Clinical Review of Depression

Introduction to Depression

Depression is divided into two general types: primary and secondary type. Under the primary type, the most dominant disorder is Major Depressive Disorder (MDD), also known as clinical depression. MDD is divided into three subtypes: (1) melancholia or classic depression, (2) atypical or non-classic depression, and (3) psychotic depression.

Major subtypes of MDD

  • Melancholia is a type of depression where the essential feature is the loss of interest or pleasure in all, or almost all activities, or a lack of reactivity to usually pleasurable stimuli. Your depressed mood does not improve, even temporarily, when something good happens to you. In addition, you experience at least three of the following symptoms: a distinct quality of the depressed mood, depression that is regularly worse in the morning, early morning awakening, psychomotor retardation or agitation, significant anorexia or weight loss, or excessive and inappropriate guilt.
  •  In atypical depression, there is mood reactivity and the presence of at least two of the following features: increased appetite or weight gain, hypersomnia, leaden paralysis, and the long-standing pattern of extreme sensitivity to perceived interpersonal rejection.

These features predominate during the most recent 2-week period.When you manifest mood reactivity, it means that you cheer up when you are presented with positive events, like a visit from your children, or brothers and sisters, or receiving compliments from others. When you experience hypersomnia, you usually extend your nighttime sleep or daytime napping that totals at least 10 hours of sleep per day. When you are feeling heavy, leaden, weighted down, usually in the arms of legs, then you experience the so-called leaden paralysis.

  • In psychotic depression, you are observed to experience delusions, which are false beliefs, wrong judgments, or hallucinations. These are subjective perceptions of what does not exist. In mood-congruent psychotic features, your delusions or hallucinations are consistent with depressive themes. Hence, you may believe that you are responsible for the illness of your loved one, which is an example of delusions of guilt. You may believe that you deserved to be punished because you were not attending masses or religious rites, which is delusions of deserved punishment. In some cases, however, you may manifest mood-incongruent psychotic features such as the belief that an outside force is controlling you (delusions of control), that others could hear your thoughts (delusions of thought broadcasting), or that what you are thinking is not your own (delusions of thought insertion). These delusions do not possess, or not connected with, depressive themes. Thus, they are mood-incongruent.

Major Depressive Disorder is a primary type and the most dominant type of depression. If you suffer from MDD, it is possible that other members of your family have the disease too. The reason is that the predisposition to have the disease is programmed in the genes. It is a familial disease—that is, it runs in the family. If you are predisposed to have the disease and at the same time are exposed to severe stresses of life, such as financial woes, marital and work-related problems, then very likely you will suffer from it.

Main Causes of Depression

Role of genes and serotonin

The cells in your brain are called neurons and they communicate to each other through chemical substances medically known as neurotransmitters, which move and travel in between them. One of these neurotransmitters is serotonin, which serves as the pivotal substance to which all the manifestations of MDD are attributed to. It was initially thought that when your serotonin level was low that you manifest MDD. However, in some instances, that observation did not happen. It took place only when the individual concerned happened to have a positive family history of MDD. In another saying, it is not enough that your serotonin level needs to be low so that MDD could take place. In addition, you must have the predisposition or genetic make-up to experience it. Thus, genes and serotonin level are probably involved in causing MDD, showing at a certain point that multiple factors are involved.

Your genes could predispose you to manifest MDD in several ways. Genes could influence the production and destruction of neurotransmitters and their receptors. Hence, they could increase or decrease the level of your serotonin. Receptors, on the other hand, are structures of your neurons which receive the serotonin; they serve as the landing pad of your serotonin molecules which will, in turn, act on other structures. Without the receptors, the serotonin has nothing to land on and it can’t do its functions. The genes could also influence the nature and competence of these receptors.

Your genes could also determine the type of your neurons and the type of their connections to other neurons, which, in turn, could affect the speed of neuronal signals traveling in and in between your neurons. This neuronal speed needs to be at par with what is normal so that you could respond properly to environmental stressors, such as pressure from work and from family affairs. If the speed is not within the required range, you could manifest MDD upon exposure to an environmental stress.

Your genes could also determine the type of your neurons and the type of their connections to other neurons, which, in turn, could affect the speed of neuronal signals traveling in and in between your neurons. This neuronal speed needs to be at par with what is normal so that you could respond properly to environmental stressors, such as pressure from work and from family affairs. If the speed is not within the required range, you could manifest MDD upon exposure to an environmental stress.

