Psychopathology of depression

This review assesses some of the important advances that have been made in our understanding of the psychopathology of depression. While the monoamine theory, that postulates dysfunctional noradrenergic and serotonergic systems as the underlying cause of depression, has been valuable in the development of conventional antidepressants that are thought to act by reversing these dysfunctional states, recent clinical and experimental studies have questioned this reductionist view of depression. This has led to an assessment of the role of dysfunctional endocrine and immune systems in the aetiology of depression. In addition to explaining the link between defective neurotransmitter function and the symptoms of depression, changes in the endocrine and immune axes also help to explain the link between major depression and physical ill health. In addition, experimental and clinical studies have extended the possible involvement of neurotransmitters to include the glutamate and GABA systems. Such approaches may stimulate the development of new types of antidepressants that hopefully will combine increased efficacy with shorter speed of onset and improved side effect profiles.     

Mutagenesis and knockout models: NK1 and substance P

Tachykinins play an important role as peptide modulators in the CNS. Based on the concentration and distribution of the peptides and their receptors, substance P (SP) and its cognate receptor neurokinin 1 (NK1R) seem to play a particularly important role in higher brain functions. They are expressed at high levels in the limbic system, which is the neural basis of emotional responses. Three different lines of evidence from physiological studies support such a role of SP in the regulation of emotionality: (1) stress is often associated with elevated level of SP in animals and humans; (2) systematic and local injections of SP influence anxiety levels in a dose-dependent and site-specific manner; (3) NK1 receptor antagonists show anxiolytic effects in different animal models of anxiety. Although these studies point to the NK1 receptor as a promising target for the pharmacotherapy of anxiety disorders, high affinity antagonists for the human receptors could not be studied in rats or mice due to species differences in the antagonist binding sites. However, studies on anxiety and depression-related behaviors have now been performed in mouse mutants deficient in NK1 receptor or SP and NKA. These genetic studies have shown that anxiety and depression-related phenotypes are profoundly affected by the tachykinin system. For example, NK1R-deficient mice seem to be less prone depression-related behaviors in models of depression, and one study also provided evidence for reduced anxiety levels. Mice deficient in SP and NKA behaved similarly as the NK1R knockouts. In animal models of anxiety they performed like wildtype mice treated with anxiolytic drugs. In behavioral paradigms related to depression they behaved like wildtype animals treated with antidepressants. In summary, the genetic studies clearly show that the SP/NK1 system plays an important role in the modulation of emotional behaviors.     

Designing new treatments for depression and anxiety

Depression and anxiety are disabling disorders that affect many individuals. Drugs that interfere with the reuptake and/or metabolism of biogenic amines have been used to treat depression for more than four decades. An important development in the treatment of depression has been the emergence of triple reuptake inhibitors (SNDRIs), which inhibit the reuptake of serotonin, norepinephrine and dopamine. Preclinical and clinical research indicates that drugs inhibiting the reuptake of all of these neurotransmitters can produce a more rapid onset of action and greater efficacy than traditional antidepressants. Allosteric modulation of GABAA receptors can produce anxiolytic, sedative/hypnotic and anesthetic effects, presumably from enhancing the inhibitory neurotransmission of GABAA through a facilitation of receptor function. Benzodiazepines have been used with great success as anxiolytics, but the use of these drugs is limited because of their addictive potential and sedative side effects. This feature review discusses the design and synthesis of antidepressants based on the monoamine hypothesis of depression, and presents the current status of research on GABAA receptor modulators as a potential treatment for anxiety disorders.     

Usefulness of antidepressants for improving the neuropathic pain-like state and pain-induced anxiety through actions at different brain sites.

Clinically, it is well known that chronic pain induces depression, anxiety, and a reduced quality of life. There have been many reports on the relationship between pain and emotion. We previously reported that chronic pain induced anxiety with changes in opioidergic function in the central nervous system. In this study, we evaluated the anxiolytic-like effects of several types of antidepressants under a chronic neuropathic pain-like state and searched for the brain site of action where antidepressants show anxiolytic or antinociceptive effects. Sciatic nerve-ligated mice exhibited thermal hyperalgesia and tactile allodynia from days 7 to 28 after nerve ligation. At 4 weeks after ligation, these mice showed a significant anxiety-related behavior in the light-dark test and the elevated plus-maze test. Under these conditions, repeated administration of antidepressants, including the tricyclic antidepressant (TCA) imipramine, the serotonin noradrenaline reuptake inhibitor (SNRI) milnacipran, and the selective serotonin reuptake inhibitor (SSRI) paroxetine, significantly prevented the anxiety-related behaviors induced by chronic neuropathic pain. These antidepressants also produced a significant reduction in thermal hyperalgesia and tactile allodynia. Moreover, the microinjection of paroxetine into the basolateral amygdala or cingulate cortex reduced anxiety-related behavior, and microinjection into the primary somatosensory cortex significantly attenuated thermal hyperalgesia. These findings suggest that serotonergic antidepressants are effective for treating anxiety associated with chronic neuropathic pain and may be useful for treating neuropathic pain with emotional dysfunction such as anxiety. Furthermore, SSRIs show anxiolytic and antinociceptive effects by acting on different brain regions.     

