deficient in their ability to produce long-term potentiation (LTP) in hippocampal slices (Korte et al., 1995), one of the physiological paradigms most closely linked to normal processes of learning and memory (Malenka, 1995). Consistent with these LTP data are the findings that BDNF(+/ ) animals are unable to navigate in a Morris water maze, a spatial learning task at which mice are normally quite adept (Linnarsson et al., 1997). BDNF(+/ ) heterozygotes also have decreased neurogenesis and size of the hippocampus (Lee et al., 2002), and decreased mossy fiber sprouting in the dentate gyrus of the hippocampus after electroconvulsive seizures (ECS) (Vaidya et al., 1999). A deficit in BDNF is also associated with a variety of neurochemical and behavioral alterations, including decreases in serotonin (5-HT) in association with the development of aggressiveness and hyperphagia (Lyons et al., 1999). BDNF function is eliminated in animals that have their Trk B receptors altered or knocked-out. Trk B dominant-

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negative mice are resistant to the positive effects of antidepressants in the forced swim test (Saarelainen et al., 2003), an animal model of behavioral despair commonly used to assess antidepressant activity. Trk B knock-out animals, but not BDNF knock-out animals, are unable to achieve the normal seizure progression associated with amygdala kindling (He et al., 2004). This kindling paradigm was originally identified by Goddard and Douglas (1975) as one that is useful for dissecting aspects of long-term learning and memory, because a kindled animal shows permanent increases in neural and convulsive excitability based on repeated presentations of initially subthreshold stimulation of the amygdala. Detailed reviews of the effects of BDNF on neurogenesis, learning and behavior, and synaptic plasticity can be found elsewhere (Green and Craddock, 2005; Hashimoto et al., 2004; Russo-Neustadt, 2003). In addition to the important effects of BDNF noted above, a number of animal and human studies have suggested a role of BDNF in the pathogenesis of recurrent mood disorders, as schematized in Fig. 1. We will briefly review these data, and then examine in greater detail the findings suggesting an association of the val66val allele of proBDNF with bipolar disorder and early onset, and, conversely, the val66met allele with cognitive dysfunction in several patient populations. Lastly, we discuss the potential clinical and theoretical implications of these findings for early recognition and treatment of bipolar disorders. 2. Environmental impacts on BDNF expression 2.1. Stressors Stress plays an important role in the development and progression of mood disorders (Kendler et al., 2000; Leverich et al., 2002b; Paykel, 2003; Post, 1992; Tsuchiya et al., 2005). Data from animal studies show that stressors greatly impact BDNF in the brain. Neonatal stressors in the rodent (such as maternal deprivation) induce significant decreases in hippocampal BDNF acutely (Kuma et al., 2004; Roceri et al., 2004; Roceri et al., 2002; Zhang et al., 2002). However, repeated neonatal stressors result in long-term decreases in BDNF in the frontal cortex which persist into adulthood (Russo-Neustadt et al., 2001). Thus, in addition to potential effects in the hippocampus, stressors could lead to long-lasting changes in cortical BDNF

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BDNF in Affective Illness Vulnerability, Treatment, and Prevention I.Genetic Vulnerability pro BDNF: III. Medications Lithium

II. Experiential Vulnerability (A.B.C.)

A. Neonatal Stressors

B. Adult Stressors

C. Recurrent Depressions

Single Stressor ↓ BDNFhippo. Repeated Stressors

↓ MRs, GRs ↑ cortisol

↑ BDNF & trkB ↑ neurogenesis* no hippocampal size decrease in depression vs. no ADs

• Antisuicide Effects • Normalizes increased medical mortality of depression • ↑ gray matter in BPI • ↑ NAA

Antidepressants s ↑MRs, GRs

Valproate ↓BDNFprefrontal cortex in adults Single Stressor

No effect

Repeated Stressor

Antidepressants

↑BDNF & Bcl-2 ↓ Bax & P53 ↑neurogenesis ↑ glia-genesis

↓cortisol

↓ trkB blocks antidepressant effects *x-irradiation of hippocampus ↓ neurogenesis and ↓behavioral effects of antidepressants

↓

Depression

Mania

↓ ↓

val66val Early onset val66met Cognitive difficulties • prefrontal neuronal and glial deficits • ↓ hippocampal size and activation

↑ BDNF & Bcl-2 ↓ histone deacetylase

↓ BDNFhippo.

Fig. 1. Summary of the effects of BDNF in affective illness vulnerability, treatment, and prevention. The interaction of BDNF on the life course of a patient and his or her treatment are schematized on the backdrop of a life chart; increasing mania is represented above the midline, and increasing depression is represented below the midline. The three general areas of genetic vulnerability, experiential vulnerability, and medications (treatment) are shown, as well as the specific implications of the interactions of each with BDNF. BDNF, brain-derived neurotrophic factor; MRs, mineralocorticoid receptors; GRs, glucocorticoid receptors; AD, antidepressant; NAA, N-acetyl aspartate; BPI, bipolar I; hippo., hippocampus;

(Russo-Neustadt et al., 2001) which could be pertinent to the finding of prefrontal cortical deficits in structure or function reported in the unipolar and bipolar disorders (see below). Moreover, in adult animals, repeated or chronic (but not acute) stress results in a reduction in hippocampal BDNF (Duman, 1998; Smith et al., 1995b), findings of potential relevance to hippocampal volume reductions and deficits commonly seen in mood disorders (Bertolino et al., 2003; Blumberg et al., 2003; Monkul et al., 2003; Sheline et al., 2003; Videbech and Ravnkilde, 2004). Tsankova et al. (2006) report that repeated defeat stress in the mouse induces a long-lasting downregulation of specific BDNF transcripts in hippocampus via increased histone acetylation. The BDNF decrements were reversed by chronic imipramine treatment which increased histone acetylation (via downregulation of histone deacetylase). Berton et al. (2006) also reported an essential role for increased BDNF in the mesolimbic dopamine pathway mediating long-term response to defeat stress and its reversal with antidepressants. The new findings of Berton et al. (2006) are particularly striking because of the hypothesized role of the mesolimbic dopamine pathway in the modulation of motor activity and hedonic reward, two of the critical symptom areas in major depression, as well as in stress sensitization. The fact that antidepressants reverse this increase in BDNF in this dopaminergic pathway in association with their reversal of defeat stress, also reveals a role for the antidepressants beyond their typically understood role only on hippocampal BDNF, and perhaps into more areas of core symptomatology of depression. Opposite effects of stress were also observed on BDNF mRNA in the hippocampus versus the pituitary (Smith et al., 1995a).

