Ketamine Infusions for Anhedonia and Bipolar Depression | How Ketamine Therapy can Help Improve Loss of Interest and Improve Motivation | Northern Virginia Ketamine Infusion Center

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What is Anhedonia?  It is defined as the diminished pleasure from, or interest in previously rewarding activity and this is considered to be part of a depressive episode However, depression may be relieved with medical treatments, yet the anhedonia can remain with associated reward blunting.  

Depression is a major cause of disability in the world and its symptoms include loss of interest, depressed mood, and loss of pleasure in daily activities with frequent associated loss of sleep, appetite changes, intrusive thoughts, suicidal thoughts, and issues with focus and concentration (brain fog). 

Anhedonia is a component of depression and other mental health disorders that is not tracked as closely. The loss of excitement in anticipating activities that were once pleasurable defines anhedonia. The treatment of depression with traditional medications may relieve depression without restoring the circuits involved with the enjoyment of anticipation – the “wanting’ of something. This leaves an anhedonic person without hope or passions for the future. They may enjoy consuming things placed before them, but effectively they are unable to achieve the motivation to reach out for their old hobbies and passions. They aren’t interested in learning about new rewarding experiences.  

The fulfilment of life experiences hinges on the anticipation and excitement of future adventures. Anhedonia robs people of this treat and can be as life-threatening as the depression itself through an increase suicidality or overall medical illnesses such as heart disease due to the stress and anxiety that remains. 

Either way, anhedonia may indicate a poorer prognosis in depressed people as they are unable to achieve the motivation and cognition to return to work, accrue more medical problems, have an increased risk of substance abuse, and an increased risk of suicidality. The loss of emotions, sexual interests, and physical blunting (decreased activity) frequently accompanies depressed patients who are treated with traditional antidepressants.  

Ketamine has been shown to be one of the only effective therapies for anhedonia. 

Anhedonia as a Clinical Correlate of Suicidal Thoughts in Clinical Ketamine Trials 

Can Anhedonia Be Considered a Suicide Risk Factor? A Review of the Literature 


Relationships between anhedonia, suicidal ideation and suicide attempts in a large sample of physicians 


The Neurobiology of Anhedonia and Other Reward-Related Deficits 


Anhedonia is commonly present in bipolar disorder, anxiety, Major Depressive Disorder (MDD), and other psychiatric illnesses. Some studies have demonstrated that ketamine can reduce anhedonia symptoms as measured by the Snaith-Hamilton Pleasure Scale (SHAPS). Anhedonia responds to treatment differently than does depression . In fact, regular antidepressant treatment may lead to sexual anhedonia and anorgasmia, and emotionabluntingAnti-anhedonic effects of ketamine were found to be related to increased glucose metabolism in the dorsal anterior cingulate cortex and putamen.   

Standard treatments for depression do little to alleviate anhedonia. These standard treatments also cause other issues: 


Anhedonia can be seen as having a consummatory component, such as the enjoyment of a good meal, and a motivational component, such as the anticipation and drive towards rewarding stimuli, such as looking towards a good movie. These have a biological basis. Most patients with MDD and Bipolar depression have normal consummatory behaviors but low motivation to obtain the consumable items they might enjoy. 

Although someone who is depressed may find sugar to be enjoyable or cartoons to be funny as do non-depressed people, they will not have the actual motivation to seek out such enjoyments. Thus again, the consumption of rewards is still present in MDD patients, but the positive anticipatory stimulus and motivation to obtain these rewards is diminished. Anhedonia in depression is primarily associated with a deficit in non-consummatory reward behaviors. 

Anticipation, motivation, and learning is a result of dopaminergic signaling as related to pleasurable stimuli; Howeverdopamine signaling is not related to the consumption of pleasurable items. When there is an unexpected result, the Ventral tegmental area (VTA) fires off signals as there is ‘new learning’ to be had regarding the event. A violation of an expected reward involves dopamine signaling and reward learning. The VTA connects to the Nucleus accumbens where reward motivation is processed. 

Other areas involved with reward processing and receive or send out dopaminergic neurons include: 

These areas are recruited during reward processing. 

We are aware of motivational disorders in MDD yet there is not much direct evidence of dopamine signaling errors in MDD. However, medications that involve dopaminergic stimulation, such as Pramipexole, a D2 agonist, has been found to help MDD and Bipolar Depression (BD). 

Ketamine acts on the glutamate system, which is impacted in depression. Blocking glutamate uptake into astrocytes in animal models resulted in anhedonia, and ketamine, an NMDA-receptor antagonist, reversed anhedonia-type behaviors in lab animals placed under stressful conditions.  

Ketamine improved dopaminergic and glutamate signaling pathways  to the prefrontal cortex and decreased anhedonia symptoms. Ketamine reverses anticipatory anhedonia through these pathways. 

18FDG-PET measures glucose metabolism.  Glial uptake of glucose in response to glutamate release from neurons principally reflects glutamatergic neurotransmitter release and cycling which determines much of glucose metabolism in the brainGlucose in the brain is transformed into glutamate and this is the basis for using PET scanning to determine regional brain metabolism and glutamate metabolism. 

One study used a randomized, placebo-controlled, double-blind crossover design to examine whether a single ketamine infusion could reduce anhedonia levels in 36 patients with treatment-resistant bipolar depression and also evaluated PET scans of the brain to determine the neurobiological basis of anhedonia. The study demonstrated that the reduction of anhedonia was independent from the reduction of depression, and the reduction of anhedonia was related to increased glucose metabolism in the dorsal anterior cingulate cortex and putamen.   