Specifically, the neuronal speed is primarily handled by the so-called serotonin transporter, whose nature is determined and influenced by the nature of your genes. Depending on the nature of your genes, the production and synthesis of your serotonin transporter could be slowed down. If the said transporter is low in number, even if your serotonin level is high, you could not immediately react to a stressor because your serotonin has nothing to ride on. Consequently, it cannot reach its destination.

Role of norepinephrine

There is a particular set of MDD symptoms called the positive effect. Clinical symptoms belonging to this group are a loss of pleasure, loss of interest, fatigue, and loss of energy. It was observed that this set of symptoms improves if the level of norepinephrine in your brain is normal. When it is reduced, the symptoms of positive affect manifest or start to come out. Thus there is an indication that norepinephrine is another neurotransmitter which is involved in the causation of MDD.

The proposition that norepinephrine affects another set of symptoms in MDD was bolstered when it was observed that the drug used for increasing the level of serotonin, otherwise known as the selective serotonin reuptake inhibitor, does not improve the symptoms of positive affect, whereas a drug which is known to increase the level of norepinephrine improves the said set of symptoms.

Role of dopamine

The third neurotransmitter that could be involved in the causation of MDD is dopamine. Results of scientific research tend to show that diminished dopaminergic neurotransmission could cause MDD. This reduction in transmission could be due to either diminished release of dopamine from the presynaptic neuron or there is impairment in the intracellular transduction of signals. In some occasions, where dopamine-related disturbances are involved, giving antidepressants may relieve your symptoms. However, in others, there are still symptoms that remain and persist. That is, not all of your symptoms could be alleviated by the drugs. This means that the present drugs being used in clinical practice do not directly enhance the dopamine transmission, thus failing to relieve some of your symptoms of MDD, such as impaired motivation, concentration, and pleasure. In some studies, including some post-mortem investigations, it was found out that the levels of dopamine metabolites in both the cerebrospinal fluid and the brain regions that mediate mood were low, indicating that indeed dopamine plays a great role in modulating your mood.

Other factors that could very likely trigger you to have MDD are hormonal imbalance, alcohol or drug abuse, medical conditions like cancer and hypothyroidism, and medications like steroids.

Major Depressive Disorder, also known as clinical depression, is the most dominant type of depression.

You are suffering from MDD if you have been experiencing one or more Major Depressive Episode (MDE) that has taken place during the last two weeks of your life.

An MDE has taken place if you experienced five or more of the symptoms.

Symptoms of Major Depressive Disorder

Symptoms vary person to person, but displaying several of the following traits would be a sign you may have major depressive disorder. Contact your medical provider if you are experiencing these symptoms.

  • You have depressed mood most of the day, nearly every day, which is either reported by you or observed by others.
  • You have markedly diminished interest or pleasure in all, or almost all activities most of the day, nearly every day, as reported by you or observed by others.
  • You have significant weight loss even if you are not dieting or weight gain, such as increase of 5% in your body weight in a month, or decrease or increase in your appetite nearly every day.
  • You experience insomnia (failing to sleep) or hypersomnia (excessive sleeping) nearly every day.
  • You show psychomotor agitation or retardation nearly every day, as reported by you and observed by others.
  • You experience fatigue or loss of energy nearly every day.
  • You feel worthless or excessively or inappropriately guilty nearly every day.
  • You have diminished the ability to think or concentrate, or are indecisive, nearly every day, either reported by you or observed by others.
  • You have recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.

Diagnosis of Major Depressive Disorder

The diagnosis of whether you have MDD is based mainly on your clinical history. This is the combination of what you narrated to the physician, what others observed from you, and what the physician observed and heard from you when you were interviewed. If you have five or more of the symptoms listed in the preceding with depressed mood or loss of interest or pleasure as one of them, then you are diagnosed to be suffering from MDD. Laboratory tests and other procedures are seldom availed of when it comes to MDD. They do not play a significant role in arriving at the diagnosis of MDD.

Major Depressive Disorder is a primary type and the most dominant type of depression. If you suffer from MDD, your management will be a two-pronged approach: (1) intake of medications or drugs (2) psychotherapy. In some occasions, depending on your response to the first two modes of treatment, you could be subjected to electroconvulsive therapy (ECT).