2.2. Depression Low BDNF has been associated with neuroticism (a risk factor for depression) in a study of 118 healthy volunteers (Lang et al., 2004). Four studies (Aydemir et al., 2005; Gonul et al., 2005; Karege et al., 2002; Shimizu et al., 2003) report that depressed patients have low serum BDNF that correlates with the severity of their depression, and that improves with recovery. In an autopsy study using frozen postmortem anterior hippocampal sections, brain BDNF was found to be low in depressed patients who had not been previously treated with antidepressants, compared with those so treated (Chen et al., 2001). Serum BDNF has also been reported to be low in patients with bipolar disorder, in both the depressive and manic phases (Cunha et al., 2006; Machado-Vieira et al., in press). In the study of Machado-Vieira et al. (in press), the severity of a manic episode was significantly negatively correlated with plasma BDNF levels. Kaufman et al. (2006) reported a three-way interaction between the met allele of BDNF and two short alleles of the serotonin transporter (5HT-TLPR); those patients with all three had the highest depression score, but this was evident only in maltreated children. These clinical data are compatible with the preclinical findings that BDNF heterozygous knock-out mice, when bred with serotonin-knockout mice, show greater abnormalities than mice with either knock-out alone (Ren-Patterson et al., 2005). D. Weinberger (personal communication, 2005) also found moderating effects of val66met BDNF on hippocampal volume deficits associated with the ss allele of the 5HT-TLPR gene. Together, these findings suggest the potential importance of multiple gene–gene interactions in conveying neuropsychiatric vulnerability.

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2.3. Psychotropic drugs Smith and colleagues (1995c) were the first to observe, in animals, that stress-induced decreases in hippocampal BDNF occurred. Nibuya and colleagues (1995) followed these observations with documentation that a wide range of antidepressant modalities with different mechanisms of action were all capable of increasing hippocampal BDNF upon chronic, but not acute administration in animals and could, to varying degrees, prevent the stress-induced decreases in BDNF. Interestingly, repeated administration of ECS is a particularly robust way of increasing BDNF in animals (Altar et al., 2003), perhaps to some extent paralleling the superior efficacy of ECT to most pharmacological agents in head-to-head controlled studies in depression (Pagnin et al., 2004). Although the reliability of the clinical antidepressant effects of repetitive transcranial magnetic stimulation (rTMS) remain controversial, this experimental antidepressant modality also increases BDNF in rodent brain (Muller et al., 2000) and in serum (blood) of humans (Zanardini et al., 2006). Two recent studies show that antidepressant treatment increases serum BDNF in depressed patients. Gonul et al. (2005) reported increased serum BDNF levels in 28 depressed patients after 8 weeks of antidepressant treatment (venlafaxine or SSRIs). Likewise, Aydemir et al. (2005) found that after 12 weeks of treatment with venlafaxine, serum BDNF levels of the depressed patients were no longer significantly different from controls. Two of the most widely studied mood stabilizers, lithium and valproate, increase BDNF in animals (Einat et al., 2003). For lithium, this effect on BDNF does not appear to be an isolated effect, because lithium also increases other cell survival factors such as Bcl-2, and inhibits the production of cell death factors such as Bax and p53 (Chen et al., 1999; Chen and Chuang, 1999). Moreover, both lithium and valproate exert effects on the mitogen-activated protein (MAP) kinase pathway (Einat et al., 2003) that likely also contribute to observed neuroprotective effects. In the only study of the effect of an atypical antipsychotic on BDNF, chronic quetiapine, like the antidepressants, was shown to inhibit the stress-induced BDNF depletions (Xu et al., 2002). Quetiapine has shown highly significant antidepressant (Calabrese et al., 2005) and anti-anxiety (Hirschfeld et al., 2006) effects compared with placebo in bipolar depression. The BDNF and stress data raise the question of whether common effects of antidepressants and quetiapine in blocking or reversing stress-induced decreases in BDNF are important to their clinical antidepressant efficacy. Lithium and all of the antidepressants studied also increase the rate of neurogenesis (Chen et al., 2000; Hao et al., 2004; Malberg et al., 2000; Manji et al., 2000a), although the precise relationship to BDNF increases is not yet clear. Castren (2004) reported that BDNF/TrkB is involved in the survival, but not the proliferation, of

new neurons in the hippocampus. It is possible that antidepressant-induced changes in BDNF or neurogenesis could represent a convergence of pathways for mediating the antidepressant effects of a variety of categories of antidepressant modalities. The antidepressants could act via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP responsive element-binding protein (CREB) pathway (Garno et al., 2005), whereas several of the mood stabilizers could act via the TrkB pathway. BDNF shows antidepressant-like properties when administered intracerebrally into the midbrain, hippocampus, or ventral tegmental area (VTA) of animals in appropriate animal models of depression (Eisch et al., 2003; Shirayama et al., 2002; Siuciak et al., 1997). The data of Berton et al. (2006) and Tsankova et al. (2006) (noted above) now suggest essential roles for BDNF in the hippocampus and the VTA, respectively, in the defeat stress model of depression and its amelioration by antidepressants. 3. Emerging genetic findings for common alleles of proBDNF A number of genetic loci and candidate genes have been suggested as potential risk factors for the onset of bipolar illness, but few have been multiply replicated. A number of studies have now indicated that variations in the single nucleotide polymorphism (SNP) at the 66 position in the promoter sequence of the proBDNF allele are differentially associated with cognitive dysfunction on the one hand, and risk of bipolar disorder onset in North American subject populations on the other. These findings could alter our conceptualization of bipolar disorder and its early intervention and treatment. 3.1. The val66met allele of BDNF and cognitive dysfunction The particular SNP associated with cognitive dysfunction is called the val66met polymorphism because in these people there is a methionine substitution at position 66 for the usual valine group at this position. In addition to cognitive dysfunction, the val66met form of BDNF has been associated with decreased volume of the hippocampus and increased activation of the hippocampus during learning and memory tasks in normal volunteers (Bueller et al., 2006; Egan et al., 2003). Hariri et al. (2003) found a significant decrease in memory performance in 64 healthy subjects with the val66met versus the val66val allele. In 115 Chinese females, Tsai et al. (2004) found lower scores on performance IQ tests in healthy patients with the val66met allele. Egan and associates (2003) found that in three populations (schizophrenic patients, their unaffected siblings, and normal volunteers), those individuals with either the val66met allele or met66met allele had selective difficulties with episodic or working memory; those with the met66met allele had the most difficulty.