Intranasal delivery of rapid-onset antidepressants: a new trend of treating major depressive disorder

Existing antidepressants seem to have an onset time of several weeks. However, newly found depression-related receptors and pathways may enlighten us to find more rapid-onset antidepressants, in which ketamine is one of the most potential antidepressants. By intranasal administration, drugs can be directly delivered to the brain via olfactory nerve route, which is proved to be suitable for some antidepressants. Well-designed rapid-onset antidepressants are the urgent requirements of the patients with depression. Intranasal administration, as a potential strategy to deliver antidepressants to brain, can improve drug efficacy and largely shorten the onset time. In this article, we sorted out some new formulation approaches in treating depression with different mechanisms and pathways compared with traditional treating strategies, along with new findings in clinical studies, proving that the combination of rapid-onset antidepressants with intranasal delivery will lead a new trend in treating depression.     

Roles of glutamate signaling in preclinical and/or mechanistic models of depression

Accumulating evidence suggests that the glutamatergic system plays important roles in the pathophysiology and treatment of major depressive disorder (MDD). Abnormalities in the glutamatergic system are definitely observed in this disorder, and certain glutamatergic agents exhibit antidepressant effects in patients with MDD. In this review, we summarize the preclinical findings suggesting the involvement of glutamate signaling in the pathophysiology and treatment of MDD. Preclinical animal models for depression are often characterized by changes in molecules related to glutamatergic signaling. Some antidepressants exert their effects by affecting glutamatergic system components in animals. Animals with genetically modified glutamatergic function exhibit depression-like behaviors or anti-depressive behavior. In addition, several types of glutamatergic agents have shown antidepressant-like effects in preclinical models for depression. Many types of glutamate receptors (NMDA, AMPA, and metabotropic glutamate receptors) or transporters appear to be involved in the etiology of depression or in the mechanisms of action of antidepressants. These functional proteins related to glutamate signal transduction are potential targets for a new generation of antidepressants with fast-onset effects, such as the NMDA antagonist ketamine.     

Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders

There is extensive comorbidity between depression and anxiety disorders. Dimensional psychiatric and psychometric approaches have suggested that dysregulation of a limited number of behavioural dimensions that cut across diagnostic categories can account for both the shared and unique symptoms of depression and anxiety disorders. Such an approach recognizes that anxiety, the emotional response to stress, is a key element of depression as well as the defining feature of anxiety disorders, and many antidepressants appear to be effective in the treatment of anxiety disorders as well as depression. Therefore, the pharmacological actions of these drugs must account for their efficacy in both. Brain noradrenergic and serotonergic systems, and perhaps to a more limited extent the dopaminergic system, regulate or modulate many of the same behavioural dimensions (e.g. negative or positive affect) that are affected in depression and anxiety disorders, and that are ameliorated by drug treatment. Whereas much recent research has focused on the regulatory effects of antidepressants on synaptic function and cellular proteins, less emphasis has been placed on monoaminergic regulation at a more global systemic level, or how such systemic alterations in monoaminergic function might alleviate the behavioural, cognitive, emotional and physiological manifestations of depression and anxiety disorders. In this review, we discuss how chronic antidepressant treatment might regulate the tonic activity and/or phasic reactivity of brain monoaminergic systems to account for their ability to effectively modify the behavioural dimensions underlying improvement in both depression and anxiety disorders.     

Pharmacotherapy of Behavioral and Psychological Symptoms of Dementia: Time for a Different Paradigm?