Medications and Treatment for Major Depressive Disorder:

Selective serotonin reuptake inhibitors (SSRIs)

In the preceding discussion, it was mentioned that the low level of serotonin in your brain causes the manifestation of MDD symptoms. For this reason, a group of anti-depressants was developed and was called the selective serotonin reuptake inhibitors (SSRIs) because they inhibit the recycling of serotonin. Thus maintaining its high level in your neurons and preventing the appearance of MDD symptoms. Examples of SSRIs are the following:

· Citalopram (Celexa)

· Escitalopram (Lexapro)

· Fluoxetine (Prozac)

· Paroxetine (Paxil, Pexeva)

· Sertraline (Zoloft)

· Vilazodone (Viibryd)

It has been determined that 30-50% of MDD patients do not respond to this class of drugs.

Serotonin/norepinephrine reuptake inhibitors (SNRIs)

Sometimes, you do not fully respond to the SSRIs. If this happens, it is possible that you manifest more of the positive effect. Thus, you need to take a norepinephrine reuptake inhibitor. But since you at the same time have symptoms which are responsive to the SSRI, then the most logical treatment is to give you a combination of both the SSRI and selective norepinephrine reuptake inhibitor. Thus, the so-called serotonin/norepinephrine reuptake inhibitors (SNRIs) were developed. True enough, it was observed that SNRIs were more effective than SSRIs for treating MDD. Examples of SNRIs are the following:

· Desvenlafaxine (Pristiq)

· Duloxetine (Cymbalta)

· Venlafaxine (Effexor)

· Venlafaxine XR (Effexor XR)

· Milnacipran (Savella)

· Levomilnacipran (Fetzima)

The most common side effects of SNRIs are nausea, dizziness, and sweating.

Atypical antidepressants

These antidepressants are different from each other and do not fit into any of the conventional classifications. They do not have a common mechanism of alleviating the symptoms of MDD, although each one of them acts on the dopamine, and/or serotonin, and/or norepinephrine. They are usually resorted to when the first line drugs, belonging to the SSRIs, fail to improve your symptoms. Examples of atypical antidepressants are:

· Bupropion (Wellbutrin, Forfivo XL, Aplenzin)

· Mirtazapine (Remeron)

· Nefazodone (Serzone)

· Trazodone (Desyrel, Oleptro)

· Vortioxetine (Brintellix)

Tricyclic antidepressants (TCAs)

The tricyclic antidepressants (TCAs) were one of the first groups of drugs that were used to treat MDD. They were effective as antidepressants but had a number of side effects which are not observed and found in the newer drugs. They act on serotonin and norepinephrine; however, they also block your muscarinic (M1), histamine (H1), and alpha-adrenergic receptors. Because of this wide-ranging influence, inevitably they could exact a number of unwanted and side effects on other systems of your body. This led to the reduction in the number of medical doctors who prescribe these drugs.

Examples of TCAs are the following:

· Amitriptyline (Elavil)

· Desipramine (Norpramin)

· Doxepine (Sinequan)

· Imipramine (Tofranil)

· Nortriptyline (Pamelor)

· Clomipramine (Anafranil)

· Maprotiline (Ludiomil)

· Trimipramine (Surmontil)

· Protriptyline (Vivactil)

The most common side effects of TCAs are the following: dry mouth, constipation, blurred vision, urinary retention, dizziness, tachycardia (increased heart rate), memory impairment, and disturbance of consciousness.

Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs) are drugs that block the activity of an enzyme monoamine oxidase which breaks down norepinephrine, serotonin, and dopamine in your brain and other parts of your body. The drawback of MAOIs is that they have a number of interactions with other drugs and foods, causing more side effects compared to the newer drugs. Examples of MAOIs are:

· Phenelzine (Nardil)

· Selegiline (Emsam)

· Tranylcypromine (Parnate)

Common side effects are postural hypotension, weight gain, and sexual disturbances.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is a form of treatment where electric current is applied so that your body will experience some form of generalized seizure. It is expected that by having a seizure, the concentration levels of some of the neurotransmitters that you lack will increase and you will be treated with your disease. With the advent of new drugs, ECT is now rarely used; however, there are indications when to use it as enumerated below:

· Need for a rapid response to antidepressants

· Failure of drug therapies

· History of good response to ECT

· Patient’s preference

· High risk of suicide

· High risk of medical morbidity and mortality

Although MDD is treated with drugs and medication, there are times when your symptoms are not totally cured or treated. Thus, there is a need to add another mode of therapy, such as psychotherapy.

Interpersonal psychotherapy

Interpersonal psychotherapy (IPT) is a method of treating you through an interaction with your therapist, be it a medical doctor or a psychologist. It is a one on one engagement where the therapist talks to you and will try to uncover the root of your problem. This method is time limited—that is, it will run a certain length of time, usually 12-16 weeks, and it is a present-focused treatment which encourages you to regain control of your mood and functioning. It is a treatment alliance between your therapist and you. He emphatically engages you and helps you feel that you are being understood. He arouses your emotions so that again you will start to feel things.