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Table 1 Allelic variation in proBDNF and bipolar disorder onset or rapid cycling Study

# of Bipolar subjects

Findings/(Country)

A. Positive associations of val66val and bipolar illness in North American populations Sklar et al., 2002 334 The val66val BDNF polymorphism was associated with bipolar disorder in 334 parent-proband trios Neves-Pereira et al., 2002

283

Significant association between val66val BDNF polymorphism and bipolar disorder in 283 bipolar probands

Geller et al., 2004a

53

The val66val BDNF polymorphism was preferentially transmitted in bipolar children with bipolar parents

Skibinska et al., 2004a

28

Only in subset of patients with early onset for bipolar illness was there a significant association, not in the whole population (N = 352)

Lohoff et al., 2005

621

Replication study confirming that the val66val polymorphism in the BDNF gene might increase susceptibility to bipolar disorder in the Caucasian population

Green et al., 2006

131

In patients with rapid cycling (but not whole bipolar populations [N = 3062]), there was a significant association of the val allele (p = .004)

B. Positive association for other BDNF variants Association with dinucleotide repeat (GT)n and the val/short haplotype, but not the val66met allele of Strauss et al., 2004a proBDNF for childhood onset mood disorders (BP-I, II, dysthymia, depression) C. No Associations of Nakata et al., 2003 Hong et al., 2003 Kunugi et al., 2004 Neves-Pereira et al., 2005 a

val66val BDNF and bipolar illness 132 (Japan) 108 (China) 519 (Japan) 263 (Scotland; where an association to schizophrenia was observed)

Association with early or childhood onset.

In 54 bipolar patients, Rybakowski et al. (2003) found that the val66met allele was associated with poorer performance in all domains of the Wisconsin Card Sort Test (WCST), even though these patients had a later onset of bipolar illness than those with the val66val allele, and would have been expected to have fewer illness-related performance deficits. 3.2. The val66val BDNF allele and the incidence of bipolar disorder Seven studies have found an association between the val66val allele and an incidence of bipolar disorder. However, all of these studies were performed in North American or British patients, and five other studies found no association between the val66 allele and bipolar disorder; three of these studies were in Asian populations, one was in a Polish population, and one was in Scottish population, suggesting that genes will contribute different levels of vulnerability in different families and ethnic sub-populations (Table 1). 3.2.1. Positive association studies In addition to Geller et al. (2004) noted below, three other large studies noted a positive association between the val66val BDNF allele and bipolar disorder. Sklar et al. (2002) tested the association between 76 candidate genes and bipolar disorder in 90 SNPs. The only finding in the original 136 parent-proband trios that was replicable in an additional sample of 334 parent-proband trios was an association between the val66val allele and bipolar disorder.

Neves-Pereira et al. (2002) tested the presence of linkage disequilibrium between two polymorphisms in the BDNF gene (a dinucleotide repeat [GT]n and the val66val SNP) in 283 nuclear families, and found linkage disequilibrium between both polymorphisms and bipolar disorder. Lohoff et al. (2005) performed a replication study of the studies by Sklar et al. and Neves-Pereira et al. to confirm an association between the val66val variation in the BDNF gene and bipolar disorder. In 621 bipolar patients and 998 healthy controls genotyped, the allele frequencies of val66val differed significantly between bipolar patients and controls, confirming the association of the previous two studies. 3.2.2. Negative bipolar association studies and other illness associations Five different studies found no association between the val66met allele and bipolar disorder. These negative studies included patients from Asian backgrounds (Hong et al., 2003; Kunugi et al., 2004; Nakata et al., 2003), and a study in Polish patients (Skibinska et al., 2004). Neves-Pereira et al. (2005), in a recent study of 321 Scottish patients with schizophrenia and 263 with bipolar disorder, found a positive association with the val66met allele and schizophrenia, but not with bipolar disorder. 3.3. The BDNF alleles and early age of bipolar onset or rapid cycling A series of findings rapidly emerged after the study of Rybakowski et al. (2003) indicating that in childhood-onset bipolar illness (Geller et al., 2004; Skibinska et al., 2004),

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the val66met allele was protective for bipolar illness onset, and those with the val66val BDNF allele had an earlier onset of illness. Geller and colleagues investigated the transmission of the BDNF val66 allele in 53 complete, independent biological trios (child or adolescent with bipolar disorder + both biological parents). In this patient and parent sample, with a child or early adolescent mean age of 10.7 years, the BDNF val66val allele was preferentially transmitted to the children or adolescents with bipolar disorder. Skibinska et al. (2004) found no significant overall difference between schizophrenic patients and controls, but in a subset of bipolar (N = 28) patients with early onset (18 years or younger), did find an association between the val66val allele and the early-onset bipolar disorder subgroup. Strauss et al. (2004) tested two different genetic polymorphisms of BDNF for their association with childhood-onset mood disorders (COMD) in a case-control study design. These two polymorphisms – a dinucleotide repeat (GT)n, and the SNP val66met – were genotyped in 99 adults with a history of COMD (major depressive disorder, dysthymic disorder, or bipolar I/II disorder). Strauss found that the allele distribution of (GT)n for COMD patients differed significantly for controls, particularly an excess of the 168 bp allele and a val/short haplotype, but the val66 alleles were not associated with COMD. The val66 allele of BDNF has also been associated with the rapid cycling variant of bipolar disorder. While no overall association was seen in the entire case-control sample (N = 3062 total and 962 bipolar), in 131 individuals with a history of rapid cycling there was a significant (p = 0.004) association with the val66 allele (Green et al., 2006). This was also observed in a previous family-based association study by these authors (p < .03, one-tailed) (Sklar et al., 2002). In another independent sample, Muller et al. (2006) found that the rapid cycling cases explained the association with val66 BDNF observed in the original study (NevesPereira et al., 2002) when different phenotypic subtypes were examined. Thus, there is conflicting evidence surrounding the val66val association with bipolar disorder, and not all of the positive studies are entirely internally consistent enough to point to a single conclusion. As listed in Table 1, three studies have revealed an overall association with bipolar illness, two more with the early-onset subtype (and a third with early onset and a separate BDNF variant), and two more with the rapid cycling subtype. Although each potential finding has been separately replicated, there are also a number of non-replications, particularly in Asian populations where the balance of allele variations may be different, but in some European populations as well. It is of interest that early- or childhood-onset bipolar disorder is itself a powerful risk factor for a subsequent rapid cycling course (Leverich and Post, 2006; Leverich