Behavioral and psychological symptoms of dementia can occur in 60-80% of patients with Alzheimer's disease or other dementing illnesses, and are important in that they are a source of significant caregiver stress and often precipitate nursing home placement. These symptoms, namely, aggression, delusions, hallucinations, apathy, anxiety, and depression, are clinically managed with a variety of psychotropic drugs such as antipsychotics, antidepressants, antiepileptic drugs, and benzodiazepines. Various advances in the neuropathophysiology and pharmacotherapy must be considered in the optimal design of regimens for patients with these symptoms.     

Coping with somatic comorbidities: striving for complete recovery

Depression is increasingly being recognized as a common comorbid disorder in patients with severe and chronic medical conditions. However, patients with depression and anxiety frequently present with somatic complaints such as aches and pains, headache, and chronic fatigue. This leads to underrecognition and undertreatment of the psychiatric disorder in an attempt to identify the medical cause of the somatic complaint. Reports are demonstrating the efficacy of antidepressants in treating disorders other than depression and anxiety. Tricyclic antidepressants have shown their usefulness in the treatment of diabetic neuropathy, fibromyalgia, and headache. Controlled studies of several selective serotonin reuptake inhibitors have been shown to be efficacious in relieving the symptoms of premenstrual dysphoric disorder and fibromyalgia. Pilot studies have also been conducted with the serotonin and norepinephrine reuptake inhibitor venlafaxine for the treatment of diabetic neuropathy, fibromyalgia, migraine, premenstrual dysphoric disorder, and stroke. The results encourage further controlled studies.     

New directions in the development of antidepressants: the interface of neurobiology and psychiatry

There have been considerable advances in neurobiology in recent years that are providing new directions for the development of novel classes of antidepressants. For example, the finding that corticotropin-releasing factor (CRF) is hypersecreted in depressed patients and mediates certain symptoms of depression has led to the development of specific antagonists of the CRF(1) receptor. These are expected to prove highly effective for the treatment of mood and anxiety disorders. Another related avenue of research is based on evidence that cortisol is integral to the pathophysiology of major depression with psychotic features. One alternative for treating this subtype of affective disorder is, therefore, to block the action of glucocorticoids using a receptor antagonist such as mifepristone. These are just two of the many new directions that will likely lead to the development of antidepressants in the near future.     

The approaches in the discovery of antidepressants using affective disorder models]

With the recent appearance of SSRI and SNRI, medication options with respect to depression have broadened. However, patients displaying clear improvement with existing antidepressants still do not exceed about 60 percent of total patients. New types of therapeutic agent development are currently required. Conditions for the determination of new antidepressants are: 1) instantaneous medications displaying a high level of antidepressant action in the early stages of treatment and 2) medications displaying efficacy with respect to patients that are therapy-resistant. However, drug discovery using new animal models is critical as part of drug development of these types of antidepressants in addition to models used in the past such as the forced swim test. We adopted two animal models (olfactory bulbectomy model and conditioned fear stress (CFS) model) developed for pharmacological evaluation of antidepressants. It has been well known that olfactory bulbectomied rats display extreme emotional response (aggressiveness and anxiety). However the improvement of this response occurs following chronic but not acute antidepressant treatment. Thus, we used this model to evaluate the period of the manifestation of antidepressant action. Mice exhibited a marked suppression of motility when they were returned to the same environment in which they had previously received an electric foot shock. Thus, it is suggested that the CFS stress model may be a useful model for therapy-resistant depression due to the fact that motor suppression is not readily attenuated by antidepressant treatment. In this report, we provide an overview of the approaches in the discovery of new antidepressants using these affective disorder models.     

Fibromyalgia syndrome: an overview of potential drug targets

Fibromyalgia syndrome (FMS) is a chronic disease of widespread and debilitating pain. The cause of FMS is unknown and its risk factors are poorly understood. It occurs frequently in the general population where it is often co-morbid with other rheumatoid and pain disorders, and psychiatric disorders such as anxiety and depression, making diagnosis particularly difficult. Several types of drugs are used to treat FMS, but none are specifically approved for this indication. FMS appears to be strongly associated with depression or at least with some symptoms of depression, and antidepressants appear to be effective in the treatment of this disorder. The advent of new classes of antidepressants with fewer side effects than older drugs has suggested new avenues of therapy for patients diagnosed with FMS.     