Based on the preceding, IPT generates two basic principles:

  • That depression is a medical illness and it is not the patient’s fault or defect. Furthermore, it is highly treatable.
  • That mood and life situations are related and that IPT connects your mood. Also that any disturbing events in your life that either trigger or follow from the onset of the mood disorder.

Research results showed that depression usually comes after any disturbing situation in your life, such as the death of a loved one, changes in career, marital separation, or illness. Once you become depressed, your symptoms compromise your interpersonal skills. Worse, you may start to blame yourself for the situation and completely ignore your environment.

Whether life events follow or precede your mood changes, your task in therapy is to resolve your disturbing life event(s) by building social skills and learning to organize your life. If you can solve your life problem then your depressive symptoms will subsequently disappear. Your therapist will help you on how to achieve your goal.

Cognitive-behavioral therapy

Cognitive-behavioral therapy (CBT) is another form of “talk therapy” where a one on one engagement and encounter is done with the therapist facing and talking to you. The main assumption of CBT is that your mood is very much determined by the way you think—specifically termed as your pattern of thinking. If you think negatively about yourself, then that will adversely affect your mood, sense of self, behavior, and even physical state. The main purpose of CBT is to help you recognize your negative patterns of thought, assess their validity, and replace them with healthier ways of thinking.

The way you think determines the way you behave. If you think negatively, then you will behave in a very inappropriate manner. To remedy this, CBT aims to change your behavior which arises from a negative thinking. Thus, CBT helps you change your thoughts and behavior. All of these are done because dysfunctional thoughts and behavior predispose you to suffer from depression. When negative thoughts and behavior are changed to healthier ones, your mood will correspondingly change for the better.

Problem-solving therapy

Problem-solving therapy (PST) is a form of treatment where a therapist engages you on one on one conversation and teaches you how to effectively manage the negative effects of stressful events that take place in your life. The stressors in your life vary in form, intensity, and duration. In terms of intensity, it could be large or small. Even with small, if it happens most of the time in your life, it could transform itself into a big stressor. When a stressful situation creates and generates other serious problems, be it psychological or medical, then PST could be utilized. This can be done either using it as the sole intervention method or in combination with other modes of psychotherapy.

PST helps you develop problem-solving skills so that you could resolve and cope with whatever stressful problems cross your way. Such skills include: making effective decisions, generating creative means of dealing with your problem, and accurately identifying barriers to reaching your goals.

In general, PST aims to do the following:

· To identify which stressors tend to trigger emotions, such as sadness, tension, and anger

· To better understand and manage negative emotions

· To become more hopeful about your abilities to deal with difficult problems in your life

· To be more accepting of problems that are unsolvable

· To be more keen in planning and systematic in solving stressful situations

· To be not evasive in facing and confronting problems

· To be less impulsive in choosing “quick fix” solutions to your problems

So far, PST is considered a very effective approach because it equips you with skills to deal more effectively with wide range of difficulties and stressful problems in your life. Scientific research results revealed that negative stressful events in your life could exact a toll on your health—specifically mental health disorders. Thus, PST is developed to assist you in coping more effectively with stressful life problems and can, therefore, decrease psychological and emotional difficulties. This, in turn, leads to the improvement in the quality of your life.

Behavioral activation

Behavioral activation (BA) is one of the methods in psychotherapy wherein your good behavior is reinforced by the therapist so that your bad behavior is gradually and ultimately replaced by it. This method has been found to be very effective, even for those who experienced failure in the other methods or approaches. Researchers have determined that BA is at par with the use of medications and it is slightly superior to cognitive therapy in the treatment of depression. It shifts away from cognitions and feelings and it concentrates on your behavior and environment.

BA contends that giving importance to negative life events, such as grief, trauma, daily stressors, or genetic predispositions to depression provides no space for you to have positive reinforcement. In fact, by allowing you to look at the negative sides of your life, you might even resort to unhealthy behaviors such as drug use, sleeping late in the afternoon, social withdrawal, and much more—so that you will avoid the negative feelings. Initially, these changes in your behavior provide temporary relief, but in due time they will lead to more negative outcomes and worsening depression.