et al., in press; Perlis et al., 2004), and it remains to be ascertained how one or the other (or both) are eventually going to be related to the val66val BDNF allele. One possibility that could further clarify these relationships and explain some of the differences across studies is that there may be potent gene–environment interactions at work, similar to those reported by Caspi et al. (2003) where allelic variation in the serotonin transporter was only revealed as a powerful risk factor for depression as it interacted with environmental adversity (both in childhood and in relationship to concurrent adult stressors). Given the observations of powerful and lasting environmental effects on BDNF levels and expression reviewed here, such gene–environment interactions in val66met relationships might very well be expected. How these interactions unfold in future BDNF studies will be a very exciting area of new investigation. Moffitt and colleagues (2005) have suggested that the era of looking for simple gene behavior relationships in psychiatry is over, and that the most promising approach for the future is in the examination of hypothesized mechanism-based gene–environment interaction studies. As such, the BDNF findings already evident – positive findings for environmental stressors, and promising findings for gene relationships to illness onset and cognitive dysfunction – would appear to be a most fruitful area for further study. We also wish to emphasize that val66val BDNF and its val66met variant may not be the only important BDNF SNPs (Green and Craddock, 2005; Strauss et al., 2004), and that BDNF alleles are likely to be one of a large number of genetic vulnerability factors for bipolar illness, each of relatively small effect (Mathews and Reus, 2003). Nonetheless, these SNP findings are the first well-replicated findings for bipolar illness, and their integration with the neurochemical and functional consequences of BDNF protein alterations noted above provide a unique opportunity to consider its potential implications for the pathophysiology and therapeutics of the recurrent affective disorders. Although one study suggested that negative symptoms of schizophrenia may also be associated with the 172 bp allele of BDNF (Fanous et al., 2004), Egan et al. (2003) found no association of the val66met allele with schizophrenia. In contrast, as noted above, Neves-Pereira et al. (2005) did find this association in Scottish patients. Several studies (Koizumi et al., 2004; Ribases et al., 2003) found an association between the val66met allele and eating disorders, including a multi-center collaborative study that suggested an association with the risk for all eating disorder subtypes (anorexia nervosa, restricting anorexia nervosa, binge eating/purging anorexia nervosa, and bulimia nervosa) (Ribases et al., 2004). Hall et al. (2003) found a significant association between val66met and obsessive-compulsive disorder in 164 triads with the illness. Thus, further work is necessary to define the range of populations where the BDNF alleles may be risk factors.

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4. Theoretical and clinical implications of BDNF alterations in unipolar and bipolar disorder The BDNF findings noted here need to be viewed in a broader context, as one example of a potential vulnerability factor for minor difficulties in cognitive processing that even occur within normal variations and with bipolar illness occurrence, early onset, or rapid cycling patterns. For example, even in normal volunteers the val66met allele is associated with poorer episodic memory (Egan et al., 2003), reduced hippocampal volume (Bueller et al., 2006; Pezawas et al., 2004), reduced N-acetylaspartate (Egan et al., 2003), increased bilateral hippocampal activation (Egan et al., 2003), and reduced gray matter volume in the dorsolateral prefrontal cortex (Pezawas et al., 2004). Conversely, the val66val allele is associated with bipolar onset. Why this better functioning allele is related to bipolar illness remains to be further studied. However, proB DNF and BDNF may have opposing actions, and which predominates at given times is not yet clear. The long forms of both pro nerve-growth factor (proNGF) and proBDNF are secreted presynaptically and interact with a high affinity to the nonspecific neurotrophic factor receptor p75NTR to induce preprogrammed cell death (apoptosis) (Hempstead, 2002; Lee et al., 2001). In contrast, BDNF itself interacts weakly with low affinity to the p75NTR receptor, but with high affinity to the trkB receptor where it is neuroprotective. ProBDNF is converted to the shorter, mature BDNF via the intrasynaptic actions of plasminogen and (as converted by tissue plasminogen activator) plasmin. Hempstead postulates that BDNF acting at postsynaptic trkB receptors is associated with late-phase LTP, whereas proB DNF acting at p75 (which is markedly increased in the juvenile hippocampus) may be associated with long-term depression (LTD). Thus, there may be opposite physiological effects of proBDNF (LTD/apoptosis) and BDNF itself (LTP/neuronal survival). Furthermore, in contrast to proNGF (Nykjaer et al., 2004), the interaction of proBDNF with sortilin (a receptor for neurotensin) prevents cell death. The val66met allele of proBDNF may bind sortilin less well (Hempstead, unpublished data, 2005), leading to more cell death, in addition to its decreased intracellular transport and decreased release. Thus, exactly how the val66 alleles of proBDNF versus BDNF interact in the affective disorders remains to be better delineated. 4.1. Prediction of treatment response Given these new data that the val66val allele of BDNF represents a vulnerability factor for bipolar illness onset, and that the val66met allele is a vulnerability factor for selective cognitive difficulties across a variety of subject populations (including those with bipolar illness), one can ask how these observations could begin to be used to

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enhance clinical therapeutics. One question to be answered would be whether one could reverse the mild cognitive deficiencies in those patients with the val66met allele of BDNF, or in those with decreases in BDNF protein in serum, by treating these patients with agents that increase BDNF in general, such as the antidepressants, lithium, or valproate. One could also directly test the hypothesis that the already good-functioning val66val allele could contribute to the increased risk of switching into mania upon treatment with antidepressants that further increase BDNF. Perhaps the most important clinical use would be the assessment of the possible role of val66met in predicting drug responsivity; this allele could possibly be used in conjunction with a variety of other candidate SNPs to help predict individual responsiveness to different types of treatments that do or do not increase BDNF. David Cox of Perlegen Sciences has made the argument that using a focused array of some 40–50 currently available SNP assays could help facilitate the choice of more optimal and targeted therapeutic strategies for each patient, and in this fashion the recent striking advances in molecular genetics could most rapidly be converted to major health assets. The use of a series of SNPs for the prediction of personal clinical response and side-effect risks could occur much faster than the more traditional approach of molecular genetics aimed at identifying novel pathophysiological mechanisms for the development of new therapeutic targets and drugs. Although this traditional approach has much merit, it has yet to bear fruit, even in a single-gene disease such as Huntington’s chorea. Most would agree that in complex illnesses, such as bipolar disorder and schizophrenia, there will not only be multiple genes involved, but also each will have only a small effect, thus vastly complicating any translation to a new therapeutic approach. Given this likely reality and the current great need to more rationally and efficiently choose among the already existing panoply of treatment options for bipolar disorder, the use of a focused array of SNP markers to help better predict individual treatment response could yield major clinical advances in the very near future. 4.2. Early intervention to alter the poor prognosis of childhood-onset bipolar disorder If the val66val BDNF allele proves to be a risk factor for childhood onset, it (along with a panel of other SNPs) could be used to help further assess those at already high risk for bipolar illness based on a uni-lineal or bi-lineal positive family history of bipolar illness, (Lapalme et al., 1997). Studies of adults with bipolar illness indicate that a history of childhood onset (prior to age 13), or adolescent onset (age 13–19), are potent risk factors for eventual poor outcome (Leverich and Post, 2006; Leverich et al., in press; Perlis et al., 2004). These two early-onset groups account