Zimelidine: a review of its pharmacological properties and therapeutic efficacy in depressive illness

Zimelidine is a new antidepressant, which is structurally unrelated to the tricyclic and tetracyclic antidepressants. The pharmacological profile of zimelidine is different to that of other antidepressants in that it appears to owe the major part of its activity to the inhibition of serotonin uptake within the central nervous system. It appears that the demethylated metabolite, norzimelidine, may be responsible for most of the pharmacological activity. Studies to date suggest that zimelidine has overall efficacy comparable with that of amitriptyline, desipramine, maprotiline and doxepin in depressive illness, but at dosages which have achieved a similar overall clinical improvement zimelidine does not cause sedation, and anticholinergic side effects are mild and occur infrequently. Preliminary evidence suggests that zimelidine is effective against concomitant anxiety in depressed patients, and that it may also be useful in treating phobic anxiety. Zimelidine appears less likely to cause serious cardiotoxicity, in therapeutic dosages or an overdosage, than the tricyclic antidepressants, but it has not been studied in patients with cardiovascular disease. Sleep disturbance has occurred significantly more frequently during zimelidine therapy than during therapy with other sedative antidepressants, but whether this simply reflects the absence of sedation with zimelidine, or an effect on sleep as such, is presently unclear. Zimelidine appears to be effective and well tolerated in elderly patients. Thus, some aspects of the drug's profile (e.g. apparent low incidence of anticholinergic effects or drowsiness) may offer potential advantages in some patients; however, clinical experience with zimelidine to date has been limited, and further well designed studies are required to define the role of the drug more clearly in treating depressive illness compared with other antidepressants, and particularly to define whether some types of depression may respond more readily to zimelidine than to other antidepressants.     

Neuroactive steroids and affective disorders

Neuroactive steroids modulate neurotransmission through modulation of specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABA(A)) receptors. Preclinical studies suggested that neuroactive steroids may modulate anxiety and depression-related behaviour and may contribute to the therapeutical effects of antidepressant drugs. Attenuations of such neuroactive steroids have been observed during major depression and in several anxiety disorders, suggesting a pathophysiological role in such psychiatric conditions. In panic disorder patients a dysequilibrium of neuroactive steroid composition has been observed, which may represent a counterregulatory mechanism against the occurrence of spontaneous panic attacks. Furthermore, alterations of 3alpha-reduced pregnane steroids during major depression were corrected by successful treatment with antidepressant drugs. However in contrast, non-pharmacological antidepressant treatment strategies did not affect neuroactive steroid composition. In addition, changes in neuroactive steroid concentrations after mirtazapine therapy occurred independently from the clinical response, thereby suggesting that changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of antidepressants rather than clinical improvement in general. Nevertheless, the effects of antidepressant pharmacotherapy on the composition of neuroactive steroids may contribute to the alleviation of certain depressive symptoms, such as amelioration of anxiety, inner tension or sleep disturbances. Moreover, first studies investigating the therapeutical effects of dehydroepiandrosterone revealed promising results in the treatment of major depression. In conclusion, neuroactive steroids are important endogenous modulators of depression and anxiety and may provide a basis for development of novel therapeutic agents in the treatment of affective disorders.     

Treatment of depression: time to consider folic acid and vitamin B12

We review the findings in major depression of a low plasma and particularly red cell folate, but also of low vitamin B12 status. Both low folate and low vitamin B12 status have been found in studies of depressive patients, and an association between depression and low levels of the two vitamins is found in studies of the general population. Low plasma or serum folate has also been found in patients with recurrent mood disorders treated by lithium. A link between depression and low folate has similarly been found in patients with alcoholism. It is interesting to note that Hong Kong and Taiwan populations with traditional Chinese diets (rich in folate), including patients with major depression, have high serum folate concentrations. However, these countries have very low life time rates of major depression. Low folate levels are furthermore linked to a poor response to antidepressants, and treatment with folic acid is shown to improve response to antidepressants. A recent study also suggests that high vitamin B12 status may be associated with better treatment outcome. Folate and vitamin B12 are major determinants of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional marker of both folate and vitamin B12 deficiency. Increased homocysteine levels are found in depressive patients. In a large population study from Norway increased plasma homocysteine was associated with increased risk of depression but not anxiety. There is now substantial evidence of a common decrease in serum/red blood cell folate, serum vitamin B12 and an increase in plasma homocysteine in depression. Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the association. On the basis of current data, we suggest that oral doses of both folic acid (800 microg daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression.     