The study evaluating the efficacy of ketamine for anhedonia involved 36 patients with BD who were given one dose of ketamine and a follow-up PET scan to determine glucose metabolism in the brain.  

  • Ketamine rapidly reduced anhedonia with results lasting 14 days in many. 
  • Anhedonia reduction was independent of depressive symptom reduction. 
  • PET scanning revealed that the dorsal anterior cingulate nucleus (DACC) had a resulting increase in metabolism. 
  • There are no other treatments available for anhedonia despite its presence in many mental health disorders. 
  • Improvement in depression was associated with increased ventral striatum glucose metabolism following ketamine infusions yet this area is not involved in anhedonia relief. 
  • Areas of the nucleus accumbens (NACthat have opioid receptors are involved with the ‘liking’ of hedonistic activities or consummatory pleasures. 
  • Motivational behavior centers in the brain achieve their innervation from multiple receptors in the NAC. 
  •  Patients showing the greatest antidepressant response to ketamine, as measured by the MADRS ( a depression scoring system) , may be experiencing high levels of pleasure. The anhedonia scale (SHAPSmight not be sensitive enough to distinguish the pleasure of being less depressed from low motivation that anhedonia produces. 
  • This study found that increased glucose metabolism in the putamen and DACC resulted in much improvement in anhedonia separate from the relief in depression. 
  • Both the dACC and putamen are highly involved in reward processinglearning and decision-making. 
  • The dACC has also been strongly linked with the anticipation of rewarding events in humans. 
  • Deficits in the ability to imagine future events, particularly positive ones, have been reliably identified in MDD patients experiencing an MDE. The ability to anticipate pleasure is associated with the diminishing of depression. 
  • Other studies, as did this one, demonstrated that anticipating a reward such as a sugary snack elicited heightened activity in the right putamen compared with anticipating a punishment (salt water). Levels of anhedonia, as measured by the Fawcett–Clark Pleasure Scale, were positively correlated with activity in the right putamen during an emotional face-processing task that required MDD patients to compare sad and neutral faces. Other measures of anhedonia include a SAAS self-assessment scale for anhedonia. 
  • Studies of the medial prefrontal cortex (mPFC) (an area of decision-making and anti-depressant area) demonstrate that the synaptogenic and antidepressant-like effects of a single dose of ketamine in rodents are dependent upon activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway together with inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3), which relieves its inhibitory in influence on mTOR. The use of lithium allows this inhibition of GSK-3 and may be useful for improvement of the anti-anhedonia effects of ketamine as found in one study. 
  • Lithium may enhance the anti-anhedonic effects of ketamine in individuals with BD through enhanced plasticity and antidepressant-like effects. 
  • Glutamate has a central role in anhedonia and depression. 
  • Ketamine is also a partial agonist of the dopamine D2 receptor and it has been found to increase dopamine levels in the striatum, including the caudate and the putamen. Of note, in MDD patients with motor retardation, there are lower extracellular levels of dopamine. Ketamine may, in part, modulate dopamine levels in anhedonia and depression through its initial effects of glutamate, which then affect the dopamine systems of reward. 
  • recent study in primates demonstrated that an “area 25” of the brain was overactive in anhedonia models of depression and ketamine could decrease that overactivity. 
  • Anhedonia is present in many psychiatric and neurological illnesses, such as schizophrenia, Parkinson’s disease, drug addiction and both mood and anxiety disorders. Anhedonia influences outcomes of treatment and needs to be monitored. 
  • Ketamine ameliorates anhedonia independent of its already considerable antidepressant effects. 
  • Ketamine is the only medication available to treat and improve anhedonia. 

recent study from the Canadian Rapid Treatment Center for Depression demonstrated that ketamine infusions can rapidly treat consummatory anhedonia symptoms in depression and relieve suicidality, depression, and anxiety. Again, there are no effective treatments outside of ketamine therapy for the anhedonia that accompanies depression, so if you have improved your depression but still have no energy, motivation, or sense of enjoyment, ketamine therapy may offer an additional line of treatment to make you feel more excited about the basic things in life. It is time to find the next great adventure. 

NOVA Health Recovery Ketamine Infusion Center utilizes ketamine therapies for the treatment of depression and anhedonia. Why suffer with low motivation, loss of pleasure and interest, anxiety, and brain fog? Traditional medications may improve some measures of depression, but ketamine can provide rapid relief in many for both their depression and anhedonia. No other medication has demonstrated the ability to restore hope and anticipation of pleasures as can ketamine therapy in the setting of anhedonia. Ketamine targets key areas of the brain to restore the appropriate reward circuitry to lead a more fulfilling life. The ability to have the energy and motivation for your next adventure is crucial for your happiness. This is where ketamine therapy may be able to bridge the gaps your other treatments could not. 

NOVA Health Recovery is a Ketamine Treatment Center in Fairfax, Virginia (Northern Virginia Ketamine) that specializes in the treatment of depression, anxiety, bipolar disorder, OCD, and chronic pain such as CRPS, cluster headaches, and fibromyalgia using Ketamine therapies. We offer ketamine infusions and home-based ketamine nasal spray and oral tablets. For CRPS, we offer multi-day, high-dose infusions and prescriptions for maintenance ketamine therapies for home. We utilize integrative psychiatric therapies for mood disorders as well and offer IV Vitamin support as well as IV NAD+ for mental health, pain, opioid detox, and mood disorders. We also offer addiction treatment services with Suboxone, Vivitrol, and Sublocade therapies for opiate addiction as well as alcohol treatment regimens. Contact us at 703-844-0184 for more information or to schedule. No referral is needed. 

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