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for a high proportion (50–66%) of all adults with bipolar illness. These early-onset patients showed a more adverse course of illness compared with those patients with adult onset bipolar disorder, including increased rates of anxiety disorder and comorbid substance abuse, more episode recurrences and suicide attempts, and less time well (Leverich and Post, 2006; Leverich et al., in press; Perlis et al., 2004). These retrospective reports by patients were confirmed prospectively by clinician ratings, indicating that those with early onset had increased severity of depression and cycling assessed during one year in a naturalisticallytreated cohort (Leverich et al., 2003; Leverich et al., 2002a; Nolen et al., 2004; Post et al., 2003a), indicating an increased degree of treatment-resistance in general (Leverich et al., in press). Disappointingly, the average delay from the onset of first symptoms to the onset of the first treatment for depression or mania was approximately ten years (Leverich et al., 2003; Leverich and Post, 2006). As in the data of Wang et al. (2005), the delay was inversely proportional to the age of onset, such that those with early onsets had the longest delays to first treatment. It is possible that earlier treatment could have ameliorated those poor outcomes in adulthood. Thus, the potential development of SNP profiles of vulnerability factors, such as BDNF in connection with an array of other SNPS, could help shorten the delay to the onset of treatment with its associated occurrence of many affective episodes and the development of considerable dysfunction. 4.3. Countering stigma with new data on neurobiology and treatment The emerging BDNF findings can be combined with the growing data on the substantial number of replicated neurochemical, neurophysiological, and structural brain alterations seen in patients with bipolar illness compared with controls (Glitz et al., 2002; Ketter et al., 1997; Ketter et al., 2001; Manji et al., 2000b; Post, 2000; Post et al., 2003b; Strakowski et al., 2005) to help further address issues of stigma. Bipolar illness pathophysiology is clearly brain-based, and not all a product of one’s mind. Moreover, if there are well-replicated deficits in structure, function, and subtleties of biochemical regulation, perhaps these can be reversed or prevented with appropriate treatments targeted toward increased BDNF and other neurotropic and cell survival factors, further changing the conceptual treatment paradigm from mere episode prevention to the possibility of direct approaches to pathophysiology. If perinatal stress-induced decrements in prefrontal BDNF can persist in experimental animals into adulthood (Russo-Neustadt et al., 2001), could these or adult stressors affecting BDNF in a long-lasting fashion (Berton et al., 2006; Tsankova et al., 2006) occur in humans and account for some of the cognitive and biophysiological deficits observed in patients with bipolar illness? The deficits in

bipolar patients include alterations in neural and glial number (Drevets et al., 1998; Rajkowska, 2000) and glial activity (Xing et al., 2002), as well as relative prefrontal decreases in activity or neuronal integrity revealed with different brain imaging techniques ranging from positron emission tomography (PET) scans to magnetic resonance spectroscopy (MRS) (Chang et al., 2003; Ketter et al., 2001; Post et al., 2003b; Winsberg et al., 2000). 4.4. Medication effects on the neurobiology of bipolar illness Lithium increases cortical gray matter in most bipolar subjects, but not in those recently treated with lithium and not in normal controls (Moore et al., 2000b; Sassi et al., 2004). It also increases NAA on MRS (Moore et al., 2000a). Increased sprouting of the dentate granule cells has been reported in autopsy specimens from subjects with bipolar illness compared with controls (Dowlatshahi et al., 2000). Tsai (2004) has speculated that manic states could also induce increases in BDNF and be associated with such increased sprouting of mossy fibers, similar to that in kindling (Cavazos et al., 1991; Golarai and Sutula, 1996). Animals subjected to repeated neonatal maternal separation show long-lasting increases in anxiety-related behaviors and in corticosterone (the rodent equivalent of the stress hormone cortisol in man) (Kaufman et al., 2000; Ladd et al., 2000; Plotsky and Meaney, 1993), and repeated defeat stresses induce changes in behavior and BDNF lasting 40 days or more (Berton et al., 2006; Tsankova et al., 2006). Both of these alterations are reversed by chronic treatment with antidepressants, although upon discontinuation of these agents, the animal’s behavior and cortisol status reverts to its altered baseline (Huot et al., 2001). As noted above, patients with bipolar illness who have a history of early childhood adversity have an earlier onset and more severe retrospective and prospective course of their illness (Garno et al., 2005; Leverich et al., 2002a; Leverich et al., 2002b). Whether or not this progression is mediated through genetic or environmentally-induced alterations in BDNF or both (Roceri et al., 2002; Roceri et al., 2004; Russo-Neustadt et al., 2001; Smith et al., 1995a; Smith et al., 1995b; Smith et al., 1995c; Zhang et al., 2002), it is possible that effective pharmacotherapeutic intervention with agents targeted towards BDNF could counter some of these biochemical and course-of-illness adversities as shown in the preclinical stress studies. We know that lithium exerts a variety of positive clinical effects in patients with recurrent affective disorders (Baldessarini and Tondo, 2000; Goodwin and Jamison, 1990). Not only does lithium help prevent episodes of mania and depression, it decreases the risk of suicide (Baldessarini et al., 2003), and decreases the enhanced medical mortality resulting from causes other than suicide that are associated with untreated depression (Muller-Oerlinghausen et al., 2003). In addition to these known clinical benefits, we can now ask whether lithium’s neurotrophic and

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neuroprotective effects – perhaps in part mediated through effects on BDNF as well as on Bcl-2 and decrements in cell death factors (Bax and p53) (Chuang et al., 2002) – could also yield changes in the brain that are positive and alter relapse vulnerability. 5. Conclusions The findings reviewed here indicate that BDNF: (1) is a risk factor for bipolar illness onset and/or cognitive dysfunction; (2) is altered in affective illness and by stressors; and (3) is increased by a range of effective treatments. These findings help make the case that bipolar disorder is a genetically- and neurochemically-based complex, recurrent, and potentially progressive neuropsychiatric disorder involving multiple brain and endocrine systems that carries the risk of illness mortality (directly by suicide and indirectly from other associated medical illnesses). These findings also suggest that the pharmacological agents used in the treatment of these illnesses not only prevent affective episodes, but may also help prevent or reverse pathological changes in the brain associated with bipolar illness, i.e., in addition to untoward side effects, these drugs may have positive effects on the brain as well. These emerging views of the pathophysiology and implications for treatment could help drive medical practice and public policy toward reversing the gaps in the recognition and treatment of bipolar disorder (Demyttenaere et al., 2004; Hirschfeld et al., 2003), leading to earlier intervention with effective agents. At the same time, these new views of recurrent affective illness and its treatments may help patients in their own consideration of the risk-to-benefit ratios for initiating and maintaining long-term prophylaxis. In addition to evaluating the therapeutic effects and side effects of the antidepressants and mood stabilizers, one could now also consider their potential neurotrophic and neuroprotective effects on the brain. While we have focused the discussion on BDNF, the balance of cell survival versus cell death is an extraordinarily complex process and many of our current and future therapeutic agents may interact at an array of other important targets. Thus, not only are other and perhaps novel pathways likely involved, but also synergistic effects of multiple systems may be important to the longterm effects of prophylactic medications. Acknowledgment The support of the Dalio Foundation is gratefully acknowledged. References Altar CA, Whitehead RE, Chen R, Wortwein G, Madsen TM. Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biological Psychiatry 2003;54:703–9. Aydemir O, Deveci A, Taneli F. The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in