When you submit yourself to behavioral activation psychotherapy, your clinician will intervene on your behalf in two primary ways:

  •  He increases positive reinforcement for your good behavior that needs to be sustained and
  • He ends negative behavior patterns that cause depression to worsen. Rewarding new and good behavior increases your positive reinforcement and reduces negative reinforcement.

Seemingly, the goal of BA is simple: just replace negative behaviors with positive alternatives. However, when it is implemented in your real life, there are a lot of challenges to meet and overcome. Firstly, the good effect of BA is not immediate; it will take some time before you will reap it. Therefore, before starting BA, you need to be educated about it. This is the first challenge. Secondly, there are unhealthy avoidant behaviors that you will be tempted to avail of while waiting for the good effect of BA. However, your clinician needs to discourage them. This is another challenge.

As mentioned in the preceding, you need to be educated about the nature of BA so you are motivated to follow through. Considering that the good effects of BA will not be immediately realized, you may be tempted to return to your avoidant behavior. It is the work of your clinician to help you recognize how avoidant behavior is worsening your depression. Thus, your clinician needs to listen, pinpoint negative behavior patterns, and collaborate with you to figure out how your avoidant behavior could be damaging to you. After you have been educated about BA and your clinician has identified some of your negative behavior patterns, the next step is for your clinician to come up with some positive replacement behaviors, which are both easy and rewarding.

Depression is considered a chronic and recurrent illness. This has been proven with the finding of long-term follow-up studies of psychiatric outpatients. Among depressed patients treated by specialists, up to 50% do not recover by 6 months and 10% show a chronic course. Among those who recover, the risk of relapse is 40% or more over 2 years and exceeds 80% if the period of observation is extended to 15 years.

One of the reasons why Major Depressive Disorder (MDD) is turning out to be chronic and recurrent is that patients tend not to stop taking the medications prescribed by their doctor. Many stop their medications even if the medical doctor has not told them to do so. A common reason people stopped the medications was due to unpleasant side effects. This problem which is inherent in the nature of the drug needs to be addressed by both the medical community and the pharmaceutical industry. If the antidepressants are largely free from intolerable side effects, you will probably keep on using the drug for as long as it is needed, and the prevalence of chronicity and recurrence of MDD could be reduced.

MDD could be reduced.

In another study, it was revealed that when you do not respond to a medication or combination of medications for MDD within, or after, two weeks of treatment, then your chance of having a stable response or stable remission is very small. It is thus necessary that as much as possible your medical doctor needs to change your medical management if your current treatment has not been working. Chronicity and recurrence of your MDD will take place if you insist on using a drug that does not work for you.

When your MDD has psychotic features your doctor will need to monitor you closely. It has been determined and found that psychotic symptoms during major depressive episodes increase the risk of completed suicide after serious suicide attempts. For this reason, the quality of your treatment needs to be improved to prevent the consummation of your suicide.

Futuristic and evolving management of Major Depressive Disorder

Symptom profile

MDD is a complex and frequent psychiatric condition that poses challenges to both you and your physician. It is complex because if you follow the diagnostic criteria as mentioned and defined in the preceding, you will have a number of different combinations and each combination presents different kinds of clinical manifestations.

Considering that each combination presents as a different disease, for you and for the other patients to get well, the treatment needs to be highly individualized. Therefore, each of you will need a different kind of medicine. It is now recognized that psychiatric symptoms correlate well with a particular malfunctioning brain circuits. Thus, understanding your symptom profile is a key to individualizing treatment because different symptoms may reflect differences in underlying neuropathology, including differences in neurotransmitter-related abnormalities. Knowing this, your physician could properly select the most appropriate medications that have the mechanism of action appropriate for you and for other patients. This will lead to highly individualized treatment.

Treatment outcomes

In evaluating the effectiveness of your current medications, there are four levels of treatment outcomes as shown in

Treatment outcomes and criteria

Several decades ago the criteria for successful treatment of MDD was the achievement of greater than 50% reduction in total symptom severity—classified as “response” in Table above. With this criterion, however, it was obvious that significant residual symptoms remain that you are predisposed to experience recurrence, chronicity, and suicidality. To avoid this, over the last 3 decades, the desired outcome for the treatment of MDD has shifted from “response” to “remission” as shown in the table above.

For you to have achieved remission, you need to experience the following outcomes:

  • Absence of symptoms of depression
  • Presence of positive mental health (such as optimism, vigor, self-confidence)
  • Feeling like your usual, normal self
  • Return to usual level of functioning at work, home, or school
  • Feeling in emotional control
  • Participating in, and enjoying, relationships with family and friends

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