5HT2 receptors, depression and anxiety

The distinction between non-psychotic repressive illness and anxiety states is blurred. Large scale trials in the neuroses indicate that benzodiazepines are ineffective in depression, and transiently and partially effective in anxiety. In contrast, tricyclic antidepressants are effective in both. All effective antidepressants decrease 5HT2 receptors number and this may mediate antidepressant efficacy. Our studies indicate that reduction of 5HT2 relative to 5HT1 neurotransmission would reverse the neuroendocrine abnormalities we have described in depression. Reduced 5HT2 neurotransmission may also be a mechanism of anxiolytic action in view of 5HT theories of punishment. There is clinical evidence for anxiolytic and antidepressant action of selective 5HT2 antagonists.     

Triple uptake inhibitors: therapeutic potential in depression and beyond

Drugs that interfere with the uptake and/or metabolism of biogenic amines have been used to treat depression for > 4 decades. Early medications such as tricyclic antidepressants and monoamine oxidase inhibitors are effective but possess many side effects that limit their usefulness. Selective serotonin reuptake inhibitors (SSRIs) or selective noradrenaline reuptake inhibitors (SNRIs) are the results of rational design to find drugs that are as effective as the tricyclic antidepressants, but with more selectivity towards a single monoamine transporter. The SSRI class of drugs, which includes fluoxetine, paroxetine and sertraline, were previously viewed as the agents of choice for treating major depression. Recently, inhibitors of both serotonin and noradrenaline uptake ('dual uptake inhibitors'; SSRI/SNRI such as venlafaxine, duloxetine and milnacipran) have gained acceptance in the market. However, neither the SSRIs nor the SSRI/SNRI are fully satisfactory due to a delayed onset of action, low rate of response and side effect that can affect compliance. An important recent development has been the emergence of the triple uptake inhibitors (SSRI/SNRI/selective dopamine reuptake inhibitor), which inhibit the uptake of all three neurotransmitters that are most closely linked to depression: serotonin, noradrenaline and dopamine. Preclinical studies and clinical trials indicate that a drug inhibiting the uptake of all three of these neurotransmitters could produce a more rapid onset of action and possess greater efficacy than traditional antidepressants. This review discusses the evolution of biogenic amine-based therapies, the emerging strategies involved in the design and synthesis of novel triple uptake inhibitors as antidepressants and the therapeutic potential of triple uptake inhibitors.     

Effects of psychopharmacological treatment with antidepressants on the vascular system

Psychopharmacological treatment with antidepressants is an essential part of guideline-based treatment strategies in affective disorders, such as major depressive disorder, persistent depressive disorder, and bipolar disorder. Furthermore, antidepressants are frequently prescribed in patients with physical disorders, such as cardiovascular diseases, and comorbid depression. The type of association between physical diseases, particularly chronic diseases, and depression is bidirectional, meaning that affective disorders enhance the risk for the development of cardiovascular and metabolic disorders, and that cardiovascular/metabolic disorders enhance the risk for the development of depressive disorders. Therefore, knowledge of vascular side effects of psychopharmacological treatment is important for clinicians. This clinical orientated review article covers direct and indirect effects of commonly prescribed antidepressant drugs on the vascular system.     

Effects of antidepressants on the production of cytokines

There is now evidence that major depression is associated with an up-regulation of the inflammatory response system (IRS). One of the major factors in this IRS activation is the hyperproduction of pro-inflammatory cytokines. Recently, a number of studies examined whether there is a causative role of these inflammatory mediators in the aetiology of major depression. Studies with animal models and cytokine immune therapy in humans suggest that pro-inflammatory cytokines induce depressive symptomatology. Moreover, these depressive symptoms can be effectively reversed by antidepressant treatment. Thus, it may be suggested that antidepressants suppress pro-inflammatory cytokine production and/or action, resulting in improvement of depressive symptoms. The influence of antidepressants on cytokine production has been examined in culture systems in vitro, and in animal models of depression - in which cytokine production is induced by endotoxin administration. Results suggest that antidepressants of several classes decrease the production of pro-inflammatory cytokines such as interferon-gamma and tumour necrosis factor-alpha, and increase that of interleukin-10, an anti-inflammatory cytokine. Further, the effect of antidepressive treatment on cytokine secretion and on plasma levels of cytokines in depressed patients has been studied. Unfortunately, different approaches to examine cytokine production and different techniques to measure cytokines in plasma are used in these studies. Despite this, current data indicate a normalization of cytokine plasma levels and cytokine production after antidepressant treatment. It is clear, however, that more research is warranted and we strongly argue the need for higher standardization in the methodology used to examine the cytokine network in depressed patients.