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depressed patients: a preliminary study. Progress in Neuropsychopharmacology & Biological Psychiatry 2005;29:261–5. Baldessarini RJ, Tondo L. Does lithium treatment still work? Evidence of stable responses over three decades. Archives of General Psychiatry 2000;57:187–90. Baldessarini RJ, Tondo L, Hennen J. Lithium treatment and suicide risk in major affective disorders: update and new findings. Journal of Clinical Psychiatry 2003;64(Suppl. 5):44–52. Bertolino A, Frye M, Callicott JH, Mattay VS, Rakow R, Shelton-Repella J, et al. Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging. Biological Psychiatry 2003;53:906–13. Berton O, McClung CA, DiLeone RJ, Krishnan V, Renthal W, Russo SJ, et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 2006;311:864–8. Blumberg HP, Kaufman J, Martin A, Whiteman R, Zhang JH, Gore JC, et al. Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder. Archives of General Psychiatry 2003;60:1201–8. Bueller JA, Aftab M, Sen S, Gomez-Hassan D, Burmeister M, Zubieta JK. BDNF val(66)met allele is associated with reduced hippocampal volume in healthy subjects. Biological Psychiatry 2006;59:812–5. Calabrese JR, Keck Jr PE, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. American Journal of Psychiatry 2005;162:1351–60. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301:386–9. Castren E. Neurotrophic effects of antidepressant drugs. Current Opinion in Pharmacology 2004;4:58–64. Cavazos JE, Golarai G, Sutula TP. Mossy fiber synaptic reorganization induced by kindling: time course of development, progression, and permanence. Journal of Neuroscience 1991;11:2795–803. Chang K, Adleman N, Dienes K, Barnea-Goraly N, Reiss A, Ketter T. Decreased N-acetylaspartate in children with familial bipolar disorder. Biological Psychiatry 2003;53:1059–65. Chen RW, Chuang DM. Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. Journal of Biological Chemistry 1999;274:6039–42. Chen G, Zeng WZ, Yuan PX, Huang LD, Jiang YM, Zhao ZH, et al. The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS. Journal of Neurochemistry 1999;72:879–82. Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK. Enhancement of hippocampal neurogenesis by lithium. Journal of Neurochemistry 2000;75:1729–34. Chen B, Dowlatshahi D, MacQueen GM, Wang J, Young LT. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biological Psychiatry 2001;50:260–5. Chuang DM, Chen RW, Chalecka-Franaszek E, Ren M, Hashimoto R, Senatorov V, et al. Neuroprotective effects of lithium in cultured cells and animal models of diseases. Bipolar Disorders 2002;4:129–36. Cunha AB, Frey BN, Andreazza AC, Goi JD, Rosa AR, Goncalves CA, et al. Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neuroscience Letters 2006;398:215–9. Demyttenaere K, Bruffaerts R, Posada-Villa J, Gasquet I, Kovess V, Lepine JP, et al. Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization World Mental Health Surveys. JAMA 2004;291:2581–90. Dowlatshahi D, MacQueen G, Wang JF, Chen B, Young LT. Increased hippocampal supragranular Timm staining in subjects with bipolar disorder. NeuroReport 2000;11:3775–8. Drevets WC, Ongur D, Price JL. Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders. Molecular Psychiatry 1998;3:220–1.

988

R.M. Post / Journal of Psychiatric Research 41 (2007) 979–990

Duman RS. Novel therapeutic approaches beyond the serotonin receptor. Biological Psychiatry 1998;44:324–35. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003;112:257–69. Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, et al. The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. Journal of Neuroscience 2003;23:7311–6. Eisch AJ, Bolanos CA, de Wit J, Simonak RD, Pudiak CM, Barrot M, et al. Brain-derived neurotrophic factor in the ventral midbrainnucleus accumbens pathway: a role in depression. Biological Psychiatry 2003;54:994–1005. Fanous AH, Neale MC, Straub RE, Webb BT, O’Neill AF, Walsh D, et al. Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study. American Journal of Medical Genetics 2004;125B:69–78. Garno JL, Goldberg JF, Ramirez PM, Ritzler BA. Impact of childhood abuse on the clinical course of bipolar disorder. British Journal of Psychiatry 2005;186:121–5. Geller B, Badner JA, Tillman R, Christian SL, Bolhofner K, Cook Jr EH. Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. American Journal of Psychiatry 2004;161:1698–700. Glitz DA, Manji HK, Moore GJ. Mood disorders: treatment-induced changes in brain neurochemistry and structure. Semin Clin Neuropsychiatry 2002;7:269–80. Goddard GV, Douglas RM. Does the engram of kindling model the engram of normal long term memory? Canadian Journal of Neurological Sciences 1975;2:385–94. Golarai G, Sutula TP. Functional alterations in the dentate gyrus after induction of long-term potentiation, kindling, and mossy fiber sprouting. Journal of Neurophysiology 1996;75:343–53. Gonul AS, Akdeniz F, Taneli F, Donat O, Eker C, Vahip S. Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. European Archives of Psychiatry and Clinical Neuroscience 2005;255:381–6. Goodwin FK, Jamison KR. Manic-depressive illness. New York: Springer; 1990. Green E, Craddock N. Brain-derived neurotrophic factor as a potential risk locus for bipolar disorder: evidence, limitations, and implications. Current Psychosis and Therapeutics Reports 2005;2:153–9. Green EK, Raybould R, MacGregor S, Hyde S, Young AH, O’Donovan MC, et al. Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder: case-control study of over 3000 individuals from the UK. British Journal of Psychiatry 2006;188:21–5. Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M. Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. American Journal of Human Genetics 2003;73:370–6. Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, et al. Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. Journal of Neuroscience 2004;24:6590–9. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. Journal of Neuroscience 2003;23:6690–4. Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived neurotrophic factor in mood disorders. Brain Research, Brain Research Reviews 2004;45:104–14. He XP, Kotloski R, Nef S, Luikart BW, Parada LF, McNamara JO. Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model. Neuron 2004;43:31–42. Hempstead BL. The many faces of p75NTR. Current Opinion in Neurobiology 2002;12:260–7.

Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder. Journal of Clinical Psychiatry 2003;64:161–74. Hirschfeld RM, Weisler RH, Raines S, Macfadden W. Quetiapine in the treatment of anxiety in patients with bipolar I or II depression: A secondary analysis from a randomized, double-blind, placebo-controlled study. Journal of Clinical Psychiatry 2006;67:355–62. Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ. Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology 2003;8:186–9. Huot RL, Thrivikraman KV, Meaney MJ, Plotsky PM. Development of adult ethanol preference and anxiety as a consequence of neonatal maternal separation in Long Evans rats and reversal with antidepressant treatment. Psychopharmacology (Berlin) 2001;158:366–73. Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Research 2002;109:143–8. Kaufman J, Plotsky PM, Nemeroff CB, Charney DS. Effects of early adverse experiences on brain structure and function: clinical implications. Biological Psychiatry 2000;48:778–90. Kaufman J, Yang BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S, et al. Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biological Psychiatry 2006;59:673–80. Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the ‘‘kindling’’ hypothesis. American Journal of Psychiatry 2000;157:1243–51. Ketter TA, George MS, Kimbrell TA, Benson BE, Post RM. Functional brain imaging in mood and anxiety disorders. Current Review of Mood and Anxiety Disorders 1997;1:95–112. Ketter TA, Kimbrell TA, George MS, Dunn RT, Speer AM, Benson BE, et al. Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder. Biological Psychiatry 2001;49:97–109. Koizumi H, Hashimoto K, Itoh K, Nakazato M, Shimizu E, Ohgake S, et al. Association between the brain-derived neurotrophic factor 196G/A polymorphism and eating disorders. American Journal of Medical Genetics B, Neuropsychiatry Genetics 2004;127:125–7. Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Hippocampal long-term potentiation is impaired in mice lacking brainderived neurotrophic factor. Proceedings of the National Academy of Sciences of the United States of America 1995;92:8856–60. Kuma H, Miki T, Matsumoto Y, Gu H, Li HP, Kusaka T, et al. Early maternal deprivation induces alterations in brain-derived neurotrophic factor expression in the developing rat hippocampus. Neuroscience Letters 2004;372:68–73. Kunugi H, Iijima Y, Tatsumi M, Yoshida M, Hashimoto R, Kato T, et al. No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: a multicenter study. Biological Psychiatry 2004;56:376–8. Ladd CO, Huot RL, Thrivikraman KV, Nemeroff CB, Meaney MJ, Plotsky PM. Long-term behavioral and neuroendocrine adaptations to adverse early experience. Progress in Brain Research 2000;122:81–103. Lang UE, Hellweg R, Gallinat J. BDNF serum concentrations in healthy volunteers are associated with depression-related personality traits. Neuropsychopharmacology 2004;29:795–8. Lapalme M, Hodgins S, LaRoche C. Children of parents with bipolar disorder: a metaanalysis of risk for mental disorders. Canadian Journal of Psychiatry 1997;42:623–31. Lee R, Kermani P, Teng KK, Hempstead BL. Regulation of cell survival by secreted proneurotrophins. Science 2001;294:1945–8. Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the

R.M. Post / Journal of Psychiatric Research 41 (2007) 979–990 enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. Journal of Neurochemistry 2002;82:1367–75. Leverich GS, Post RM. Course of bipolar illness after history of childhood trauma. Lancet 2006;367:1040–2. Leverich GS, Post RM, Keck Jr PE, Altshuler LL, Frye MA, Kupka RW, et al. The poor prognosis of childhood-onset bipolar disorder: The need for earlier recognition and treatment. Journal of Pediatrics [in press]. Leverich GS, McElroy SL, Suppes T, Keck Jr PE, Denicoff KD, Nolen WA, et al. Early physical and sexual abuse associated with an adverse course of bipolar illness. Biological Psychiatry 2002a;51:288–97. Leverich GS, Perez S, Luckenbaugh DA, Post RM. Early psychosocial stressors: relationship to suicidality and course of bipolar illness. Clinical Neuroscience Research 2002b;2:161–70. Leverich GS, Altshuler LL, Frye MA, Suppes T, Keck PE, McElroy SL, et al. Factors associated with suicide attempts in 648 patients with bipolar disorder in the Stanley Foundation Bipolar Network. Journal of Clinical Psychiatry 2003;64:506–15. Linnarsson S, Bjorklund A, Ernfors P. Learning deficit in BDNF mutant mice. European Journal of Neuroscience 1997;9:2581–7. Lohoff FW, Sander T, Ferraro TN, Dahl JP, Gallinat J, Berrettini WH. Confirmation of association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and bipolar I disorder. American Journal of Medical Genetics B, Neuropsychiatry Genetics 2005;139:51–3. Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH, et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proceedings of the National Academy of Sciences of the United States of America 1999;96:15239–44. Machado-Vieira R, Dietrich MO, Leke R, Cereser VH, Zanatto V, Kapczinski F, Souza DO, Portela LV, Gentil V. Decreased plasma brain derived neurotrophic factor levels in unmedicated bipolar patients during manic episode. Biological Psychiatry [in press]. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Journal of Neuroscience 2000;20:9104–10. Malenka RC. LTP and LTD: dynamic and interactive processes of synaptic plasticity. The Neuroscientist 1995;1:35–42. Manji HK, Moore GJ, Chen G. Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness. Biological Psychiatry 2000a;48:740–54. Manji HK, Moore GJ, Rajkowska G, Chen G. Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry 2000b;5:578–93. Mathews CA, Reus VI. Genetic linkage in bipolar disorder. CNS Spectr. 2003;8:891–904. Moffitt TE, Caspi A, Rutter M. Strategy for investigating interactions between measured genes and measured environments. Archives of General Psychiatry 2005;62:473–81. Monkul ES, Malhi GS, Soares JC. Mood disorders - review of structural MRI studies. Acta Neuropsychiatrica 2003;15:368–80. Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, et al. Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biological Psychiatry 2000a;48:1–8. Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK. Lithium-induced increase in human brain grey matter. Lancet 2000b;356:1241–2. Muller MB, Toschi N, Kresse AE, Post A, Keck ME. Long-term repetitive transcranial magnetic stimulation increases the expression of brainderived neurotrophic factor and cholecystokinin mRNA, but not neuropeptide tyrosine mRNA in specific areas of rat brain. Neuropsychopharmacology 2000;23:205–15. Muller DJ, De Luca V, Sicard T. The brain derived neurotrophic factor (BDNF) gene and rapid-cycling bipolar disorder. Br J Psychiatry 2006;189:317–23. Muller-Oerlinghausen B, Berghofer A, Ahrens B. The antisuicidal and mortality-reducing effect of lithium prophylaxis: conse-

989

quences for guidelines in clinical psychiatry. Canadian Journal of Psychiatry 2003;48:433–9. Nakata K, Ujike H, Sakai A, Uchida N, Nomura A, Imamura T, et al. Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder. Neuroscience Letters 2003;337:17–20. Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL. The brain-derived neurotrophic factor ene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet 2002;71:651–5. Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P, et al. BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry 2005;10:208–12. Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. Journal of Neuroscience. 1995;15:7539–47. Nolen WA, Luckenbaugh DA, Altshuler LL, Suppes T, McElroy SL, Frye MA, et al. Correlates of 1-year prospective outcome in bipolar disorder: results from the Stanley Foundation Bipolar Network. American Journal of Psychiatry 2004;161:1447–54. Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature 2004;427:843–8. Pagnin D, De Q V, Pini S, Cassano GB. Efficacy of ECT in depression: a meta-analytic review. J ECT. 2004;20:13–20. Patapoutian A, Reichardt LF. Trk receptors: mediators of neurotrophin action. Current Opinion in Neurobiology 2001;11:272–80. Paykel ES. Life events and affective disorders. Acta Psychiatrica Scand Suppl 2003:61–6. Perlis RH, Miyahara S, Marangell LB, Wisniewski SR, Ostacher M, DelBello MP, et al. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biological Psychiatry 2004;55:875–81. Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE, et al. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. Journal of Neuroscience 2004;24:10099–102. Plotsky PM, Meaney MJ. Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Mol Brain Res 1993;18:195–200. Post RM. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. American Journal of Psychiatry 1992;149:999–1010. Post RM. Neural substrates of psychiatric syndromes. In: Mesulam MM, editor. Principles of Behavioral and Cognitive Neurology. second ed. New York: Oxford University Press; 2000, p. 406–38. Post RM, Denicoff KD, Leverich GS, Altshuler LL, Frye MA, Suppes TM, et al. Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH Life Chart Method. Journal of Clinical Psychiatry 2003a;64:680–90. Post RM, Speer AM, Hough CJ, Xing G. Neurobiology of bipolar illness: implications for future study and therapeutics. Ann Clin Psychiatry 2003b;15:85–94. Rajkowska G. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biological Psychiatry 2000;48:766–77. Ren-Patterson RF, Cochran LW, Holmes A, Sherrill S, Huang SJ, Tolliver T, et al. Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice. Journal of Neuroscience Res. 2005;79:756–71. Ribases M, Gratacos M, Armengol L, de Cid R, Badia A, Jimenez L, et al. Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type. Mol Psychiatry 2003;8:745–51. Ribases M, Gratacos M, Fernandez-Aranda F, Bellodi L, Boni C, Anderluh M, et al. Association of BDNF with anorexia, bulimia and

990

R.M. Post / Journal of Psychiatric Research 41 (2007) 979–990

age of onset of weight loss in six European populations. Hum Mol Genet ;13:1205–12. Roceri M, Hendriks W, Racagni G, Ellenbroek BA, Riva MA. Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol Psychiatry 2002;7:609–16. Roceri M, Cirulli F, Pessina C, Peretto P, Racagni G, Riva MA. Postnatal repeated maternal deprivation produces age-dependent changes of brain-derived neurotrophic factor expression in selected rat brain regions. Biological Psychiatry 2004;55:708–14. Russo-Neustadt A. Brain-derived neurotrophic factor, behavior, and new directions for the treatment of mental disorders. Semin Clin Neuropsychiatry 2003;8:109–18. Russo-Neustadt A, Ha T, Ramirez R, Kesslak JP. Physical activityantidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model. Behav Brain Res 2001;120:87–95. Rybakowski JK, Borkowska A, Czerski PM, Skibinska M, Hauser J. Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients. Bipolar Disord 2003;5:468–72. Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressantinduced behavioral effects. Journal of Neuroscience 2003;23:349–57. Sassi RB, Brambilla P, Hatch JP, Nicoletti MA, Mallinger AG, Frank E, et al. Reduced left anterior cingulate volumes in untreated bipolar patients. Biological Psychiatry 2004;56:467–75. Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. American Journal of Psychiatry 2003;160:1516–8. Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biological Psychiatry 2003;54:70–5. Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS. Brainderived neurotrophic factor produces antidepressant effects in behavioral models of depression. Journal of Neuroscience 2002;22:3251–61. Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 1997;56:131–7. Skibinska M, Hauser J, Czerski PM, Leszczynska-Rodziewicz A, Kosmowska M, Kapelski P, et al. Association analysis of brain-derived neurotrophic factor (BDNF) gene val66met polymorphism in schizophrenia and bipolar affective disorder. World J Biological Psychiatry 2004;5:215–20. Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G, et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry 2002;7:579–93. Smith MA, Makino S, Kim SY, Kvetnansky R. Stress increases brainderived neurotropic factor messenger ribonucleic acid in the hypothalamus and pituitary. Endocrinology 1995a;136:3743–50. Smith MA, Makino S, Kvetnansky R, Post RM. Effects of stress on neurotrophic factor expression in the rat brain. Ann NY Acad Sci. 1995b;771:234–9.

Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. Journal of Neuroscience 1995c;15:1768–77. Strakowski SM, DelBello MP, Adler CM. The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings. Molecular Psychiatry 2005;10:105–16. Strauss J, Barr CL, George CJ, King N, Shaikh S, Devlin B, et al. Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder. American Journal of Medical Genetics B, Neuropsychiatry Genetics 2004;131:16–9. Tsai SJ. Is mania caused by overactivity of central brain-derived neurotrophic factor? Medical Hypotheses 2004;62:19–22. Tsai SJ, Hong CJ, Yu YW, Chen TJ. Association study of a brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and personality trait and intelligence in healthy young females. Neuropsychobiology 2004;49:13–6. Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature Neuroscience 2006;9:519–25. Tsuchiya KJ, Agerbo E, Mortensen PB. Parental death and bipolar disorder: a robust association was found in early maternal suicide. Journal of Affectective Disorders 2005;86:151–9. Vaidya VA, Siuciak JA, Du F, Duman RS. Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures. Neuroscience 1999;89:157–66. Videbech P, Ravnkilde B. Hippocampal volume and depression: a metaanalysis of MRI studies. American Journal of Psychiatry 2004;161:1957–66. Wang PS, Berglund P, Olfson M, Pincus HA, Wells KB, Kessler RC. Failure and delay in initial treatment contact after first onset of mental disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 2005;62:603–13. Winsberg ME, Sachs N, Tate DL, Adalsteinsson E, Spielman D, Ketter TA. Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder. Biological Psychiatry 2000;47:475–81. Xing G, Chavko M, Zhang LX, Yang S, Post RM. Decreased calciumdependent constitutive nitric oxide synthase (cNOS) activity in prefrontal cortex in schizophrenia and depression. Schizophrenia Research 2002;58:21–30. Xu H, Qing H, Lu W, Keegan D, Richardson JS, Chlan-Fourney J, et al. Quetiapine attenuates the immobilization stress-induced decrease of brain-derived neurotrophic factor expression in rat hippocampus. Neuroscience Letters 2002;321:65–8. Zanardini R, Gazzoli A, Ventriglia M, Perez J, Bignotti S, Maria RP, et al. Effect of repetitive transcranial magnetic stimulation on serum brain derived neurotrophic factor in drug resistant depressed patients. Journal of Affective Disorders 2006;91:83–6. Zhang LX, Levine S, Dent G, Zhan Y, Xing G, Okimoto D, et al. Maternal deprivation increases cell death in the infant rat brain. Brain Research, Developmental Brain Research 2002;133:1–11.